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Sample records for adjuvant temozolomide tmz

  1. Effective sensitization of temozolomide by ABT-888 is lost with development of TMZ resistance in glioblastoma xenograft lines

    PubMed Central

    Clarke, Michelle J.; Mulligan, Evan A.; Grogan, Patrick T.; Mladek, Ann C.; Carlson, Brett L.; Schroeder, Mark A.; Curtin, Nicola J.; Lou, Zhenkun; Decker, Paul A.; Wu, Wenting; Plummer, E. Ruth; Sarkaria, Jann N.

    2009-01-01

    Resistance to temozolomide (TMZ) and radiotherapy (RT) is a major problem for patients with GBM but may be overcome using the PARP-inhibitor ABT-888. Using two primary GBM xenografts, the efficacy of ABT-888 combined with RT and/or TMZ was evaluated. Treatment with ABT-888 combined with TMZ resulted in significant survival prolongation (GBM12: 55.1%, p=0.005; GBM22: 54.4%, p=0.043). ABT-888 had no effect with RT alone, but significantly enhanced survival in GBM12 when combined with concurrent RT/TMZ. With multi-cycle therapy, ABT-888 further extended the survival benefit of TMZ in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for TMZ resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with TMZ, and a similar lack of efficacy was observed in two other TMZ resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that had not been previously exposed to TMZ, and these results suggest that patients with newly diagnosed GBM may be more likely to respond to combined TMZ/PARP inhibitor therapy than patients with recurrent disease. PMID:19174557

  2. Outcomes of pediatric glioblastoma treated with adjuvant chemoradiation with temozolomide and correlation with prognostic factors

    PubMed Central

    Mallick, Supriya; Gandhi, Ajeet Kumar; Joshi, Nikhil P.; Kumar, Anupam; Puri, Tarun; Sharma, Daya Nand; Haresh, Kunhi Parambath; Gupta, Subhash; Julka, Pramod Kumar; Rath, Goura Kisor; Sarkar, Chitra

    2015-01-01

    Background: Pediatric glioblastoma (pGBM) patients are underrepresented in major trials for this disease. We aimed to explore the outcome of pGBM patients treated with concurrent and adjuvant temozolomide (TMZ). Materials and Methods: 23 patients of pGBM treated from 2004 to 2010 were included in this retrospective analysis. Adjuvant therapy included conformal radiation 60 gray at 2 gray/fraction daily over 6 weeks with concurrent TMZ 75 mg/m2 followed by six cycles of adjuvant TMZ 150-200 mg/m2 (day 1-5) every 4 weeks. Kaplan-Meier estimates of overall survival (OS) were determined. Univariate analysis with log-rank test was used to determine the impact of prognostic variables on survival. Results: Median age at presentation was 11.5 years (range: 7-19 years) and M:F ratio was 15:8. All patients underwent maximal safe surgical resection; 13 gross total resection and 10 sub-total resection. At a median follow-up of 18 months (range: 2.1-126 months), the estimated median OS was 41.9 months. The estimated median OS for patients receiving only concurrent TMZ was 8 months while that for patients receiving concurrent and adjuvant TMZ was 41.9 months (P = 0.081). Estimated median OS for patients who did not complete six cycles of adjuvant TMZ was 9.5 months versus not reached for those who completed at least six cycles (P = 0.0005). Other prognostic factors did not correlate with survival. Conclusions: Our study shows the benefit of TMZ for pGBM patients. Both concurrent and adjuvant TMZ seem to be important for superior OS in this group of patients. PMID:26157286

  3. Prospective Evaluation of Radiotherapy With Concurrent and Adjuvant Temozolomide in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

    SciTech Connect

    Jalali, Rakesh; Raut, Nirmal; Arora, Brijesh; Gupta, Tejpal; Dutta, Debnarayan; Munshi, Anusheel; Sarin, Rajiv; Kurkure, Purna

    2010-05-01

    Purpose: To present outcome data in a prospective study of radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ) in children with diffuse intrinsic pontine gliomas (DIPGs). Methods and Materials: Pediatric patients with newly diagnosed DIPGs were prospectively treated with focal RT to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m{sup 2}, Days 1-42). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m{sup 2}, Days 1-5) was given every 28 days to a maximum of 12 cycles. Response was evaluated clinically and radiologically with magnetic resonance imaging and positron emission tomography scans. Results: Between March 2005 and November 2006, 20 children (mean age, 8.3 years) were accrued. Eighteen patients have died from disease progression, one patient is alive with progressive disease, and one patient is alive with stable disease. Median overall survival and progression-free survival were 9.15 months and 6.9 months, respectively. Grade III/IV toxicity during the concurrent RT-TMZ phase included thrombocytopenia in 3 patients, leucopenia in 2, and vomiting in 7. Transient Grade II skin toxicity developed in the irradiated fields in 18 patients. During the adjuvant TMZ phase, Grade III/IV leucopenia developed in 2 patients and Grade IV thrombocytopenia in 1 patient. Patients with magnetic resonance imaging diagnosis of a high-grade tumor had worse survival than those with a low-grade tumor (p = 0.001). Patients with neurologic improvement after RT-TMZ had significantly better survival than those who did not (p = 0.048). Conclusions: TMZ with RT has not yielded any improvement in the outcome of DIPG compared with RT alone. Further clinical trials should explore novel treatment modalities.

  4. Concomitant treatment of brain metastasis with Whole Brain Radiotherapy [WBRT] and Temozolomide [TMZ] is active and improves Quality of Life

    PubMed Central

    Addeo, Raffaele; Caraglia, Michele; Faiola, Vincenzo; Capasso, Elena; Vincenzi, Bruno; Montella, Liliana; Guarrasi, Rosario; Caserta, Luigi; Del Prete, Salvatore

    2007-01-01

    Background Brain metastases (BM) represent one of the most frequent complications related to cancer, and their treatment continues to evolve. We have evaluated the activity, toxicity and the impact on Quality of Life (QoL) of a concomitant treatment with whole brain radiotherapy (WBRT) and Temozolomide (TMZ) in patients with brain metastases from solid tumors in a prospective Simon two stage study. Methods Fifty-nine patients were enrolled and received 30 Gy WBRT with concomitant TMZ (75 mg/m2/day) for ten days, and subsequently TMZ (150 mg/m2/day) for up to six cycles. The primary end points were clinical symptoms and radiologic response. Results Five patients had a complete response, 21 patients had a partial response, while 18 patients had stable disease. The overall response rate (45%) exceeded the target activity per study design. The median time to progression was 9 months. Median overall survival was 13 months. The most frequent toxicities included grade 3 neutropenia (15%) and anemia (13%), and only one patient developed a grade 4 thrombocytopenia. Age, Karnofsky performance status, presence of extracranial metastases and the recursive partitioning analysis (RPA) were found to be predictive factors for response in patients. Overall survival (OS) and progression-free survival (PFS) were dependent on age and on the RPA class. Conclusion We conclude that this treatment is well tolerated, with an encouraging objective response rate, and a significant improvement in quality of life (p < 0.0001) demonstrated by FACT-G analysis. All patients answered the questionnaires and described themselves as 'independent' and able to act on their own initiatives. Our study found a high level of satisfaction for QoL, this provides useful information to share with patients in discussions regarding chemotherapy treatment of these lesions. PMID:17254350

  5. Effects of temozolomide (TMZ) on the expression and interaction of heat shock proteins (HSPs) and DNA repair proteins in human malignant glioma cells.

    PubMed

    Castro, Gisela Natalia; Cayado-Gutiérrez, Niubys; Zoppino, Felipe Carlos Martín; Fanelli, Mariel Andrea; Cuello-Carrión, Fernando Darío; Sottile, Mayra; Nadin, Silvina Beatriz; Ciocca, Daniel Ramón

    2015-03-01

    We previously reported the association of HSPA1A and HSPB1 with high-grade astrocytomas, suggesting that these proteins might be involved in disease outcome and response to treatment. With the aim to better understand the resistance/susceptibility processes associated to temozolomide (TMZ) treatment, the current study was performed in three human malignant glioma cell lines by focusing on several levels: (a) apoptotic index and senescence, (b) DNA damage, and (c) interaction of HSPB1 with players of the DNA damage response. Three human glioma cell lines, Gli36, U87, and DBTRG, were treated with TMZ evaluating cell viability and survival, apoptosis, senescence, and comets (comet assay). The expression of HSPA (HSPA1A and HSPA8), HSPB1, O6-methylguanine-DNA methyltransferase (MGMT), MLH1, and MSH2 was determined by immunocytochemistry, immunofluorescence, and Western blot. Immunoprecipitation was used to analyze protein interaction. The cell lines exhibited differences in viability, apoptosis, and senescence after TMZ administration. We then focused on Gli36 cells (relatively unstudied) which showed very low recovery capacity following TMZ treatment, and this was related to high DNA damage levels; however, the cells maintained their viability. In these cells, MGMT, MSH2, HSPA, and HSPB1 levels increased significantly after TMZ administration. In addition, MSH2 and HSPB1 proteins appeared co-localized by confocal microscopy. This co-localization increased after TMZ treatment, and in immunoprecipitation analysis, MSH2 and HSPB1 appeared interacting. In contrast, HSPB1 did not interact with MGMT. We show in glioma cells the biological effects of TMZ and how this drug affects the expression levels of heat shock proteins (HSPs), MGMT, MSH2, and MLH1. In Gli36 cells, the results suggest that interactions between HSPB1 and MSH2, including co-nuclear localization, may be important in determining cell sensitivity to TMZ. PMID:25155585

  6. Phase II Study of Short-Course Radiotherapy Plus Concomitant and Adjuvant Temozolomide in Elderly Patients With Glioblastoma

    SciTech Connect

    Minniti, Giuseppe; Lanzetta, Gaetano; Scaringi, Claudia; Caporello, Paola; Salvati, Maurizio; Arcella, Antonella; De Sanctis, Vitaliana; Giangaspero, Felice; Enrici, Riccardo Maurizi

    2012-05-01

    Purpose: Radiotherapy (RT) and chemotherapy may prolong survival in older patients (age {>=}70 years) with glioblastoma multiforme (GBM), although the survival benefits remain poor. This Phase II multicenter study was designed to evaluate the efficacy and safety of an abbreviated course of RT plus concomitant and adjuvant temozolomide (TMZ) in older patients with GBM. Patients and Methods: Seventy-one eligible patients 70 years of age or older with newly diagnosed GBM and a Karnofsky performance status {>=}60 were treated with a short course of RT (40 Gy in 15 fractions over 3 weeks) plus TMZ at the dosage of 75 mg/m{sup 2} per day followed by 12 cycles of adjuvant TMZ (150-200 mg/m{sup 2} for 5 days during each 28-day cycle). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival and toxicity. Results: The Median OS was 12.4 months, and the 1-year and 2-year OS rates were 58% and 20%, respectively. The median and 1-year rates of progression-free survival were 6 months and 20%, respectively. All patients completed the planned programme of RT. Grade 3 or 4 adverse events occurred in 16 patients (22%). Grade 3 and 4 neutropenia and/or thrombocytopenia occurred in 10 patients (15%), leading to the interruption of treatment in 6 patients (8%). Nonhematologic Grade 3 toxicity was rare, and included fatigue in 4 patients and cognitive disability in 1 patient. Conclusions: A combination of an abbreviated course of RT plus concomitant and adjuvant TMZ is well tolerated and may prolong survival in elderly patients with GBM. Future randomized studies need to evaluate the efficacy and toxicity of different schedules of RT in association with chemotherapy.

  7. Radiosensitizing effects of TMZ observed in vivo only in a subset of MGMT methylated GBM xenografts

    PubMed Central

    Carlson, Brett L.; Grogan, Patrick T.; Mladek, Ann C.; Schroeder, Mark A.; Kitange, Gaspar J.; Decker, Paul A.; Giannini, Caterina; Wu, Wenting; Ballman, Karla A.; James, C. David; Sarkaria, Jann N.

    2009-01-01

    Purpose Concurrent temozolomide (TMZ) and radiation therapy (RT) followed by adjuvant TMZ is standard treatment for patients with GBM, although the relative contribution of concurrent versus adjuvant TMZ is unknown. In this study, the efficacy of TMZ/RT was tested in a panel of 20 primary GBM xenografts. Methods and Materials Mice with intracranial xenografts were treated with TMZ, RT, TMZ/RT, or placebo. Survival ratio for a given treatment/line was defined as the ratio of median survival for treatment vs. placebo. Results The median survival ratio was significantly higher for MGMT methylated tumors versus unmethylated tumors following treatment with TMZ (median survival ratio 3.6 vs. 1.5, respectively; p=0.008) or TMZ/RT (5.7 vs. 2.3, respectively; p=0.001), but not RT alone (1.7 vs. 1.6; p=0.47). In an ANOVA analysis, MGMT methylation status and p53 mutation status were significantly associated with treatment response. In analyzing the additional survival benefit conferred specifically by combined therapy, only a subset (5 of 11) MGMT methylated tumors derived substantial additional benefit from combined therapy, while none of the MGMT unmethylated tumors did. Consistent with a true radiosensitizing effect of TMZ, sequential treatment, in which RT (week 1) was followed by TMZ (week 2), proved significantly less effective than TMZ followed by RT or concurrent TMZ / RT (survival ratios of 4.0, 9.6, and 12.9, respectively; p<0.0001). Conclusions Concurrent treatment with TMZ and RT provides significant survival benefit only in a subset of MGMT methylated tumors, and provides superior anti-tumor activity relative to sequential administration of RT and TMZ. PMID:19695438

  8. Standard (60 Gy) or Short-Course (40 Gy) Irradiation Plus Concomitant and Adjuvant Temozolomide for Elderly Patients With Glioblastoma: A Propensity-Matched Analysis

    SciTech Connect

    Minniti, Giuseppe; Scaringi, Claudia; Lanzetta, Gaetano; Terrenato, Irene; Esposito, Vincenzo; Arcella, Antonella; Pace, Andrea; Giangaspero, Felice; Bozzao, Alessandro; Enrici, Riccardo Maurizi

    2015-01-01

    Purpose: To evaluate 2 specific radiation schedules, each combined with temozolomide (TMZ), assessing their efficacy and safety in patients aged ≥65 years with newly diagnosed glioblastoma (GBM). Methods and Materials: Patients aged ≥65 years with Karnofsky performance status (KPS) ≥60 who received either standard (60 Gy) or short-course (40 Gy) radiation therapy (RT) with concomitant and adjuvant TMZ between June 2004 and October 2013 were retrospectively analyzed. A propensity score analysis was executed for a balanced comparison of treatment outcomes. Results: A total of 127 patients received standard RT-TMZ, whereas 116 patients underwent short-course RT-TMZ. Median overall survival and progression-free survival times were similar: 12 months and 5.6 months for the standard RT-TMZ group and 12.5 months and 6.7 months for the short-course RT-TMZ group, respectively. Radiation schedule was associated with similar survival outcomes in either unadjusted or adjusted analysis. O{sup 6}-methylguanine-DNA methyltransferase promoter methylation was the most favorable prognostic factor (P=.0001). Standard RT-TMZ therapy was associated with a significant rise in grade 2 and 3 neurologic toxicity (P=.01), lowering of KPS scores during the study (P=.01), and higher posttreatment dosing of corticosteroid (P=.02). Conclusions: In older adults with GBM, survival outcomes of standard and short-course RT-TMZ were similar. An abbreviated course of RT plus TMZ may represent a reasonable therapeutic approach for these patients, without loss of survival benefit and acceptable toxicity.

  9. Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review.

    PubMed

    Ashby, Lynn S; Smith, Kris A; Stea, Baldassarre

    2016-08-24

    Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III

  10. Phase 2 Trial of Hypofractionated High-Dose Intensity Modulated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Newly Diagnosed Glioblastoma

    SciTech Connect

    Iuchi, Toshihiko; Hatano, Kazuo; Kodama, Takashi; Sakaida, Tsukasa; Yokoi, Sana; Kawasaki, Koichiro; Hasegawa, Yuzo; Hara, Ryusuke

    2014-03-15

    Purpose/Objectives: To assess the effect and toxicity of hypofractionated high-dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m{sup 2}/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m{sup 2}/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. Results: No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. Conclusions: Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial.

  11. Temozolomide

    MedlinePlus

    ... by slowing or stopping the growth of cancer cells in your body. ... during, and after your treatment to check your body's response to temozolomide and to see if your blood cells are affected by this drug.Do not let ...

  12. Health-Related Quality of Life in Elderly Patients With Newly Diagnosed Glioblastoma Treated With Short-Course Radiation Therapy Plus Concomitant and Adjuvant Temozolomide

    SciTech Connect

    Minniti, Giuseppe; Scaringi, Claudia; Baldoni, Alessandra; Lanzetta, Gaetano; De Sanctis, Vitaliana; Esposito, Vincenzo; Enrici, Riccardo Maurizi

    2013-06-01

    Purpose: To describe the quality of life (QOL) in elderly patients with glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT; 40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ). Methods and Materials: Health-related QOL (HRQOL) was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30, version 3) and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score of 9 preselected domains (global QLQ, social functioning, cognitive functioning, emotional functioning, physical functioning, motor dysfunction, communication deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter every 8 weeks during the treatment until disease progression. The proportion of patients with improved HRQOL scores, defined as a change of 10 points or more, and duration of changes were recorded. Results: Sixty-five patients completed the questionnaires at baseline. The treatment was consistently associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time; mean score differed by 9.6 points between baseline and 6-month follow-up (P=.03). For social functioning and cognitive functioning, mean scores improved over time, with a maximum difference of 10.4 points and 9.5 points between baseline and 6-month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4-month follow-up (P=.02). Conclusions: A short course of RT in combination with TMZ in elderly patients with GBM was associated with survival benefit without a negative effect on HRQOL until the time of disease progression.

  13. Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

    PubMed

    Balana, Carmen; De Las Penas, Ramon; Sepúlveda, Juan Manuel; Gil-Gil, Miguel J; Luque, Raquel; Gallego, Oscar; Carrato, Cristina; Sanz, Carolina; Reynes, Gaspar; Herrero, Ana; Ramirez, Jose Luis; Pérez-Segura, Pedro; Berrocal, Alfonso; Vieitez, Jose Maria; Garcia, Almudena; Vazquez-Estevez, Sergio; Peralta, Sergi; Fernandez, Isaura; Henriquez, Ivan; Martinez-Garcia, Maria; De la Cruz, Juan Jose; Capellades, Jaume; Giner, Pilar; Villà, Salvador

    2016-05-01

    We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity. PMID:26847813

  14. Radiosensitizing Effects of Temozolomide Observed in vivo only in a Subset of O6-Methylguanine-DNA Methyltransferase Methylated Glioblastoma Multiforme Xenografts

    SciTech Connect

    Carlson, Brett L.; Grogan, Patrick T.; Mladek, Ann C.; Schroeder, Mark A.; Kitange, Gaspar J.; Decker, Paul A.; Giannini, Caterina; Wu Wenting; Ballman, Karla A.; James, C. David; Sarkaria, Jann N.

    2009-09-01

    Purpose: Concurrent temozolomide (TMZ) and radiation therapy (RT) followed by adjuvant TMZ is standard treatment for patients with glioblastoma multiforme (GBM), although the relative contribution of concurrent versus adjuvant TMZ is unknown. In this study, the efficacy of TMZ/RT was tested with a panel of 20 primary GBM xenografts. Methods and Materials: Mice with intracranial xenografts were treated with TMZ, RT, TMZ/RT, or placebo. Survival ratio for a given treatment/line was defined as the ratio of median survival for treatment vs. placebo. Results: The median survival ratio was significantly higher for O6-methylguanine-DNA methyltransferase (MGMT) methylated tumors versus unmethylated tumors following treatment with TMZ (median survival ratio, 3.6 vs. 1.5, respectively; p = 0.008) or TMZ/RT (5.7 vs. 2.3, respectively; p = 0.001) but not RT alone (1.7 vs. 1.6; p = 0.47). In an analysis of variance, MGMT methylation status and p53 mutation status were significantly associated with treatment response. When we analyzed the additional survival benefit conferred specifically by combined therapy, only a subset (5 of 11) of MGMT methylated tumors derived substantial additional benefit from combined therapy, while none of the MGMT unmethylated tumors did. Consistent with a true radiosensitizing effect of TMZ, sequential treatment in which RT (week 1) was followed by TMZ (week 2) proved significantly less effective than TMZ followed by RT or concurrent TMZ/RT (survival ratios of 4.0, 9.6 and 12.9, respectively; p < 0.0001). Conclusions: Concurrent treatment with TMZ and RT provides significant survival benefit only in a subset of MGMT methylated tumors and provides superior antitumor activity relative to sequential administration of RT and TMZ.

  15. Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study.

    PubMed

    Franceschi, Enrico; Depenni, Roberta; Paccapelo, Alexandro; Ermani, Mario; Faedi, Marina; Sturiale, Carmelo; Michiara, Maria; Servadei, Franco; Pavesi, Giacomo; Urbini, Benedetta; Pisanello, Anna; Crisi, Girolamo; Cavallo, Michele A; Dazzi, Claudio; Biasini, Claudia; Bertolini, Federica; Mucciarini, Claudia; Pasini, Giuseppe; Baruzzi, Agostino; Brandes, Alba A

    2016-05-01

    The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age >70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1 months (95 % CI 8.8-13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6 months (95 % CI 8.6-14.6), and 9.3 months (95 % CI 8.1-10.6) in patients treated with RT alone (P = 0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2 months, 95 % CI 11.5-22.9) (P = 0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only. PMID:26943851

  16. Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study.

    PubMed

    Franceschi, Enrico; Depenni, Roberta; Paccapelo, Alexandro; Ermani, Mario; Faedi, Marina; Sturiale, Carmelo; Michiara, Maria; Servadei, Franco; Pavesi, Giacomo; Urbini, Benedetta; Pisanello, Anna; Crisi, Girolamo; Cavallo, Michele A; Dazzi, Claudio; Biasini, Claudia; Bertolini, Federica; Mucciarini, Claudia; Pasini, Giuseppe; Baruzzi, Agostino; Brandes, Alba A

    2016-05-01

    The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age >70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1 months (95 % CI 8.8-13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6 months (95 % CI 8.6-14.6), and 9.3 months (95 % CI 8.1-10.6) in patients treated with RT alone (P = 0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2 months, 95 % CI 11.5-22.9) (P = 0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only.

  17. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction

    PubMed Central

    Mallick, Supriya; Gandhi, Ajeet Kumar; Rath, Goura Kishor

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ) (oral alkylating agent) is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations. PMID:26811592

  18. Radiotherapy with or without temozolomide in elderly patients aged ≥ 70 years with glioblastoma

    PubMed Central

    Karaoglanoglu, Ozden; Akyazici, Emine

    2016-01-01

    Introduction Although the recommended optimal treatment of glioblastoma multiforme (GBM) is adjuvant chemoradiotherapy, trials in GBM have excluded patients older than 70 years. In this study, we aimed to assess overall survival (OS) and prognostic factors in elderly patients (≥ 70 years) with newly diagnosed GBM treated with radiotherapy (RT) ± concurrent/adjuvant temozolomide (TMZ). Material and methods Inclusion criteria were patients ≥ 70 years, pre-RT Karnofsky performance status (KPS) ≥ 60, and time between diagnosis and start of RT ≤ 2 months. A total of 40 patients aged ≥ 70 years, 12 female and 28 male, treated between January 2004 and December 2012, were evaluated. Median age was 73.5 years (range, 70–83 years). The median RT dose was 60 Gy (range, 30–62 Gy). Twenty-one (52.5%) received concurrent TMZ, and of those 12 (30%) went on to receive adjuvant TMZ. Results The median OS was 7 months (95% CI: 5.45–8.54). One- and two-year OS for the whole cohort was 38% and 16%, respectively. Sex, type of surgery, tumor size, and RT dose did not significantly affect the OS. Presence of concurrent TMZ (p < 0.005) and presence of adjuvant TMZ (p < 0.001) were associated with longer OS in our cohort. Conclusions RT ± TMZ seems to be a well-tolerated treatment in patients ≥ 70 years with GBM. Even though no superiority was found between conventional or hypofractionated RT regimens (p = 0.405), the addition of concurrent and adjuvant TMZ to RT increased the OS in our study.

  19. Radiotherapy with or without temozolomide in elderly patients aged ≥ 70 years with glioblastoma

    PubMed Central

    Karaoglanoglu, Ozden; Akyazici, Emine

    2016-01-01

    Introduction Although the recommended optimal treatment of glioblastoma multiforme (GBM) is adjuvant chemoradiotherapy, trials in GBM have excluded patients older than 70 years. In this study, we aimed to assess overall survival (OS) and prognostic factors in elderly patients (≥ 70 years) with newly diagnosed GBM treated with radiotherapy (RT) ± concurrent/adjuvant temozolomide (TMZ). Material and methods Inclusion criteria were patients ≥ 70 years, pre-RT Karnofsky performance status (KPS) ≥ 60, and time between diagnosis and start of RT ≤ 2 months. A total of 40 patients aged ≥ 70 years, 12 female and 28 male, treated between January 2004 and December 2012, were evaluated. Median age was 73.5 years (range, 70–83 years). The median RT dose was 60 Gy (range, 30–62 Gy). Twenty-one (52.5%) received concurrent TMZ, and of those 12 (30%) went on to receive adjuvant TMZ. Results The median OS was 7 months (95% CI: 5.45–8.54). One- and two-year OS for the whole cohort was 38% and 16%, respectively. Sex, type of surgery, tumor size, and RT dose did not significantly affect the OS. Presence of concurrent TMZ (p < 0.005) and presence of adjuvant TMZ (p < 0.001) were associated with longer OS in our cohort. Conclusions RT ± TMZ seems to be a well-tolerated treatment in patients ≥ 70 years with GBM. Even though no superiority was found between conventional or hypofractionated RT regimens (p = 0.405), the addition of concurrent and adjuvant TMZ to RT increased the OS in our study. PMID:27647990

  20. An efficient and practical radiosynthesis of [11C]temozolomide

    PubMed Central

    Moseley, Christian K.; Carlin, Stephen M.; Neelamegam, Ramesh

    2014-01-01

    Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [11C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [11C]TMZ synthesis and reformulation make it difficult for routine production. Herein we report a highly reproducible one-pot radiosynthesis of [11C]TMZ with a radiochemical yield of 17±5% and >97% radiochemical purity. PMID:23151019

  1. AI-29ANGIOGENIC SWITCH FROM VEGFR2/HIF1α IN NEWLY DIAGNOSED GLIOBLASTOMA (GB) TO CXCR4-SDF1 PATHWAY IN RECURRENT PAIRED TUMOR AFTER RADIOTHERAPY (RT)-TEMOZOLOMIDE (TMZ)

    PubMed Central

    Tabouret, Emeline; Tchoghandjian, Aurelie; Denicolai, Emilie; Delfino, Christine; Metellus, Philippe; Padovani, Laetitia; Nanni, Isabelle; Barrie, Maryline; Boucard, Celine; Ouafik, L'Houcine; Figarella-Branger, Dominique; Chinot, Olivier

    2014-01-01

    BACKGROUND: Angiogenesis is one of the key features of GB. Our objective was to explore the potential changes of angiogenic factors expression between initial diagnosis of GB and recurrence after RT/TMZ. METHODS: Paired frozen tumor tissues from both initial and recurrent surgery were available for 29 patients with GB treated with RT/TMZ without bevacizumab upfront. Screening of over 150 genes expressions related to angiogenesis was performed on first 10 paired samples, using RT- PCR arrays (Qiagen®). Comparative expressions were determined using Qiagen® software. In a second step, RNA expressions of the selected identified genes were analyzed on all samples (29 paired tumors) using quantitative RT-PCR (qRT-PCR). Protein expression was examined by immunohistochemistry (IHC) with a semi-quantitative measure. Anti-tumoral effect of an anti-CXCR4 (AMD3100) in addition to TMZ and RT was tested in GB explants. RESULTS: In the screening step performed by RT-PCR arrays the initial-recurrence expression changes contributed to a selection of seven genes for which expression was then quantified by qRT-PCR: VEGFA, VEGFR2, VEGFR1, SDF1, CXCR4, uPA and HIF1α. From initial diagnosis to recurrence RNA expressions of CXCR4 (p = 0.029) and SDF1 (p = 0.107) were increased while expressions of HIF1α (p = 0.009) and VEGFR2 (p = 0.081) were decreased. Similarly, SDF1 protein expression (IHC) tended to increased (p = 0.096) while VEGFR2 staining was significantly decreased (p = 0.004) at recurrence. The role of CXCL4 was further supported by an increase of anti-tumoral effect observed with the combination of AMD3100 and RT/TMZ versus RT/TMZ alone in GB explants. By multivariate analysis, VEGFR2 RNA initial and recurrence expression levels were significantly correlated respectively to initial overall survival (p = 0.019, Hazard ratio (HR) =3.650) and recurrent overall survival (p = 0.024, HR = 2.536). CONCLUSION: Recurrence of GB after chemo-radiation could be associated with a

  2. Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas with Adjuvant Temozolomide Chemotherapy: A Review

    PubMed Central

    Cruz, Aurora S; Benkers, Tara; Rostad, Steven; Broyles, Frances Broyles; Yuen, Kevin; Mayberg, Marc

    2016-01-01

    Most prolactin-secreting pituitary adenomas demonstrate slow growth and are effectively managed with medical/surgical therapy. Rarely, these tumors can behave aggressively with rapid growth and invasion of local tissues, and are refractory to medical, surgical, or radio-surgical therapies. We report a case of a prolactin-secreting adenoma in a young woman, which became progressively aggressive and refractory to usual treatment modalities, but responded to treatment with the chemotherapeutic agent temozolomide. In addition, we review the literature for treatment of refractory adenomas with temozolomide. The clinical and pathologic characteristics of aggressive prolactin-secreting adenomas are reviewed, as well as their response to dopamine agonists, surgery, radiotherapy, and chemotherapy. PMID:27489751

  3. Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas with Adjuvant Temozolomide Chemotherapy: A Review.

    PubMed

    Moisi, Marc; Cruz, Aurora S; Benkers, Tara; Rostad, Steven; Broyles, Frances Broyles; Yuen, Kevin; Mayberg, Marc

    2016-01-01

    Most prolactin-secreting pituitary adenomas demonstrate slow growth and are effectively managed with medical/surgical therapy. Rarely, these tumors can behave aggressively with rapid growth and invasion of local tissues, and are refractory to medical, surgical, or radio-surgical therapies. We report a case of a prolactin-secreting adenoma in a young woman, which became progressively aggressive and refractory to usual treatment modalities, but responded to treatment with the chemotherapeutic agent temozolomide. In addition, we review the literature for treatment of refractory adenomas with temozolomide. The clinical and pathologic characteristics of aggressive prolactin-secreting adenomas are reviewed, as well as their response to dopamine agonists, surgery, radiotherapy, and chemotherapy.

  4. Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation.

    PubMed

    Xie, Li; Song, Xingguo; Guo, Wei; Wang, Xingwu; Wei, Ling; Li, Yang; Lv, Liyan; Wang, Weijun; Chen, Thomas C; Song, Xianrang

    2016-01-12

    Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy without efficient chemotherapeutic agents for it. In our current study, we demonstrated the cytotoxicity effects of a newly patented compound temozolomide-perillyl alcohol (TMZ-POH) on NPC in vitro and in vivo, and the possible mechanisms involved. Human NPC cell lines CNE1, CNE2, HNE2, and SUME-α were treated with control (DMSO), TMZ, POH, TMZ plus POH, and TMZ-POH. Our data indicated that TMZ-POH could inhibit NPC cell proliferation, cause G2/M arrest and DNA damage. TMZ-POH triggered apoptosis in NPC cells via significant activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). Importantly, TMZ-POH-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (ΔΨm) and release of mitochondrial Cytochrome c, (ii) the increase in ROS generation, and (iii) the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinases (JNK) signaling pathway. The generation of ROS in response to TMZ-POH seems to play a crucial role in the cell death process since the blockage of ROS production using the antioxidant N-acetyl-L-cysteine or catalase reversed the TMZ-POH-induced JNK activation, DNA damage, and cancer cell apoptosis. These results provide the rationale for further research and preclinical investigation of the antitumor effect of TMZ-POH against human NPC. PMID:26625208

  5. Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation.

    PubMed

    Xie, Li; Song, Xingguo; Guo, Wei; Wang, Xingwu; Wei, Ling; Li, Yang; Lv, Liyan; Wang, Weijun; Chen, Thomas C; Song, Xianrang

    2016-01-12

    Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy without efficient chemotherapeutic agents for it. In our current study, we demonstrated the cytotoxicity effects of a newly patented compound temozolomide-perillyl alcohol (TMZ-POH) on NPC in vitro and in vivo, and the possible mechanisms involved. Human NPC cell lines CNE1, CNE2, HNE2, and SUME-α were treated with control (DMSO), TMZ, POH, TMZ plus POH, and TMZ-POH. Our data indicated that TMZ-POH could inhibit NPC cell proliferation, cause G2/M arrest and DNA damage. TMZ-POH triggered apoptosis in NPC cells via significant activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). Importantly, TMZ-POH-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (ΔΨm) and release of mitochondrial Cytochrome c, (ii) the increase in ROS generation, and (iii) the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinases (JNK) signaling pathway. The generation of ROS in response to TMZ-POH seems to play a crucial role in the cell death process since the blockage of ROS production using the antioxidant N-acetyl-L-cysteine or catalase reversed the TMZ-POH-induced JNK activation, DNA damage, and cancer cell apoptosis. These results provide the rationale for further research and preclinical investigation of the antitumor effect of TMZ-POH against human NPC.

  6. KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment

    PubMed Central

    D'Alessandro, Giuseppina; Grimaldi, Alfonso; Chece, Giuseppina; Porzia, Alessandra; Esposito, Vincenzo; Santoro, Antonio; Salvati, Maurizio; Mainiero, Fabrizio; Ragozzino, Davide; Angelantonio, Silvia Di; Wulff, Heike; Catalano, Myriam; Limatola, Cristina

    2016-01-01

    Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients. Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression. PMID:27096953

  7. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function.

    PubMed

    Chen, Liangyu; Li, Xinxing; Liu, Libo; Yu, Bo; Xue, Yixue; Liu, Yunhui

    2015-03-01

    Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system xc- expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ‑induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

  8. Temozolomide nanoparticles for targeted glioblastoma therapy.

    PubMed

    Fang, Chen; Wang, Kui; Stephen, Zachary R; Mu, Qingxin; Kievit, Forrest M; Chiu, Daniel T; Press, Oliver W; Zhang, Miqin

    2015-04-01

    Glioblastoma (GBM) is a deadly and debilitating brain tumor with an abysmal prognosis. The standard therapy for GBM is surgery followed by radiation and chemotherapy with Temozolomide (TMZ). Treatment of GBMs remains a challenge, largely because of the fast degradation of TMZ, the inability to deliver an effective dose of TMZ to tumors, and a lack of target specificity that may cause systemic toxicity. Here, we present a simple method for synthesizing a nanoparticle-based carrier that can protect TMZ from rapid degradation in physiological solutions and can specifically deliver them to GBM cells through the mediation of a tumor-targeting peptide chlorotoxin (CTX). Our nanoparticle, namely NP-TMZ-CTX, had a hydrodynamic size of <100 nm, exhibited sustained stability in cell culture media for up to 2 weeks, and could accommodate stable drug loading. TMZ bound to nanoparticles showed a much higher stability at physiological pH, with a half-life 7-fold greater than that of free TMZ. NP-TMZ-CTX was able to target GBM cells and achieved 2-6-fold higher uptake and a 50-90% reduction of IC50 72 h post-treatment as compared to nontargeted NP-TMZ. NP-TMZ-CTX showed great promise in its ability to deliver a large therapeutic dose of TMZ to GBM cells and could serve as a template for targeted delivery of other therapeutics.

  9. Temozolomide Nanoparticles for Targeted Glioblastoma Therapy

    PubMed Central

    Fang, Chen; Wang, Kui; Stephen, Zachary R.; Mu, Qingxin; Kievit, Forrest M.; Chiu, Daniel T.; Press, Oliver W.; Zhang, Miqin

    2015-01-01

    Glioblastoma (GBM) is a deadly and debilitating brain tumor with an abysmal prognosis. The standard therapy for GBM is surgery followed by radiation and chemotherapy with temozolomide (TMZ). Treatment of GBMs remains a challenge, largely due to the fast degradation of TMZ, inability to deliver an effective dose of TMZ to tumors, and lack of target specificity which may cause systemic toxicity. Here, we present a simple method to synthesize a nanoparticle-based carrier that can protect TMZ from rapid degradation in physiological solutions and can specifically deliver them to GBM cells through the mediation of a tumor targeting peptide chlorotoxin (CTX). Our nanoparticle, namely NP-TMZ-CTX, had a hydrodynamic size of less than 100 nm, exhibited sustained stability in cell culture media for up to two weeks, and could accommodate stable drug loading. TMZ bound to nanoparticles showed much higher stability at physiological pH, with a half-life 7-fold greater than free TMZ. NP-TMZ-CTX was able to target GBM cells and achieved 2–6-fold higher uptake and 50–90% reduction of IC50 at 72 h post-treatment as compared to non-targeted NP-TMZ. NP-TMZ-CTX showed great promise in its ability to deliver a high therapeutic dose of TMZ to GBM cells, and could serve as a template for targeted delivery of other therapeutics. PMID:25751368

  10. Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas.

    PubMed

    Blakeley, Jaishri O; Grossman, Stuart A; Mikkelsen, Tom; Rosenfeld, Myrna R; Peereboom, David; Nabors, L Burt; Chi, Andrew S; Emmons, Gary; Garcia Ribas, Ignacio; Supko, Jeffrey G; Desideri, Serena; Ye, Xiaobu

    2015-10-01

    Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed ≥80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days × 6 weeks) in conjunction with iniparib (i.v. 2 days/week) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 years; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19 mg/kg/week (rash/hypersensitivity). At 17.2 mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2 mg/kg/week. Dose escalation stopped at 16 mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was ≤5% of the corresponding iniparib concentration. Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2 mg/kg/week with mTMZ and 16 mg/kg/week with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing. PMID:26285766

  11. Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas

    PubMed Central

    Blakeley, Jaishri O.; Grossman, Stuart A.; Mikkelsen, Tom; Rosenfeld, Myrna R.; Peereboom, David; Nabors, L. Burt; Chi, Andrew S.; Emmons, Gary; Ribas, Ignacio Garcia; Supko, Jeffrey G.; Desideri, Serena; Ye, Xiaobu

    2016-01-01

    Background Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Methods Adults with newly diagnosed MG who had successfully completed ≥ 80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m2 days 1-5/28 days) or cTMZ dosing (75 mg/m2/d × 6weeks) in conjunction with iniparib (i.v. 2 days/wk) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). Results 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 yrs; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19mg/kg/week (rash/hypersensitivity). At 17.2mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2mg/kg/wk. Dose escalation stopped at 16mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was ≤ 5% of the corresponding iniparib concentration. Conclusions Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2mg/kg/wk with mTMZ and 16mg/kg/wk with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing. PMID:26285766

  12. Phase II Trial of Hypofractionated IMRT With Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Reddy, Krishna; Damek, Denise; Gaspar, Laurie E.; Ney, Douglas; Waziri, Allen; Lillehei, Kevin; Stuhr, Kelly; Kavanagh, Brian D.; Chen Changhu

    2012-11-01

    Purpose: To report toxicity and overall survival (OS) in patients with newly diagnosed glioblastoma multiforme (GBM) treated with hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ). Methods and Materials: Patients with newly diagnosed GBM after biopsy or resection and with adequate performance status and organ or bone marrow function were eligible for this study. Patients received postoperative hypo-IMRT to the surgical cavity and residual tumor seen on T1-weighted brain MRI with a 5-mm margin to a total dose of 60 Gy in 10 fractions (6 Gy/fraction) and to the T2 abnormality on T2-weighted MRI with 5-mm margin to 30 Gy in 10 fractions (3 Gy/fraction). Concurrent TMZ was given at 75 mg/m{sup 2}/day for 28 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m{sup 2}/day for 5 days every 28 days. Toxicities were defined using Common Terminology Criteria for Adverse Events version 3.0. Results: Twenty-four patients were treated, consisting of 14 men, 10 women; a median age of 60.5 years old (range, 27-77 years); and a median Karnofsky performance score of 80 (range, 60-90). All patients received hypo-IMRT and concurrent TMZ according to protocol, except for 2 patients who received only 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 6.5 (range, 0-14).With a median follow-up of 14.8 months (range, 2.7-34.2 months) for all patients and a minimum follow-up of 20.6 months for living patients, no instances of grade 3 or higher nonhematologic toxicity were observed. The median OS was 16.6 months (range, 4.1-35.9 months). Six patients underwent repeated surgery for suspected tumor recurrence; necrosis was found in 50% to 100% of the resected specimens. Conclusion: In selected GBM patients, 60 Gy hypo-IMRT delivered in 6-Gy fractions over 2 weeks with concurrent and adjuvant TMZ is safe. OS in this small cohort of patients was comparable to that treated with current standard of care

  13. Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy.

    PubMed

    Grzmil, Michal; Seebacher, Jan; Hess, Daniel; Behe, Martin; Schibli, Roger; Moncayo, Gerald; Frank, Stephan; Hemmings, Brian A

    2016-09-01

    Current standard-of-care treatment for malignant cancers includes radiotherapy and adjuvant chemotherapy. Here, we report increased MAP kinase-interacting kinase (MNK)-regulated phosphorylation of translation initiation factor 4E (eIF4E) in glioma cells upon temozolomide (TMZ) treatment and in medullary thyroid carcinoma (MTC) cells in response to targeted radionuclide therapy. Depletion of MNK activity by using two MNK inhibitors, CGP57380 or cercosporamide, as well as by MNK1-specific knockdown sensitized glioblastoma (GBM) cells and GBM-derived spheres to TMZ. Furthermore, CGP57380 treatment enhanced response of MTC cells to (177)Lu-labeled gastrin analogue. In order to understand how MNK signaling pathways support glioma survival we analyzed putative MNK substrates by quantitative phosphoproteomics in normal condition and in the presence of TMZ. We identified MNK inhibitor-sensitive phosphorylation sites on eIF4G1, mutations of which either influenced eIF4E phosphorylation or glioma cell response to TMZ, pointing to altered regulation of translation initiation as a resistance mechanism. Pharmacological inhibition of overexpressed MNK1 by CGP57380 reduced eIF4E phosphorylation and induced association of inactive MNK1 with eIF4G1. Taken together, our data show an activation of MNK-mediated survival mechanisms in response to either glioma chemotherapy or MTC targeted radiation and suggest that inhibition of MNK activity represents an attractive sensitizing strategy for cancer treatments.

  14. Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Chen Changhu; Damek, Denise; Gaspar, Laurie E.; Waziri, Allen; Lillehei, Kevin; Kleinschmidt-DeMasters, B.K.; Robischon, Monica; Stuhr, Kelly; Rusthoven, Kyle E.; Kavanagh, Brian D.

    2011-11-15

    Purpose: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. Methods and Materials: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m{sup 2}/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m{sup 2}/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. Results: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. Conclusions: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with

  15. Phase I Study of Vandetanib With Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma

    SciTech Connect

    Drappatz, Jan; Norden, Andrew D.; Wong, Eric T.

    2010-09-01

    Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard '3 + 3' dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of {>=}60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT. Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

  16. Postoperative Treatment of Primary Glioblastoma Multiforme With Radiation and Concomitant Temozolomide in Elderly Patients

    SciTech Connect

    Combs, Stephanie E. Wagner, Johanna; Bischof, Marc; Welzel, Thomas; Wagner, Florian; Debus, Juergen; Schulz-Ertner, Daniela

    2008-03-15

    Purpose: To evaluate efficacy and toxicity in elderly patients with glioblastoma multiforme (GBM) treated with postoperative radiochemotherapy with temozolomide (TMZ). Patients and Methods: Forty-three patients aged 65 years or older were treated with postoperative with radiochemotherapy using TMZ for primary GBM. Median age at primary diagnosis was 67 years; 14 patients were female, 29 were male. A complete surgical resection was performed in 12 patients, subtotal resection in 17 patients, and biopsy only in 14 patients. Radiotherapy was applied with a median dose of 60 Gy, in a median fractionation of 5 x 2 Gy/wk. Thirty-five patients received concomitant TMZ at 50 mg/m{sup 2}, and in 8 patients 75 mg/m{sup 2} of TMZ was applied. Adjuvant cycles of TMZ were prescribed in 5 patients only. Results: Median overall survival was 11 months in all patients; the actuarial overall survival rate was 48% at 1 year and 8% at 2 years. Median overall survival was 18 months after complete resection, 16 months after subtotal resection, and 6 months after biopsy only. Median progression-free survival was 4 months; the actuarial progression-free survival rate was 41% at 6 months and 18% at 12 months. Radiochemotherapy was well tolerated in most patients and could be completed without interruption in 38 of 43 patients. Four patients developed hematologic side effects greater than Common Terminology Criteria Grade 2, which led to early discontinuation of TMZ in 1 patient. Conclusions: Radiochemotherapy is safe and effective in a subgroup of elderly patients with GBM and should be considered in patients without major comorbidities.

  17. Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study.

    PubMed

    Boccard, Sandra G; Marand, Sandie V; Geraci, Sandra; Pycroft, Laurie; Berger, François R; Pelletier, Laurent A

    2015-10-01

    Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition. PMID:26336131

  18. Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

    PubMed Central

    Boccard, Sandra G.; Marand, Sandie V.; Geraci, Sandra; Pycroft, Laurie; Berger, François R.; Pelletier, Laurent A.

    2015-01-01

    Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition. PMID:26336131

  19. Profile Analysis of Chemotherapy-induced Nausea and Vomiting in Patients Treated with Concomitant Temozolomide and Radiotherapy: Results of a Prospective Study

    PubMed Central

    MATSUDA, Masahide; YAMAMOTO, Tetsuya; ISHIKAWA, Eiichi; NAKAI, Kei; AKUTSU, Hiroyoshi; ONUMA, Kuniyuki; MATSUMURA, Akira

    2015-01-01

    Temozolomide (TMZ) as a concomitant and adjuvant chemotherapy to radiotherapy following maximal surgical resection is the established standard therapy for patients with newly diagnosed high-grade glioma. However, detailed analysis of chemotherapy-induced nausea and vomiting (CINV) associated with concomitant TMZ has not been sufficiently described. We prospectively analyzed the profile of CINV associated with concomitant TMZ. Eighteen consecutive patients with newly diagnosed high-grade glioma treated with concomitant chemoradiotherapy including TMZ were enrolled. CINV was recorded using a daily diary including nausea assessment, emetic episodes, degree of appetite suppression, and antiemetic medication use. The observed incidence rates of all grade nausea, moderate/severe (CTC grade 2, 3) nausea, emetic episodes, and appetite suppression for the overall period were 89%, 39%, 39%, and 83%, respectively. Moderate/severe nausea and severe (CTC grade 3) appetite suppression were frequently observed during the delayed phase of the treatment. Emetic episodes and moderate/severe nausea were significantly correlated with female gender. Moderate/severe nausea and severe appetite suppression were significantly correlated with low lymphocyte counts before chemoradiotherapy. For CINV associated with concomitant TMZ, enhanced antiemetic therapy focused on the delayed phase of the treatment will likely be beneficial, especially in female patients with a low lymphocyte count before chemoradiotherapy. PMID:26345664

  20. Targeting autophagy to sensitive glioma to temozolomide treatment.

    PubMed

    Yan, Yuanliang; Xu, Zhijie; Dai, Shuang; Qian, Long; Sun, Lunquan; Gong, Zhicheng

    2016-02-02

    Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

  1. Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

    PubMed Central

    Rios, Adan; Hsu, Sigmund H.; Blanco, Angel; Buryanek, Jamie; Day, Arthur L.; McGuire, Mary F.; Brown, Robert E.

    2016-01-01

    Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID:27489862

  2. Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.

    PubMed

    Jiang, Pengfei; Wang, Ping; Sun, Xiaoling; Yuan, Zhongshun; Zhan, Rucai; Ma, Xiangyu; Li, Weiguo

    2016-01-01

    Temozolomide (TMZ) is commonly used in glioma chemotherapy. However, a great clinical challenge for TMZ is chemoresistance. H19 transcripts are recognized as long noncoding RNAs, which potentially interact with chromatin-modifying complexes to regulate gene expression via epigenetic changes. Our data based on glioma patients showed that the expression of H19 was significantly upregulated in TMZ-resistant tumors compared with the TMZ-sensitive tumors. To determine the function of H19 in glioma, cell lines U87 and U251 were exposed to TMZ to establish TMZ-resistant clones U87(TMZ) and U251(TMZ). In U87(TMZ) and U251(TMZ), the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones, as determined by real-time quantitative reverse transcription polymerase chain reaction. Concomitant treatment with small interfering RNA specifically targeting H19 and TMZ in resistant glioma clones resulted in decreased IC50 values for TMZ, and increased apoptotic rates than control small interfering RNA-treated cells. This was also evident by the increased PARP cleavage in resistant cells exposed to TMZ + si-H19. Furthermore, the reduced expression of H19 altered major drug resistance genes, such as MDR, MRP, and ABCG2, both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas. PMID:27366087

  3. Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy

    PubMed Central

    Jiang, Pengfei; Wang, Ping; Sun, Xiaoling; Yuan, Zhongshun; Zhan, Rucai; Ma, Xiangyu; Li, Weiguo

    2016-01-01

    Temozolomide (TMZ) is commonly used in glioma chemotherapy. However, a great clinical challenge for TMZ is chemoresistance. H19 transcripts are recognized as long noncoding RNAs, which potentially interact with chromatin-modifying complexes to regulate gene expression via epigenetic changes. Our data based on glioma patients showed that the expression of H19 was significantly upregulated in TMZ-resistant tumors compared with the TMZ-sensitive tumors. To determine the function of H19 in glioma, cell lines U87 and U251 were exposed to TMZ to establish TMZ-resistant clones U87TMZ and U251TMZ. In U87TMZ and U251TMZ, the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones, as determined by real-time quantitative reverse transcription polymerase chain reaction. Concomitant treatment with small interfering RNA specifically targeting H19 and TMZ in resistant glioma clones resulted in decreased IC50 values for TMZ, and increased apoptotic rates than control small interfering RNA-treated cells. This was also evident by the increased PARP cleavage in resistant cells exposed to TMZ + si-H19. Furthermore, the reduced expression of H19 altered major drug resistance genes, such as MDR, MRP, and ABCG2, both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas. PMID:27366087

  4. North Central Cancer Treatment Group Phase I Trial N057K of Everolimus (RAD001) and Temozolomide in Combination With Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Sarkaria, Jann N.; Galanis, Evanthia; Wu Wenting; Peller, Patrick J.; Giannini, Caterina; Brown, Paul D.; Uhm, Joon H.; McGraw, Steven; Jaeckle, Kurt A.; Buckner, Jan C.

    2011-10-01

    Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. On the basis of promising preclinical data, the safety and tolerability of therapy with the mTOR inhibitor RAD001 in combination with radiation (RT) and temozolomide (TMZ) was evaluated in this Phase I study. Methods and Materials: All patients received weekly oral RAD001 in combination with standard chemoradiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide. RAD001 was dose escalated in cohorts of 6 patients. Dose-limiting toxicities were defined during RAD001 combination therapy with TMZ/RT. Results: Eighteen patients were enrolled, with a median follow-up of 8.4 months. Combined therapy was well tolerated at all dose levels, with 1 patient on each dose level experiencing a dose-limiting toxicity: Grade 3 fatigue, Grade 4 hematologic toxicity, and Grade 4 liver dysfunction. Throughout therapy, there were no Grade 5 events, 3 patients experienced Grade 4 toxicities, and 6 patients had Grade 3 toxicities attributable to treatment. On the basis of these results, the recommended Phase II dosage currently being tested is RAD001 70 mg/week in combination with standard chemoradiotherapy. Fluorodeoxyglucose (FDG) positron emission tomography scans also were obtained at baseline and after the second RAD001 dose before the initiation of TMZ/RT; the change in FDG uptake between scans was calculated for each patient. Fourteen patients had stable metabolic disease, and 4 patients had a partial metabolic response. Conclusions: RAD001 in combination with RT/TMZ and adjuvant TMZ was reasonably well tolerated. Changes in tumor metabolism can be detected by FDG positron emission tomography in a subset of patients within days of initiating RAD001 therapy.

  5. Impact of 1p/19q Codeletion and Histology on Outcomes of Anaplastic Gliomas Treated With Radiation Therapy and Temozolomide

    SciTech Connect

    Speirs, Christina K.; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd A.; Tran, David D.; Linette, Gerry; Chicoine, Michael R.; Dacey, Ralph G.; Rich, Keith M.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H.; Huang, Jiayi

    2015-02-01

    Purpose: Anaplastic gliomas represent a heterogeneous group of primary high-grade brain tumors, and the optimal postoperative treatment remains controversial. In this report, we present our institutional data on the clinical outcomes of radiation therapy (RT) plus temozolomide (RT + TMZ) for anaplastic gliomas, stratified by histology and 1p/19q codeletion. Methods and Materials: A single-institution retrospective review was conducted of patients with supratentorial anaplastic oligodendroglioma (AO), mixed anaplastic oligoastrocytoma (AOA), and anaplastic astrocytoma (AA). After surgery, RT was delivered at a median total dose of 60 Gy (range, 31.6-63 Gy) in daily fractions. All patients received standard concurrent TMZ, with or without adjuvant TMZ. Histological/molecular subtypes were defined as codeleted AO/AOA, non-codeleted AO/AOA, and AA. Results: From 2000 to 2012, 111 cases met study criteria and were evaluable. Codeleted AO/AOA had superior overall survival (OS) to non-codeleted AO/AOA (91% vs 68% at 5 years, respectively, P=.02), whereas progression-free survival (PFS) was not significantly different (70% vs 46% at 5 years, respectively, P=.10). AA had inferior OS to non-codeleted AO/AOA (37% vs 68% at 5 years, respectively, P=.007) and inferior PFS (27% vs 46%, respectively, P=.03). On multivariate analysis, age, performance status, and histological or molecular subtype were independent predictors for both PFS and OS. Compared to historical controls, RT + TMZ provided comparable OS to RT with procarbazine, lomustine, and vincristine (RT + PCV) for codeleted AO/AOA, superior OS to RT alone for non-codeleted AO/AOA, and similar OS to RT alone for AA. Conclusions: RT + TMZ may be a promising treatment for both codeleted and non-codeleted AO/AOA, but its role for AA remains unclear.

  6. Radiotherapy plus concomitant temozolomide in primary gliosarcoma.

    PubMed

    Adeberg, Sebastian; Bernhardt, Denise; Harrabi, Semi Ben; Diehl, Christian; Koelsche, Christian; Rieken, Stefan; Unterberg, Andreas; von Deimling, Andreas; Debus, Juergen

    2016-06-01

    Clinical guidelines for gliosarcoma (GSM) are poorly defined and GSM patients are usually treated in accordance with existing guidelines for glioblastoma (GBM), with maximal surgical resection followed by chemoradiation with temozolomide (TMZ). However, it is not clear yet if GSM patients profit from TMZ therapy and if O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is crucial. We retrospectively evaluated 37 patients with histologically proven, primary GSM who had received radiation therapy since the temozolomide era (post-2005). Twenty-five patients (67.6 %) received combined chemoradiation with temozolomide, and 12 cases (32.4 %) received radiation therapy alone. Molecular markers were determined retrospectively. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses. All cases were isocitrate dehydrogenase 1 (IDH1) wildtype, MGMT promoter methylation could be observed in 33.3 % of the assessable cases (10/30) and TERT promoter mutation was seen in a high frequency of 86.7 % (26/30). The influence of TMZ therapy on overall survival (OS) was significantly improved compared with cases in which radiation therapy alone was performed (13.9 vs. 9.9 months; p = 0.045), independently of MGMT promoter methylation. The positive effect of TMZ on OS was confirmed in this study's multivariate analyses (p = 0.04), after adjusting our results for potential confounders. In conclusion, this study demonstrates that concomitant TMZ together with radiation therapy increases GSM-patient survival independent of MGMT promoter methylation. Thus, GSM can be treated in accordance to GBM guidelines. MGMT promoter methylation was infrequent and TERT promoter mutation common without influencing the survival rates. The mechanisms of TMZ effects in GSM are still not fully understood and merit further clinical and molecular-genetic and -biological evaluation. PMID:27025857

  7. Temozolomide Treatment for Pediatric Refractory Anaplastic Ependymoma with Low MGMT Protein Expression.

    PubMed

    Komori, Kazutoshi; Yanagisawa, Ryu; Miyairi, Yosuke; Sakashita, Kazuo; Shiohara, Masaaki; Fujihara, Ikuko; Morita, Daisuke; Nakamura, Tomohiko; Ogiso, Yoshifumi; Sano, Kenji; Shirahata, Mitsuaki; Fukuoka, Kohei; Ichimura, Koichi; Shigeta, Hiroaki

    2016-01-01

    The benefit of postoperative chemotherapy for anaplastic ependymoma remains unknown. We report two pediatric patients with refractory anaplastic ependymoma treated with temozolomide (TMZ). We did not detect O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation in tumor samples; however, MGMT protein expression was low. With TMZ treatment, one patient had a 7-month complete remission; the other, stable disease for 15 months. Three other patients did not respond to TMZ; two had high and one low MGMT expression, and two showed no MGMT promoter methylation. These findings suggest that TMZ may be effective for pediatric refractory anaplastic ependymoma with low MGMT protein expression. PMID:26305586

  8. Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells.

    PubMed

    Ignarro, Raffaela Silvestre; Facchini, Gustavo; Vieira, André Schwambach; De Melo, Daniela Rodrigues; Lopes-Cendes, Iscia; Castilho, Roger Frigério; Rogerio, Fabio

    2016-07-01

    Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells. PMID:27334753

  9. Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells.

    PubMed

    Ignarro, Raffaela Silvestre; Facchini, Gustavo; Vieira, André Schwambach; De Melo, Daniela Rodrigues; Lopes-Cendes, Iscia; Castilho, Roger Frigério; Rogerio, Fabio

    2016-07-01

    Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

  10. The role of temozolomide in the management of patients with newly diagnosed anaplastic astrocytoma: a comparison of survival in the era prior to and following the availability of temozolomide

    PubMed Central

    Abuali, Inas; Ye, Xiaobu; Lu, Yao; Grossman, Stuart A.

    2016-01-01

    Adding temozolomide (TMZ) to radiation for patients with newly-diagnosed anaplastic astrocytomas (AAs) is common clinical practice despite the lack of prospective studies demonstrating a survival advantage. Two retrospective studies, each with methodologic limitations, provide conflicting advice regarding treatment. This single-institution retrospective study was conducted to determine survival trends in patients with AA. All patients ≥18 years with newly-diagnosed AA treated at Johns Hopkins from 1995 to 2012 were included. As we incorporated TMZ into high-grade glioma treatment regimens in 2004, patients were divided into pre-2004 and post-2004 groups for analysis. Clinical, radiographic, and pathologic data were collected. Median overall survival (OS) was calculated using Kaplan–Meier estimates. A total of 196 patients were identified; 74 pre-2004 and 122 post-2004; mean age 47 ± 15 years; 57 % male; 87 % white, 69 % surgical debulking. Mean RT dose 5676 + 746 cGy; duration of concurrent chemoradiation 5.8 ± 0.8 weeks; and mean adjuvant chemotherapy 4.3 + 2.8 cycles. Baseline prognostic factors did not differ between groups. Chemotherapy was administered to 12 % of patients pre-2004 (TMZ = 1, procarbazine, lomustine and vincristine = 2, carmustine wafer = 6) and 94 % post-2004 (TMZ in all, p < 0.001). Median OS was 32 months (95 % CI 23–43). Survival was longer in the post-2004 cohort (37 mo, 24–64) than pre-2004 (27 mo, 19–40; HR 0.75, 0.53–1.06, p = 0.11). Multivariate analysis controlling for age, Karnofsky performance status, and extent of resection revealed a 36 % reduced risk of death (HR 0.64, 0.44–0.91, p = 0.015) in patients treated post-2004. This retrospective review found survival in newly diagnosed patients with AA improved with the addition of temozolomide to standard radiation. Until prospective randomized phase III data are available, these data support the practice of incorporating TMZ in the management of newly-diagnosed AA

  11. Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells.

    PubMed

    Munoz, Jessian L; Walker, Nykia D; Scotto, Kathleen W; Rameshwar, Pranela

    2015-10-10

    Chemotherapeutic resistance can occur by P-glycoprotein (P-gp), a 12-transmembrane ATP-dependent drug efflux pump. Glioblastoma (GBM) has poor survival rate and uniformly acquired chemoresistance to its frontline agent, Temozolomide (TMZ). Despite much effort, overcoming TMZ resistance remains a challenge. We reported on autonomous induction of TMZ resistance by increased transcription MDR1, the gene for P-gp. This study investigated how P-gp and TMZ interact to gain resistance. Using an experimental model of Adriamycin-resistant DC3F cells (DC3F/Adx), we showed that increased P-gp caused TMZ resistance. Increasing concentrations of TMZ competed with Calcein for P-gp, resulting in reduced efflux in the DC3F/Adx cells. Three different inhibitors of P-gp reversed the resistance to TMZ in two different GBM cell lines, by increasing active Caspase 3. Molecular modeling predicted the binding sites to be the intracellular region of P-gp and also identified specific amino acids and kinetics of energy for the efflux of TMZ. Taken together, we confirmed P-gp targeting of TMZ, a crucial regulator of TMZ resistance in GBM. This study provides insights on the effectiveness by which TMZ competes with other P-gp substrates, thereby opening the door for combined targeted therapies.

  12. Adenovirus-Mediated FKHRL1/TM Sensitizes Melanoma Cells to Apoptosis Induced by Temozolomide

    PubMed Central

    Egger, Michael E.; McNally, Lacey R.; Nitz, Jonathan; McMasters, Kelly M.

    2014-01-01

    Abstract Melanoma exhibits variable resistance to the alkylating agent temozolomide (TMZ). We evaluated the potential of adenovirus expressing forkhead human transcription factor like 1 triple mutant (Ad-FKHRL1/TM) to sensitize melanoma cells to TMZ. Four melanoma cell lines were treated with Ad-FKHRL1/TM and TMZ, alone or in combination. Apoptosis was assessed by activation and inhibition of caspase pathway, nuclei fragmentation, and annexin V staining. The potential therapeutic efficacy of Ad-FKHRL1/TM with TMZ was also assessed in a mouse melanoma xenograft model. Combination therapy of Ad-FKHRL1/TM and TMZ resulted in greater cell killing (<20% cell viability) compared with single therapy and controls (p<0.05). Combination indices of Ad-FKHRL1/TM and TMZ therapy indicated significant (p<0.05) synergistic killing effect. Greater apoptosis induction was found in cells treated with Ad-FKHRL1/TM and TMZ than with Ad-FKHRL1/TM or TMZ-treated cells alone. Treatment with TMZ enhanced adenovirus transgene expression in a cell type-dependent manner. In an in vivo model, combination therapy of Ad-FKHRL1/TM with TMZ results in greater tumor growth reduction in comparison with single treatments. We suggest that Ad-FKHRL1/TM is a promising vector to sensitize melanoma cells to TMZ, and that a combination of both approaches would be effective in the clinical setting. PMID:25238278

  13. The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells

    PubMed Central

    Atif, Fahim; Patel, Neil R.; Yousuf, Seema; Stein, Donald G.

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12–15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects. Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days. Cell death was measured by MTT reduction assay. PROG and TMZ individually induced tumor cell death in a dose-dependent manner. PROG at high doses produced more cell death than TMZ alone. When combined, PROG enhanced the cell death-inducing effect of TMZ. In HDFs, PROG did not reduce viability even at the same high cytotoxic doses, but TMZ did so in a dose-dependent manner. In combination, PROG reduced TMZ toxicity in HDFs. PROG alone and in combination with TMZ suppressed the EGFR/PI3K/Akt/mTOR signaling pathway and MGMT expression in U87MG cells, thus suppressing cell proliferation. PROG and TMZ individually reduced cell migration in U87MG cells but did so more effectively in combination. PROG enhances the cytotoxic effects of TMZ in GBM cells and reduces its toxic side effects in healthy primary cells. PMID:26110872

  14. Temozolomide-perillyl alcohol conjugate induced reactive oxygen species accumulation contributes to its cytotoxicity against non-small cell lung cancer.

    PubMed

    Song, Xingguo; Xie, Li; Wang, Xingwu; Zeng, Qian; Chen, Thomas C; Wang, Weijun; Song, Xianrang

    2016-01-01

    Temozolomide-perillyl alcohol conjugate (TMZ - POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and TMZ-resistant gliomas. In a current study we had demonstrated how TMZ - POH also exhibited its cytotoxicity against non-small cell lung cancer (NSCLC), the most common type of lung cancer, as evidence from cell/tumor proliferation inhibition, G2/M arrest, DNA damage and mitochondrial apoptosis. Importantly, TMZ - POH's cytotoxicity is closely related to reactive oxygen species (ROS) accumulation because it can be reversed by two ROS scavengers, catalase (CAT) and N-acetyl-L-cysteine (NAC). TMZ - POH induces mitochondrial transmembrane potential (MTP) decrease and ROS accumulation, in turn activates mitogen-activated protein kinase (MAPKs) signaling and mitochondrial apoptosis, and then exerts its cytotoxicity, thus proposing TMZ - POH as a potential therapeutic candidate for NSCLC. PMID:26949038

  15. Temozolomide Injection

    MedlinePlus

    ... by slowing or stopping the growth of cancer cells in your body. ... during, and after your treatment to check your body's response and to temozolomide to see if your blood cells are affected by this drug.It is important ...

  16. Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM

    PubMed Central

    Biswas, Nidhan K.; Chandra, Vikas; Sarkar-Roy, Neeta; Das, Tapojyoti; Bhattacharya, Rabindra N.; Tripathy, Laxmi N.; Basu, Sunandan K.; Kumar, Shantanu; Das, Subrata; Chatterjee, Ankita; Mukherjee, Ankur; Basu, Pryiadarshi; Maitra, Arindam; Chattopadhyay, Ansuman; Basu, Analabha; Dhara, Surajit

    2015-01-01

    Neoplastic cells of Glioblastoma multiforme (GBM) may or may not show sustained response to temozolomide (TMZ) chemotherapy. We hypothesize that TMZ chemotherapy response in GBM is predetermined in its neoplastic clones via a specific set of mutations that alter relevant pathways. We describe exome-wide enrichment of variant allele frequencies (VAFs) in neurospheres displaying contrasting phenotypes of sustained versus reversible TMZ-responses in vitro. Enrichment of VAFs was found on genes ST5, RP6KA1 and PRKDC in cells showing sustained TMZ-effect whereas on genes FREM2, AASDH and STK36, in cells showing reversible TMZ-effect. Ingenuity pathway analysis (IPA) revealed that these genes alter cell-cycle, G2/M-checkpoint-regulation and NHEJ pathways in sustained TMZ-effect cells whereas the lysine-II&V/phenylalanine degradation and sonic hedgehog (Hh) pathways in reversible TMZ-effect cells. Next, we validated the likely involvement of the Hh-pathway in TMZ-response on additional GBM neurospheres as well as on GBM patients, by extracting RNA-sequencing-based gene expression data from the TCGA-GBM database. Finally, we demonstrated TMZ-sensitization of a TMZ non-responder neurosphere in vitro by treating them with the FDA-approved pharmacological Hh-pathway inhibitor vismodegib. Altogether, our results indicate that the Hh-pathway impedes sustained TMZ-response in GBM and could be a potential therapeutic target to enhance TMZ-response in this malignancy. PMID:25604826

  17. Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines.

    PubMed

    Beier, Dagmar; Schriefer, Beate; Brawanski, Konstantin; Hau, Peter; Weis, Joachim; Schulz, Jörg B; Beier, Christoph P

    2012-08-01

    The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.

  18. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

    PubMed

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-01-01

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID:27618068

  19. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

    PubMed

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-09-08

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach.

  20. Autophagy enhancement contributes to the synergistic effect of vitamin D in temozolomide-based glioblastoma chemotherapy

    PubMed Central

    BAK, DONG-HO; KANG, SEONG HEE; CHOI, DU RI; GIL, MI NA; YU, KWANG SIK; JEONG, JI HEUN; LEE, NAM-SEOB; LEE, JE-HUN; JEONG, YOUNG-GIL; KIM, DONG KWAN; KIM, DO-KYUNG; KIM, JWA-JIN; HAN, SEUNG-YUN

    2016-01-01

    Temozolomide (TMZ), an alkylating agent, is recommended as the initial treatment for high-grade glioblastoma. TMZ is widely used, but its short half-life and the frequency of tumor resistance limit its therapeutic efficacy. In the present study, the anticancer effect of vitamin D (VD) combined with TMZ upon glioblastoma was determined, and the underlying mechanism of this effect was identified. Through cell viability, clonogenic and wound healing assays, the current study demonstrated that treatment of a C6 glioblastoma cell line with TMZ and VD resulted in significantly increased in vitro antitumor effects compared with either VD or TMZ alone. Autophagy, hypothesized to be the dominant mechanism underlying TMZ-based tumor cell death, was maximally activated in TMZ and VD co-treated C6 cells. This was demonstrated by ultrastructural observations of autophagosomes, increased size and number of microtubule-associated protein 1 light chain 3 (LC3) puncta and increased conversion of LC3-I to LC3-II. However, the extent of apoptosis was not significantly different between cells treated with TMZ and VD and those treated with TMZ alone. Addition of the autophagy inhibitor 3-methyladenine markedly inhibited the anticancer effect of TMZ and VD treatment, indicating that the chemosensitizing effect of VD in TMZ-based glioblastoma therapy is generated through enhancement of cytotoxic autophagy. TMZ and VD co-treatment also significantly inhibited tumor progression and prolonged survival duration in rat glioblastoma orthotopic xenograft models when compared with TMZ treatment alone. These in vivo results are concordant with the aforementioned in vitro results, together revealing that the combined use of TMZ and VD exerts synergistic antitumor effects on rat models of glioblastoma and may represent an effective therapeutic strategy. PMID:27313664

  1. A New Epigenetic Mechanism of Temozolomide Action in Glioma Cells

    PubMed Central

    Barciszewska, Anna-Maria; Gurda, Dorota; Głodowicz, Paweł; Nowak, Stanisław; Naskręt-Barciszewska, Mirosława Z

    2015-01-01

    Temozolomide (TMZ) is an oral alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma (GBM). Despite that high TMZ potential, progression of disease and recurrence are still observed. Therefore a better understanding of the mechanism of action of this drug is necessary and may allow more durable benefit from its anti-glioma properties. Using nucleotide post-labelling method and separation on thin-layer chromatography we measured of global changes of 5-methylcytosine (m5C) in DNA of glioma cells treated with TMZ. Although m5C is not a product of TMZ methylation reaction of DNA, we analysed the effects of the drug action on different glioma cell lines through global changes at the level of the DNA main epigenetic mark. The first effect of TMZ action we observed is DNA hypermethylation followed by global demethylation. Therefore an increase of DNA methylation and down regulation of some genes expression can be ascribed to activation of DNA methyltransferases (DNMTs). On the other hand hypomethylation is induced by oxidative stress and causes uncontrolled expression of pathologic protein genes. The results of brain tumours treatment with TMZ suggest the new mechanism of modulation epigenetic marker in cancer cells. A high TMZ concentration induced a significant increase of m5C content in DNA in the short time, but a low TMZ concentration at longer time hypomethylation is observed for whole range of TMZ concentrations. Therefore TMZ administration with low doses of the drug and short time should be considered as optimal therapy. PMID:26309255

  2. Comparative Analysis of Matrix Metalloproteinase Family Members Reveals That MMP9 Predicts Survival and Response to Temozolomide in Patients with Primary Glioblastoma

    PubMed Central

    Cai, Jinquan; Sun, Ying; Wang, Guangzhi; Li, Yongli; Li, Ruiyan; Feng, Yan; Han, Bo; Li, Jianlong; Tian, Yu; Yi, Liye; Jiang, Chuanlu

    2016-01-01

    Background Glioblastoma multiform (GBM) is the most common malignant primary brain tumor in adults. Radiotherapy plus concomitant and adjuvant TMZ chemotherapy is the current standard of care for patients with GBM. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are key modulators of tumor invasion and metastasis due to their ECM degradation capacity. The aim of the present study was to identify the most informative MMP member in terms of prognostic and predictive ability for patients with primary GBM. Method The mRNA expression profiles of all MMP genes were obtained from the Chinese Glioma Genome Atlas (CGGA), the Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the GSE16011 dataset. MGMT methylation status was also examined by pyrosequencing. The correlation of MMP9 expression with tumor progression was explored in glioma specimens of all grades. Kaplan–Meier analysis and Cox proportional hazards regression models were used to investigate the association of MMP9 expression with survival and response to temozolomide. Results MMP9 was the only significant prognostic factor in three datasets for primary glioblastoma patients. Our results indicated that MMP9 expression is correlated with glioma grade (p<0.0001). Additionally, low expression of MMP9 was correlated with better survival outcome (OS: p = 0.0012 and PFS: p = 0.0066), and MMP9 was an independent prognostic factor in primary GBM (OS: p = 0.027 and PFS: p = 0.032). Additionally, the GBM patients with low MMP9 expression benefited from temozolomide (TMZ) chemotherapy regardless of the MGMT methylation status. Conclusions Patients with primary GBMs with low MMP9 expression may have longer survival and may benefit from temozolomide chemotherapy. PMID:27022952

  3. Six-month progression-free survival as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma patients receiving temozolomide

    PubMed Central

    Polley, Mei-Yin C.; Lamborn, Kathleen R.; Chang, Susan M.; Butowski, Nicholas; Clarke, Jennifer L.; Prados, Michael

    2010-01-01

    We assessed six-month progression-free survival (PFS) as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma multiforme (GBM) patients receiving temozolomide (TMZ). A total of 183 patients with newly diagnosed GBM enrolled in 3 phase II protocols at the University of California–San Francisco were included. Patients were treated with interventions based on the Stupp regimen, each with the added component of a second oral agent given concurrently with radiotherapy and TMZ, followed by its coadministration with adjuvant TMZ. We examined whether progression status at 2, 4, and 6 months predicted subsequent survival using the landmark analysis. The hazard ratios of death as a function of progression status were estimated based on the Cox proportional hazards model after adjustment for putative prognostic factors. Progression status at 2, 4, and 6 months were all consistently found to be strong predictors of subsequent survival in all studies. The study-specific hazard ratios associated with progression status at 6 months ranged from 2.03 to 3.39. The hazard ratios associated with the earlier time points (2- and 4-month progression) all exceeded 2 in magnitude, ranging from 2.29 to 4.73. P-values were statistically significant for all time points. In this report, we demonstrated a strong association between the endpoints of PFS at 2, 4, and 6 months and survival. Patients who showed the signs of early progression were at significantly higher risk of earlier death. Our analysis suggests that 6-month PFS may be an appropriate primary endpoint in the context of phase II upfront GBM trials in the TMZ era. PMID:20167815

  4. Role of Evaluating MGMT Status and 1p36 Deletion in Radiosurgery-Induced Anaplastic Ependymoma That Rapidly and Completely Resolved by Temozolomide Alone: Case Report and Review of the Literature.

    PubMed

    Hirono, Seiichiro; Iwadate, Yasuo; Kambe, Michiyo; Hiwasa, Takaki; Takiguchi, Masaki; Nakatani, Yukio; Saeki, Naokatsu

    2015-07-01

    Stereotactic gamma knife surgery (GKS)-induced brain tumors are extremely rare, and no ependymal tumors induced by GKS have been reported. Therefore, little is known about their clinical, pathologic, and genetic features. In addition, a regimen of adjuvant chemotherapy for anaplastic ependymoma (AE) has not been established. A 77-year-old man presented with a gait disturbance and left-side cerebellar ataxia more than 19 years after GKS performed for a cerebellar arteriovenous malformation. Imaging studies demonstrated an enhancing mass in the irradiated field with signs of intraventricular dissemination. Surgical resection confirmed the diagnosis of AE. Temozolomide (TMZ) was administrated postoperatively because the methylated promoter region of O(6)-methylguanine-DNA methyltransferase (MGMT) and 1p36 deletion were observed. Surprisingly, images 16 days after TMZ initiation demonstrated a complete resolution of the residual tumor that was maintained after three cycles of TMZ. This first case report of GKS-induced AE emphasizes the importance of genetic evaluation of MGMT and chromosomal deletion of 1p36 that are not commonly performed in primary ependymal tumors. In addition, it is speculated that a GKS-induced tumor may have a different genetic background compared with the primary tumor because the pathogenesis of the tumors differed.

  5. Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting—Ideal Versus Reality

    PubMed Central

    Lee, Chooi Yeng; Ooi, Ing Hong

    2016-01-01

    Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ’s efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach. PMID:27618068

  6. Temozolomide may induce cell cycle arrest by interacting with URG4/URGCP in SH-SY5Y neuroblastoma cells.

    PubMed

    Çıtışlı, Veli; Dodurga, Yavuz; Eroğlu, Canan; Seçme, Mücahit; Avcı, Çığır Biray; Şatıroğlu-Tufan, N Lale

    2015-09-01

    Temozolomide (TMZ) is an alkylating drug used usually in glioma treatment by inducing the apoptosis in glioma cell. The aim of the study is to investigate the anticancer mechanism of TMZ in SH-SY5Y human neuroblastoma cell line. Cytotoxic effects of TMZ were determined by using XTT assay. IC50 doses in the SH-SY5Y were detected as 5 mM. Expression profiles of novel genes URG4/URGCP, CCND1, CCND2, CDK4, and BCL2 were determined by real-time PCR. The apoptotic effects of TMZ were evaluated with TUNEL method. Furthermore, effects of TMZ on colony formation and invasion were investigated in this study. It was observed that TMZ in SH-SY5Y cell line caused a significant decrease in the gene expressions of URG4/URGCP, CCND1, CCND2, CDK4, and BCL2. According to TUNEL assay results, TMZ markedly induced apoptosis in SH-SY5Y cell line. It was found that TMZ in SH-SY5Y cell line suppressed invasion and colony formation using matrigel invasion chamber and colony formation assay, respectively. To conclude, it is thought that TMZ demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis, invasion, and colony formation on SH-SY5Y cells. TMZ may be an effective agent for treatment of neuroblastoma as a single or in combination with other drugs.

  7. Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression.

    PubMed

    Lan, Fengming; Yang, Yang; Han, Jing; Wu, Qiaoli; Yu, Huiming; Yue, Xiao

    2016-02-01

    The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN. PMID:26648123

  8. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide

    PubMed Central

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma. PMID:27698831

  9. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide

    PubMed Central

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-01-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.

  10. Effect of temozolomide on the viability of musculoskeletal sarcoma cells

    PubMed Central

    KUSABE, YUTA; KAWASHIMA, HIROYUKI; OGOSE, AKIRA; SASAKI, TARO; ARIIZUMI, TAKASHI; HOTTA, TETSUO; ENDO, NAOTO

    2015-01-01

    Musculoskeletal sarcomas (MSS) are a heterogeneous group of malignancies with relatively high mortality rates. The prognosis for patients with MSS is poor, with few drugs inducing measurable activity. Alkylating agents, namely ifosfamide and dacarbazine, which act nonspecifically on proliferating cells, are the typical therapy prescribed for advanced MSS. A novel alkylating agent, temozolomide (TMZ), has several advantages over existing alkylating agents. TMZ induces the formation of O6-methylguanine in DNA, thereby inducing mismatches during DNA replication and the subsequent activation of apoptotic pathways. However, due to conflicting data in the literature, the mechanism of TMZ action has remained elusive. Therefore, the present study aimed to evaluate apoptosis in MSS cells treated with TMZ, and to evaluate the correlation between TMZ action and survival pathways, including the phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 mitogen activated protein kinase (MAPK) pathways. Cell proliferation was evaluated by performing an XTT (sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate) assay. Apoptotic morphological changes, for example chromatin condensation, were evaluated by fluorescence confocal microscopy. The expression of the apoptosis-associated proteins caspase-3, poly adenosine diphosphate ribose polymerase (PARP), Akt and ERK1/2, was determined by western blotting. The results of the present study indicated that, in certain MSS cells, the IC50 value was lower than that in TMZ-sensitive U-87 MG cells. Furthermore, TMZ treatment was associated with apoptotic morphological changes and the expression levels of pro-apoptotic cleaved caspase-3 and PARP were also increased in TMZ-treated MSS cells. In addition, the results indicated that PI3K/Akt and ERK1/2 MAPK were constitutively phosphorylated in MSS cells, and phosphorylation of PI3K/Akt was suppressed in certain

  11. Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide

    PubMed Central

    Wang, Hai; Feng, Wenfeng; Lu, Yuntao; Li, Hezhen; Xiang, Wei; Chen, Ziyang; He, Minyi; Zhao, Liang; Sun, Xuegang; Lei, Bingxi; Qi, Songtao; Liu, Yawei

    2016-01-01

    Temozolomide (TMZ) is the main chemotherapeutic drug utilized for the treatment of glioblastoma multiforme (GMB), however, drug resistance often leads to tumor recurrence and poor outcomes. GMB cell lines were treated with TMZ for up to two weeks and then subjected to proteomics analysis to identify the underlying molecular pathology that is associated with TMZ resistance. Proteomics data showed that TMZ altered expression of proteins that related to cytoskeleton structure and function, such as DHC2 and KIF2B. qRT-PCR and immunofluorescence were used to verify expression of DHC2 and KIF2B in these cells. Immunohistochemistry was used to verify expression of these two proteins in xenografts of a nude mouse model, and ex vivo GBM tissue samples. Their expression was knocked down using siRNA to confirm their role in the regulation of GBM cell sensitivity to TMZ. Knockdown of DHC2 expression enhanced sensitivity of U87 cells to TMZ treatment. Ex vivo data showed that DHC2 expression in GBM tissue samples was associated with tumor recurrence after TMZ chemotherapy. These results indicated cytoskeleton related protein DHC2 reduced sensitivity of GBM cells to TMZ treatment. Further studies should assess DHC2 as a novel target in GBM for TMZ combination treatment. PMID:27375225

  12. Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide.

    PubMed

    Wang, Hai; Feng, Wenfeng; Lu, Yuntao; Li, Hezhen; Xiang, Wei; Chen, Ziyang; He, Minyi; Zhao, Liang; Sun, Xuegang; Lei, Bingxi; Qi, Songtao; Liu, Yawei

    2016-01-01

    Temozolomide (TMZ) is the main chemotherapeutic drug utilized for the treatment of glioblastoma multiforme (GMB), however, drug resistance often leads to tumor recurrence and poor outcomes. GMB cell lines were treated with TMZ for up to two weeks and then subjected to proteomics analysis to identify the underlying molecular pathology that is associated with TMZ resistance. Proteomics data showed that TMZ altered expression of proteins that related to cytoskeleton structure and function, such as DHC2 and KIF2B. qRT-PCR and immunofluorescence were used to verify expression of DHC2 and KIF2B in these cells. Immunohistochemistry was used to verify expression of these two proteins in xenografts of a nude mouse model, and ex vivo GBM tissue samples. Their expression was knocked down using siRNA to confirm their role in the regulation of GBM cell sensitivity to TMZ. Knockdown of DHC2 expression enhanced sensitivity of U87 cells to TMZ treatment. Ex vivo data showed that DHC2 expression in GBM tissue samples was associated with tumor recurrence after TMZ chemotherapy. These results indicated cytoskeleton related protein DHC2 reduced sensitivity of GBM cells to TMZ treatment. Further studies should assess DHC2 as a novel target in GBM for TMZ combination treatment.

  13. Minor changes in expression of the mismatch repair protein MSH2 exert a major impact on glioblastoma response to temozolomide

    PubMed Central

    McFaline-Figueroa, José L.; Braun, Christian J.; Stanciu, Monica; Nagel, Zachary D.; Mazzucato, Patrizia; Sangaraju, Dewakar; Cerniauskas, Edvinas; Barford, Kelly; Vargas, Amanda; Chen, Yimin; Tretyakova, Natalia; Lees, Jacqueline A.; Hemann, Michael T.; White, Forest M.; Samson, Leona D.

    2015-01-01

    Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide (TMZ) but the disease inevitably recurs in a drug-resistant form after initial treatment. Here we report that in GBM cells even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on TMZ sensitivity. RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of TMZ resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress TMZ-induced tumor regression. Using the Cancer Genome Atlas to analyze mRNA expression patterns in tumors from TMZ-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial TMZ therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades TMZ sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of TMZ resistance, and argue that MMR activity offers a predictive marker for initial therapeutic response to TMZ treatment. PMID:26025730

  14. Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

    SciTech Connect

    Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

    2007-11-15

    Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated {gamma}-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of {gamma}-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 {mu}mol/L (AMC-3046), 3 {mu}mol/L (VU-109), and 2.5 {mu}mol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to {gamma}-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gen000.

  15. Pulsed Versus Conventional Radiation Therapy in Combination With Temozolomide in a Murine Orthotopic Model of Glioblastoma Multiforme

    SciTech Connect

    Lee, David Y.; Chunta, John L.; Park, Sean S.; Huang, Jiayi; Martinez, Alvaro A.; Grills, Inga S.; Krueger, Sarah A.; Wilson, George D.; Marples, Brian

    2013-08-01

    Purpose: To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model. Methods and Materials: Orthotopic U87MG hGBM tumors were established in Nu-Foxn1{sup nu} mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry. Results: Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ. Conclusions: PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM.

  16. Cytotoxic Effects of Temozolomide and Radiation are Additive- and Schedule-Dependent

    SciTech Connect

    Chalmers, Anthony J.; Ruff, Elliot M.; Martindale, Christine; Lovegrove, Nadia; Short, Susan C.

    2009-12-01

    Purpose: Despite aggressive therapy comprising radical radiation and temozolomide (TMZ) chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor, particularly if tumors express O{sup 6}-methylguanine-DNA-methyltransferase (MGMT). The interactions between radiation and TMZ remain unclear and have important implications for scheduling and for developing strategies to improve outcomes. Methods and Materials: Factors determining the effects of combination therapy on clonogenic survival, cell-cycle checkpoint signaling and DNA repair were investigated in four human glioma cell lines (T98G, U373-MG, UVW, U87-MG). Results: Combining TMZ and radiation yielded additive cytotoxicity, but only when TMZ was delivered 72 h before radiation. Radiosensitization was not observed. TMZ induced G2/M cell-cycle arrest at 48-72 h, coincident with phosphorylation of Chk1 and Chk2. Additive G2/M arrest and Chk1/Chk2 phosphorylation was only observed when TMZ preceded radiation by 72 h. The ataxia-telangiectasia mutated (ATM) inhibitor KU-55933 increased radiation sensitivity and delayed repair of radiation-induced DNA breaks, but did not influence TMZ effects. The multiple kinase inhibitor caffeine enhanced the cytotoxicity of chemoradiation and exacerbated DNA damage. Conclusions: TMZ is not a radiosensitizing agent but yields additive cytotoxicity in combination with radiation. Our data indicate that TMZ treatment should commence at least 3 days before radiation to achieve maximum benefit. Activation of G2/M checkpoint signaling by TMZ and radiation has a cytoprotective effect that can be overcome by dual inhibition of ATM and ATR. More specific inhibition of checkpoint signaling will be required to increase treatment efficacy without exacerbating toxicity.

  17. Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models

    PubMed Central

    Cen, Ling; Carlson, Brett L.; Pokorny, Jenny L.; Mladek, Ann C.; Grogan, Patrick T.; Schroeder, Mark A.; Decker, Paul A.; Anderson, S. Keith; Giannini, Caterina; Wu, Wenting; Ballman, Karla V.; Kitange, Gaspar J.; Sarkaria, Jann N.

    2013-01-01

    Background Temozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear. Methods The efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model. Results Protracted TMZ therapy (TMZ daily M–F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O6-DNA methylguanine-methyltransferase (MGMT) promoter hypermethylated lines (GBM12) and none of the 3 MGMT unmethylated lines, while standard therapy (TMZ daily M–F, 1 wk every 4) provided superior survival to the placebo-treated group in 2 of 3 MGMT unmethylated lines (GBM14 and GBM43) and none of the methylated lines. In comparing GBM12, GBM14, and GBM43 intracranial specimens, both GBM14 and GBM43 mice treated with protracted TMZ had a significant elevation in MGMT levels compared with placebo. Similarly, high MGMT was found in a second model of acquired TMZ resistance in GBM14 flank xenografts, and resistance was reversed in vitro by treatment with the MGMT inhibitor O6-benzylguanine, demonstrating a mechanistic link between MGMT overexpression and TMZ resistance in this line. Additionally, in an analysis of gene expression data, comparison of parental and TMZ-resistant GBM14 demonstrated enrichment of functional ontologies for cell cycle control within the S, G2, and M phases of the cell cycle and DNA damage checkpoints. Conclusions Across the 7 tumor models studied, there was no consistent difference between protracted and standard TMZ regimens. The efficacy of protracted TMZ regimens may be limited in a subset of MGMT unmethylated tumors by induction of MGMT expression. PMID:23479134

  18. p53 Small Molecule Inhibitor Enhances Temozolomide Cytotoxic Activity against Intracranial Glioblastoma Xenografts

    PubMed Central

    Dinca, Eduard B.; Lu, Kan V.; Sarkaria, Jann N.; Pieper, Russell O.; Prados, Michael D.; Haas-Kogan, Daphne A.; VandenBerg, Scott R.; Berger, Mitchel S.; James, C. David

    2010-01-01

    In this study we investigated corresponding precursor and active forms of a p53 small molecule inhibitor for effect on temozolomide (TMZ) anti-tumor activity against glioblastoma (GBM), using both in vitro and in vivo experimental approaches. Results from in vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased when GBMs with wild-type p53 were co-treated with the active form of p53 inhibitor, and this heightened cytotoxic response was accompanied by increased PARP cleavage as well as elevated cellular phospho-H2AX. Analysis of the same series of GBMs, as intracranial xenografts in athymic mice, and administering corresponding p53 inhibitor precursor, that is converted to the active compound in vivo, yielded results consistent with the in vitro analyses: i.e., TMZ + p53 inhibitor precursor co-treatment, of three distinct wild-type p53 GBM xenografts, resulted in significant enhancement of TMZ anti-tumor effect relative to treatment with TMZ alone, as indicated by serial bioluminescence monitoring as well as survival analysis (p < 0.001 for co-treatment survival benefit in each case). Mice receiving intracranial injection with p53 null GBM showed similar survival benefit from TMZ treatment regardless of the presence or absence of p53 inhibitor precursor. In total, our results indicate that the p53 active and precursor inhibitor pair enhance TMZ cytotoxicity in vitro and in vivo, respectively, and do so in a p53-dependent manner. PMID:19074867

  19. Optimizing Glioblastoma Temozolomide Chemotherapy Employing Lentiviral-based Anti-MGMT shRNA Technology

    PubMed Central

    Viel, Thomas; Monfared, Parisa; Schelhaas, Sonja; Fricke, Inga B; Kuhlmann, Michael T; Fraefel, Cornel; Jacobs, Andreas H

    2013-01-01

    Despite treatments combining surgery, radiation-, and chemotherapy, patients affected by glioblastoma (GBM) have a limited prognosis. Addition of temozolomide (TMZ) to radiation therapy is the standard therapy in clinical application, but effectiveness of TMZ is limited by the tumor's overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). The goal of this study was to use the highly specific and efficient RNA interference (RNAi) pathway to modulate MGMT expression to increase TMZ efficiency in chemotherapy resistant GBM. Using lentiviral-based anti-MGMT small hairpin RNA (shRNA) technology we observed a specific inhibition of the MGMT expression in GBM cell lines as well as in subcutaneous tumors. Tumor growth inhibition was observed following TMZ treatment of xenografts with low MGMT expression in contrast to xenografts with high MGMT expression. Bioluminescence imaging (BLI) measurements indicated that luciferase and shRNA-expressing lentiviruses were able to efficiently transduce the GBM xenografts in vivo. Treatment combining injection of a lentivirus expressing an anti-MGMT shRNA and TMZ induced a reduction of the size of the tumors, in contrast with treatment combining the lentivirus expressing the control shRNA and TMZ. Our data suggest that anti-MGMT shRNA therapy could be used in combination with TMZ chemotherapy in order to improve the treatment of resistant GBM. PMID:23319055

  20. p53 Small-molecule inhibitor enhances temozolomide cytotoxic activity against intracranial glioblastoma xenografts.

    PubMed

    Dinca, Eduard B; Lu, Kan V; Sarkaria, Jann N; Pieper, Russell O; Prados, Michael D; Haas-Kogan, Daphne A; Vandenberg, Scott R; Berger, Mitchel S; James, C David

    2008-12-15

    In this study, we investigated the precursor and active forms of a p53 small-molecule inhibitor for their effects on temozolomide (TMZ) antitumor activity against glioblastoma (GBM), using both in vitro and in vivo experimental approaches. Results from in vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased when p53 wild-type (p53(wt)) GBMs were cotreated with the active form of p53 inhibitor, and this heightened cytotoxic response was accompanied by increased poly(ADP-ribose) polymerase cleavage as well as elevated cellular phospho-H2AX. Analysis of the same series of GBMs, as intracranial xenografts in athymic mice, and administering corresponding p53 inhibitor precursor, which is converted to the active compound in vivo, yielded results consistent with the in vitro analyses: TMZ + p53 inhibitor precursor cotreatment of three distinct p53(wt) GBM xenografts resulted in significant enhancement of TMZ antitumor effect relative to treatment with TMZ alone, as indicated by serial bioluminescence monitoring as well as survival analysis (P < 0.001 for cotreatment survival benefit in each case). Mice receiving intracranial injection with p53(null) GBM showed similar survival benefit from TMZ treatment regardless of the presence or absence of p53 inhibitor precursor. In total, our results indicate that the p53 active and precursor inhibitor pair enhances TMZ cytotoxicity in vitro and in vivo, respectively, and do so in a p53-dependent manner.

  1. Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis.

    PubMed

    Hiddingh, Lotte; Raktoe, Rajiv S; Jeuken, Judith; Hulleman, Esther; Noske, David P; Kaspers, Gertjan J L; Vandertop, W Peter; Wesseling, Pieter; Wurdinger, Thomas

    2014-01-01

    Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma.

  2. Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis

    PubMed Central

    Hiddingh, Lotte; Raktoe, Rajiv S.; Jeuken, Judith; Hulleman, Esther; Noske, David P.; Kaspers, Gertjan J. L.; Vandertop, W. Peter; Wesseling, Pieter; Wurdinger, Thomas

    2014-01-01

    Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma. PMID:24919120

  3. Ursolic acid attenuates temozolomide resistance in glioblastoma cells by downregulating O6-methylguanine-DNA methyltransferase (MGMT) expression

    PubMed Central

    Zhu, Zhongling; Du, Shuangshuang; Ding, Fengxia; Guo, Shanshan; Ying, Guoguang; Yan, Zhao

    2016-01-01

    The DNA-alkylating agent temozolomide (TMZ) is an effective chemotherapeutic agent against malignant glioma, including glioblastoma multiforme (GBM). However, the clinical efficacy of TMZ is limited in many patients because of O6-methylguanine-DNA methyltransferase (MGMT)-driven resistance. Thus, new strategies to overcome TMZ resistance are urgently needed. Ursolic acid (UA) is a naturally derived pentacyclic triterpene acid that exerts broad anticancer effects, and shows capability to cross the blood-brain barrier. In this study, we evaluated the possible synergistic effect of TMZ and UA in resistant GBM cell lines. The results showed that UA prevented the proliferation of resistant GBM cells in a concentration-dependent manner. Compared with TMZ or UA treatment alone, the combination treatment of TMZ and UA synergistically enhanced cytotoxicity and senescence in TMZ-resistant GBM cells. This effect was correlated with the downregulation of MGMT. Moreover, experimental results with an in vivo mouse xenograft model showed that the combination treatment of UA and TMZ reduced tumor volumes by depleting MGMT. Therefore, UA as both a monotherapy and a resensitizer, might be a candidate agent for patients with refractory malignant gliomas. PMID:27508051

  4. A Phase I Trial of Tipifarnib With Radiation Therapy, With and Without Temozolomide, for Patients With Newly Diagnosed Glioblastoma

    SciTech Connect

    Nghiemphu, Phioanh Leia; Wen, Patrick Y.; Drappatz, Jan; Fink, Karen; Malkin, Mark G.; Lieberman, Frank S.; DeAngelis, Lisa M.; Torres-Trejo, Alejandro; Chang, Susan M.; Abrey, Lauren; Fine, Howard A.; Demopoulos, Alexis; Lassman, Andrew B.; Kesari, Santosh; Prados, Michael D.; Cloughesy, Timothy F.

    2011-12-01

    Purpose: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. Patients and Methods: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Results: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. Conclusion: Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.

  5. A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma

    PubMed Central

    Nghiemphu, Phioanh Leia; Wen, Patrick Y.; Lamborn, Kathleen R.; Drappatz, Jan; Robins, H. Ian; Fink, Karen; Malkin, Mark G.; Lieberman, Frank S.; DeAngelis, Lisa M.; Torres-Trejo, Alejandro; Chang, Susan M.; Abrey, Lauren; Fine, Howard A.; Demopoulos, Alexis; Lassman, Andrew B.; Kesari, Santosh; Mehta, Minesh P.; Prados, Michael D.; Cloughesy, Timothy F.

    2010-01-01

    Purpose To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy (RT) for patients with newly diagnosed glioblastoma (GBM). MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A - patients not receiving EIAED and not receiving TMZ; Group A-TMZ - patients not on EIAED, and on treatment with TMZ; Group B – any patients receiving EIAED, but no TMZ. Methods and Materials After diagnostic surgery or biopsy, treatment with tipifarnib started 5–9 days before initiating RT, twice daily, in four-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Results Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, 20 patients in Group B. In Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg bid with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. DLTs included rash and 1 intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at one year. Conclusion Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed GBM and not on EIAED. PMID:20934264

  6. Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients

    PubMed Central

    Koch, Cameron J.; Lustig, Robert A.; Yang, Xiang-Yang; Jenkins, Walter T.; Wolf, Ronald L.; Martinez-Lage, Maria; Desai, Arati; Williams, Dewight; Evans, Sydney M.

    2014-01-01

    The standard of care for glioblastoma (GB) is surgery followed by concurrent radiation therapy (RT) and temozolomide (TMZ) and then adjuvant TMZ. This regime is associated with increased survival but also increased occurrence of equivocal imaging findings, e.g., tumor progression (TP) versus treatment effect (TE), which is also referred to as pseudoprogression (PsP). Equivocal findings make decisions regarding further treatment difficult and often delayed. Because none of the current imaging assays have proven sensitive and specific for differentiation of TP versus TE/PsP, we investigated whether blood-derived microvesicles (MVs) would be a relevant assay. METHODS: 2.8 ml of citrated blood was collected from patients with GB at the time of their RT simulation, at the end of chemoradiation therapy (CRT), and multiple times following treatment. MVs were collected following multiple centrifugations (300g, 2500g, and 15,000g). The pellet from the final spin was analyzed using flow cytometry. A diameter of approximately 300 nm or greater and Pacific Blue–labeled Annexin V positivity were used to identify the MVs reported herein. RESULTS: We analyzed 19 blood samples from 11 patients with GB. MV counts in the patients with stable disease or TE/PsP were significantly lower than patients who developed TP (P = .014). CONCLUSION: These preliminary data suggest that blood analysis for MVs from GB patients receiving CRT may be useful to distinguish TE/PsP from TP. MVs may add clarity to standard imaging for decision making in patients with equivocal imaging findings. PMID:25500085

  7. Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

    SciTech Connect

    Weiler, Markus; Hartmann, Christian; Wiewrodt, Dorothee; Herrlinger, Ulrich

    2010-07-01

    Purpose: To evaluate the toxicity and efficacy of chemoradiotherapy with temozolomide (TMZ) administered in an intensified 1-week on/1-week off schedule plus indomethacin in patients with newly diagnosed glioblastoma. Patients and Methods: A total of 41 adult patients (median Karnofsky performance status, 90%; median age, 56 years) were treated with preirradiation TMZ at 150 mg/m{sup 2} (1 week on/1 week off), involved-field radiotherapy combined with concomitant low-dose TMZ (50 mg/m{sup 2}), maintenance TMZ starting at 150 mg/m{sup 2} using a 1-week on/1-week off schedule, plus maintenance indomethacin (25 mg twice daily). Results: The median follow-up interval was 21.7 months. Grade 4 hematologic toxicity was observed in 15 patients (36.6%). Treatment-related nonhematologic Grade 4-5 toxicity was reported for 2 patients (4.9%). The median progression-free survival was 7.6 months (95% confidence interval, 6.2-10.4). The 1-year survival rate was 73.2% (95% confidence interval, 56.8-84.2%). The presence of O{sup 6}-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was associated with significantly superior progression-free survival. Conclusion: The dose-dense regimen of TMZ administered in a 1-week on/1-week off schedule resulted in acceptable nonhematologic toxicity. Compared with data from the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981-22981/CE.3, patients with an unmethylated MGMT gene promoter appeared not to benefit from intensifying the TMZ schedule regarding the median progression-free survival and overall survival. In contrast, data are promising for patients with a methylated MGMT promoter.

  8. Thymoquinone synergistically potentiates temozolomide cytotoxicity through the inhibition of autophagy in U87MG cell line

    PubMed Central

    Pazhouhi, Mona; Sariri, Reyhaneh; Rabzia, Arezou; Khazaei, Mozafar

    2016-01-01

    Objective(s): Glioblastoma multiforme (GBM) is one of the most lethal forms of human cancer and temozolomide (TMZ) is currently part of the standard treatment for this disease. Combination therapy using natural substances can enhance the anti-cancer activity of TMZ. The purpose of this study was to evaluate the effect of TMZ in combination with thymoquinone (TQ) on human GBM cell line (U87MG). Materials and Methods: The cell line was treated with TMZ and/or TQ. Cell viability was assessed using trypan blue and MTT assay. The effect of TMZ and/or TQ on colony-forming ability of the cells was investigated. Apoptosis and autophagy were quantified by fluorescent dye staining. The expression level of two autophagy related genes (ATG) were assessed using RT-PCR. Furthermore, nitric oxide (NO) production was detected by Griess reaction. Results: After treatment with TMZ and/or TQ, the cell viability was reduced in a time- and dose-dependent manner, and the cell survival fraction (SF) was significantly decreased (P=0.000). Apoptosis index of U87MG cells was also significantly increased (P=0.000). Autophagy was significantly increased by TMZ (P=0.000) and decreased by TQ (P=0.018). Also TMZ and/or TQ significantly decreased NO production by U87MG cell (P=0.000). Conclusion: TQ enhanced the anti-cancer activity of TMZ by inhibition of autophagy at the transcriptional level and decreased the colony-forming ability and NO production of U87MG cell line. PMID:27746872

  9. Continuous Low-Dose Temozolomide Chemotherapy and Microvessel Density in Recurrent Glioblastoma

    PubMed Central

    Woo, Jong-Yun; Yang, Seung Ho; Lee, Youn Soo; Lee, Su Youn; Kim, Jeana

    2015-01-01

    Objective The purpose of this study was to evaluate the clinical efficacy of continuous low-dose temozolomide (TMZ) chemotherapy for recurrent and TMZ-refractory glioblastoma multiforme (GBM) and to study the relationship between its efficacy and microvessel density within the tumor. Methods Thirty patients who had recurrent GBM following Stupp's regimen received TMZ daily at 50 mg/m2/day until tumor progression between 2007 and 2013. The median duration of continuous low-dose TMZ administration was 8 weeks (range, 2-64). Results The median progression-free survival (PFS) of continuous low-dose TMZ therapy was 2 months (range, 0.5-16). At 6 months, PFS was 20%. The median overall survival (OS) from the start of this therapy to death was 6 months (95% CI : 5.1-6.9). Microvessel density of recurrent tumor tissues obtained by reoperation of 17 patients was 22.7±24.1/mm2 (mean±standard deviation), and this was lower than that of the initial tumor (61.4±32.7/mm2) (p-value=0.001). It suggests that standard TMZ-chemoradiotherapy reduces the microvessel density within GBM and that recurrences develop in tumor cells with low metabolic burden. The efficacy of continuous low-dose TMZ could not be expected in recurrent GBM cells in poor angiogenic environments. Conclusion The efficacy of continuous low-dose TMZ chemotherapy is marginal. This study suggests the need to develop further treatment strategies for recurrent and TMZ-refractory GBM. PMID:26713142

  10. Tumor stroma and chemokines control T-cell migration into melanoma following Temozolomide treatment

    PubMed Central

    Tan, Kar Wai; Evrard, Maximilien; Tham, Muly; Hong, Michelle; Huang, Caleb; Kato, Masashi; Prevost-Blondel, Armelle; Donnadieu, Emmanuel; Ng, Lai Guan; Abastado, Jean-Pierre

    2015-01-01

    The infiltration of T lymphocytes within tumors is associated with better outcomes in cancer patients, yet current understanding of factors that influence T-lymphocyte infiltration into tumors remains incomplete. In our study, Temozolomide (TMZ), a chemotherapeutic drug used to treat metastatic melanoma, induced T-cell infiltration into transplanted melanoma and into genitourinary (GU) tumors in mice developing spontaneous melanoma. In contrast, TMZ treatment did not increase T-cell infiltration into cutaneous tumors, despite similar increases in the expression of the (C-X-C) chemokines CXCL9 and CXCL10 in all sites after TMZ exposure. Our findings reveal that the matrix architecture of the GU tumor stroma, and its ability to present CXCL9 and CXCL10 after TMZ treatment played a key role in favouring T-cell infiltration. We subsequently demonstrate that modifications of these key elements by combined collagenase and TMZ treatment induced T-cell infiltration into skin tumors. T cells accumulating within GU tumors after TMZ treatment exhibited T helper type-1 effector and cytolytic functional phenotypes, which are important for control of tumor growth. Our findings highlight the importance of the interaction between tumor stroma and chemokines in influencing T-cell migration into tumors, thereby impacting immune control of tumor growth. This knowledge will aid the development of strategies to promote T-cell infiltration into cancerous lesions and has the potential to markedly improve treatment outcomes. PMID:25949877

  11. MiR-16 modulate temozolomide resistance by regulating BCL-2 in human glioma cells

    PubMed Central

    Han, Jing; Chen, Qianxue

    2015-01-01

    Temozolomide (TMZ) with radiotherapy is the current standard of care for newly diagnosed glioma. However, glioma patients who are treated with the drug often develop resistance to it and some other drugs. Recently studies have shown that microRNAs (miRNAs) play an important role in drug resistance. In present study, we first examined the sensitivity to temozolomide in six glioma cell lines, and established a resistant variant, U251MG/TR cells from TMZ-sensitive glioma cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251MG/TR and parental cells using cancer microRNA PCR Array. Among the downregulated microRNAs was miR-16, members of miR-15/16 family, whose expression was further validated by qRT-PCR in U251MG/TR and U251MG cells. The selective microRNA, miR-16 mimics or inhibitor was respectively transfected into U251MG/TR cells and AM38 cell. We found that treatment with the mimics of miR-16 greatly decreased the sensitivity of U251MG/TR cells to temozolomide, while sensitivity to these drugs was increased by treatment with the miR-16 inhibitor. In addition, the downregulation of miR-16 in temozolomide-sensitive AM38 cells was concurrent with the upregulation of Bcl-2 protein. Conversely, overexpression of miR-16 in temozolomide-resistant cells inhibited Bcl-2 expression and decreased temozolomide resistance. In conclusion, MiR-16 mediated temozolomide-resistance in glioma cells by modulation of apoptosis via targeting Bcl-2, which suggesting that miR-16 and Bcl-2 would be potential therapeutic targets for glioma therapy. PMID:26722459

  12. MiR-16 modulate temozolomide resistance by regulating BCL-2 in human glioma cells.

    PubMed

    Han, Jing; Chen, Qianxue

    2015-01-01

    Temozolomide (TMZ) with radiotherapy is the current standard of care for newly diagnosed glioma. However, glioma patients who are treated with the drug often develop resistance to it and some other drugs. Recently studies have shown that microRNAs (miRNAs) play an important role in drug resistance. In present study, we first examined the sensitivity to temozolomide in six glioma cell lines, and established a resistant variant, U251MG/TR cells from TMZ-sensitive glioma cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251MG/TR and parental cells using cancer microRNA PCR Array. Among the downregulated microRNAs was miR-16, members of miR-15/16 family, whose expression was further validated by qRT-PCR in U251MG/TR and U251MG cells. The selective microRNA, miR-16 mimics or inhibitor was respectively transfected into U251MG/TR cells and AM38 cell. We found that treatment with the mimics of miR-16 greatly decreased the sensitivity of U251MG/TR cells to temozolomide, while sensitivity to these drugs was increased by treatment with the miR-16 inhibitor. In addition, the downregulation of miR-16 in temozolomide-sensitive AM38 cells was concurrent with the upregulation of Bcl-2 protein. Conversely, overexpression of miR-16 in temozolomide-resistant cells inhibited Bcl-2 expression and decreased temozolomide resistance. In conclusion, MiR-16 mediated temozolomide-resistance in glioma cells by modulation of apoptosis via targeting Bcl-2, which suggesting that miR-16 and Bcl-2 would be potential therapeutic targets for glioma therapy.

  13. Treatment of glioblastoma multiforme cells with temozolomide-BioShuttle ligated by the inverse Diels-Alder ligation chemistry

    PubMed Central

    Braun, Klaus; Wiessler, Manfred; Ehemann, Volker; Pipkorn, Ruediger; Spring, Herbert; Debus, Juergen; Didinger, Bernd; Koch, Mario; Muller, Gabriele; Waldeck, Waldemar

    2008-01-01

    Recurrent glioblastoma multiforme (GBM), insensitive against most therapeutic interventions, has low response and survival rates. Temozolomide (TMZ) was approved for second-line therapy of recurrent anaplastic astrocytoma. However, TMZ therapy in GBM patients reveals properties such as reduced tolerability and inauspicious hemogram. The solution addressed here concerning GBM therapy consolidates and uses the potential of organic and peptide chemistry with molecular medicine. We enhanced the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic TMZ. The TMZ connection to transporter molecules (TMZ-BioShuttle) was investigated, resulting in a much higher pharmacological effect in glioma cell lines and also with reduced dose rate. From this result we can conclude that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The TMZ-BioShuttle dramatically enhanced the potential of TMZ for the treatment of brain tumors and is an attractive drug for combination chemotherapy. PMID:19920915

  14. The synergic antitumor effects of paclitaxel and temozolomide co-loaded in mPEG-PLGA nanoparticles on glioblastoma cells

    PubMed Central

    Li, Yiming; Sun, Ying; Teng, Yanwei; Wang, Yi; Duan, Yourong

    2016-01-01

    To get better chemotherapy efficacy, the optimal synergic effect of Paclitaxel (PTX) and Temozolomide (TMZ) on glioblastoma cells lines was investigated. A dual drug-loaded delivery system based on mPEG-PLGA nanoparticles (NPs) was developed to potentiate chemotherapy efficacy for glioblastoma. PTX/TMZ-NPs were prepared with double emulsification solvent evaporation method and exhibited a relatively uniform diameter of 206.3 ± 14.7 nm. The NPs showed sustained release character. Cytotoxicity assays showed the best synergistic effects were achieved when the weight ratios of PTX to TMZ were 1:5 and 1:100 on U87 and C6 cells, respectively. PTX/TMZ-NPs showed better inhibition effect to U87 and C6 cells than single drug NPs or free drugs mixture. PTX/TMZ-NPs (PTX: TMZ was 1:5(w/w)) significantly inhibited the tumor growth in the subcutaneous U87 mice model. These results indicate that coordinate administration of PTX and TMZ combined with NPs is an efficient method for glioblastoma. PMID:26956046

  15. IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide.

    PubMed

    Ramcharan, Roger; Aleksic, Tamara; Kamdoum, Wilfride Petnga; Gao, Shan; Pfister, Sophia X; Tanner, Jordan; Bridges, Esther; Asher, Ruth; Watson, Amanda J; Margison, Geoffrey P; Woodcock, Mick; Repapi, Emmanouela; Li, Ji-Liang; Middleton, Mark R; Macaulay, Valentine M

    2015-11-24

    Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage. PMID

  16. IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide

    PubMed Central

    Ramcharan, Roger; Aleksic, Tamara; Kamdoum, Wilfride Petnga; Gao, Shan; Pfister, Sophia X.; Tanner, Jordan; Bridges, Esther; Asher, Ruth; Watson, Amanda J.; Margison, Geoffrey P.; Woodcock, Mick; Repapi, Emmanouela; Li, Ji-Liang; Middleton, Mark R.; Macaulay, Valentine M.

    2015-01-01

    Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage. PMID

  17. Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells

    SciTech Connect

    Papait, Roberto; Magrassi, Lorenzo; Rigamonti, Dorotea; Cattaneo, Elena

    2009-02-06

    Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1{alpha} bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.

  18. APE1/REF-1 down-regulation enhances the cytotoxic effects of temozolomide in a resistant glioblastoma cell line.

    PubMed

    Montaldi, Ana P; Godoy, Paulo R D V; Sakamoto-Hojo, Elza T

    2015-11-01

    Temozolomide (TMZ) is widely used for patients with glioblastoma (GBM); however, tumor cells frequently exhibit drug-resistance. Base excision repair (BER) has been identified as a possible mediator of TMZ resistance, and an attractive approach to sensitizing cells to chemotherapy. Human apurinic/apyrimidinic endonuclease/redox factor-1 (APE1) is an essential enzyme with a role in the BER pathway by repairing abasic sites, and it also acts as a reduction factor, maintaining transcription factors in an active reduced state. Thus, we aimed to investigate whether the down-regulation of APE1 expression by siRNA can interfere with the resistance of GBM to TMZ, being evaluated by several cellular and molecular parameters. We demonstrated that APE1 knockdown associated with TMZ treatment efficiently reduced cell proliferation and clonogenic survival of resistant cells (T98G), which appears to be a consequence of increased DNA damage, S-phase arrest, and H2AX phosphorylation, resulting in apoptosis induction. On the contrary, for those assays, the sensitization effects of APE1 silencing plus TMZ treatment did not occur in the TMZ-sensitive cell line (U87MG). Interestingly, TMZ-treatment and APE1 knockdown significantly reduced cell invasion in both cell lines, but TMZ alone did not reduce the invasion capacity of U87MG cells, as observed for T98G. We also found that VEGF expression was down-regulated by TMZ treatment in T98G cells, regardless of APE1 knockdown, but U87MG showed a different response, since APE1 silencing counteracted VEGF induction promoted by TMZ, suggesting that the APE1-redox function may play an indirect role, depending on the cell line. The present results support the contribution of BER in the GBM resistance to TMZ, with a greater effect in TMZ-resistant, compared with TMZ-sensitive cells, emphasizing that APE1 can be a promising target for modifying TMZ tolerance. Furthermore, genetic characteristics of tumor cells should be considered as critical

  19. Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina

    PubMed Central

    Bruno, Oscar D.; Juárez-Allen, Lea; Christiansen, Silvia B.; Manavela, Marcos; Danilowicz, Karina; Vigovich, Carlos; Gómez, Reynaldo M.

    2015-01-01

    We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson's syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing's disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration. PMID:26106414

  20. Macitentan, a dual endothelin receptor antagonist, in combination with temozolomide leads to glioblastoma regression and long-term survival in mice

    PubMed Central

    Kim, Sun-Jin; Lee, Ho Jeong; Kim, Mark Seungwook; Choi, Hyun Jin; He, Junqin; Wu, Qiuyu; Aldape, Kenneth; Weinberg, Jeffrey S.; Alfred Yung, W. K.; Conrad, Charles A.; Langley, Robert R.; Lehembre, François; Regenass, Urs; Fidler, Isaiah J.

    2016-01-01

    Purpose The objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide (TMZ) through an endothelin-dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. Experimental Design We evaluated several endothelin receptor antagonists for their ability to inhibit astrocyte- and brain endothelial cell-induced protection of glioma cells from TMZ in chemoprotection assays. We compared survival in nude mice bearing orthotopically implanted LN-229 glioblastomas or TMZ-resistant (LN-229Res and D54Res) glioblastomas that were treated with macitentan, TMZ, or both. Tumor burden was monitored weekly with bioluminescence imaging. The effect of therapy on cell division, apoptosis, tumor-associated vasculature, and pathways associated with cell survival was assessed by immunofluorescent microscopy. Results Only dual endothelin receptor antagonism abolished astrocyte- and brain endothelial cell-mediated protection of glioma cells from TMZ. In five independent survival studies, including TMZ-resistant glioblastomas, 46 of 48 (96%) mice treated with macitentan plus TMZ had no evidence of disease (P<0.0001), whereas all mice in other groups died. In another analysis, macitentan plus TMZ therapy was stopped in 16 mice after other groups had died. Only 3 of 16 mice eventually developed recurrent disease, 2 of which responded to additional cycles of macitentan plus TMZ. Macitentan downregulated proteins associated with cell division and survival in glioma cells and associated endothelial cells, which enhanced their sensitivity to TMZ. Conclusions Macitentan plus TMZ are well tolerated, produce durable responses, and warrant clinical evaluation in glioblastoma patients. PMID:26106074

  1. Phase 2 Study of Temozolomide-based Chemoradiation Therapy for High-risk Low-grade Gliomas: Preliminary Results of Radiation Therapy Oncology Group 0424

    PubMed Central

    Fisher, Barbara J.; Hu, Chen; Macdonald, David R.; Lesser, Glenn J.; Coons, Stephen W.; Brachman, David G.; Ryu, Samuel; Werner-Wasik, Maria; Bahary, Jean-Paul; Liu, Junfeng; Chakravarti, Arnab; Mehta, Minesh

    2015-01-01

    Purpose Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power. Methods and Materials Patients with LGGs with fewer than 3 risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ. Results From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%–80.8%), which was significantly improved compared to that of prespecified historical control values (P<.01). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis. Conclusions The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P<.001) and the study-hypothesized rate of 65%. PMID:25680596

  2. Phase 2 Study of Temozolomide-Based Chemoradiation Therapy for High-Risk Low-Grade Gliomas: Preliminary Results of Radiation Therapy Oncology Group 0424

    SciTech Connect

    Fisher, Barbara J.; Hu, Chen; Macdonald, David R.; Lesser, Glenn J.; Coons, Stephen W.; Brachman, David G.; Ryu, Samuel; Werner-Wasik, Maria; Bahary, Jean-Paul; Liu, Junfeng; Chakravarti, Arnab; Mehta, Minesh

    2015-03-01

    Purpose: Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power. Methods and Materials: Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of >1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ. Results: From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P<.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis. Conclusions: The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P<.001) and the study-hypothesized rate of 65%.

  3. Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study†

    PubMed Central

    Butowski, Nicholas; Chang, Susan M.; Lamborn, Kathleen R.; Polley, Mei Yin; Parvataneni, R.; Hristova-Kazmierski, Maria; Musib, Luna; Nicol, Steven J.; Thornton, Donald E.; Prados, Michael D.

    2010-01-01

    We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCβ] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status ≥60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m2 daily) followed by adjuvant temozolomide (200 mg/m2) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if ≤1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009. PMID:20156802

  4. Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins

    PubMed Central

    Kitange, Gaspar J.; Mladek, Ann C.; Schroeder, Mark A.; Pokorny, Jenny C.; Carlson, Brett L.; Zhang, Yuji; Nair, Asha A.; Lee, Jeong-Heon; Yan, Huihuang; Decker, Paul A.; Zhang, Zhiguo; Sarkaria, Jann N.

    2016-01-01

    Summary Here we provide evidence that RBBP4 modulates temozolomide (TMZ) sensitivity through coordinate regulation of 2 key DNA repair genes critical for recovery from TMZ-induced DNA damage: methylguanine-DNA-methyltransferase (MGMT) and RAD51. Disruption of RBBP4 enhanced TMZ sensitivity, induced synthetic lethality to PARP inhibition and increased DNA damage signaling in response to TMZ. Moreover, RBBP4 silencing enhanced TMZ-induced H2AX phosphorylation and apoptosis in GBM cells. Intriguingly, RBBP4 knockdown suppressed the expression of MGMT, RAD51 and other genes in association with decreased promoter H3K9 acetylation (H3K9Ac) and increased H3K9 tri-methylation (H3K9me3). Consistent with these data, RBBP4 interacts with CBP/p300 to form a chromatin modifying complex that binds within the promoter of MGMT, RAD51 and perhaps other genes. Globally, RBBP4 positively and negatively regulates genes involved in critical cellular functions including tumorigenesis. RBBP4/CBP/p300 complex may provide an interesting target for developing therapy sensitizing strategies for GBM and other tumors. PMID:26972001

  5. Polysaccharide-based nanocomplexes for co-encapsulation and controlled release of 5-Fluorouracil and Temozolomide.

    PubMed

    Di Martino, Antonio; Pavelkova, Alena; Maciulyte, Sandra; Budriene, Saulute; Sedlarik, Vladimir

    2016-09-20

    Polysaccharide-based nanocomplexes, intended for simultaneous encapsulation and controlled release of 5-Fluorouracil (5-FU) and Temozolomide (TMZ) were developed via the complexation method using chitosan, alginic and polygalacturonic acid. Investigation focused on the influence of polysaccharides on the properties of the system and amelioration of the stability of the drugs, in particular TMZ. The dimensions of particles and their ζ-potential were found to range between 100 and 200nm and -25 to +40mV, respectively. Encapsulation efficiency varied from 16% to over 70%, depending on the given system. The influence of pH on the release and co-release of TMZ and 5-FU was evaluated under different pH conditions. The stability of the loaded drug, in particular TMZ, after release was evaluated and confirmed by LC-MS analysis. Results suggested that the amount of loaded drug(s) and the release rate is connected with the weight ratio of polysaccharides and the pH of the media. One-way ANOVA analysis on the obtained data revealed no interference between the drugs during the encapsulation and release process, and in particular no hydrolysis of TMZ occurred suggesting that CS-ALG and CS-PGA would represent interesting carriers for multi-drug controlled release and drugs protection.

  6. Synthesis of TiO 2 nanostructured reservoir with temozolomide: Structural evolution of the occluded drug

    NASA Astrophysics Data System (ADS)

    López, T.; Sotelo, J.; Navarrete, J.; Ascencio, J. A.

    2006-10-01

    Sol-gel synthesized nanostructured TiO 2 matrix were produced with different channel sizes, where drug are immersed, producing a reservoir with Temozolomide (TMZ). This drug is particularly important for the treatment of cancer tumors, which are fundamentally a consequence of the uncontrolled reproduction of human cell. In this way the chemotherapy plays an important role in the treatment of both recurrent and newly diagnosed patients. In the handling of brain tumors TMZ has been discovered as a recent and efficient second generation drug employed in the control of advanced brain gliomas, and it is a welcome addition. Its active component binds to the cancerous DNA cells, thus preventing their disordered growth, destroying them. In this work, we report the synthesis of TiO 2 nanostructured reservoir with TMZ, focusing the effort to the understanding of structural effects on the TMZ configuration by using nuclear magnetic resonance, Raman and IR spectroscopy methods. Our results establish that TMZ molecules are quite sensible to chemical processes and it produces the activation of the molecule, which is followed and understood with help of quantum molecular simulation methods. The study of the molecules allows determining the conditions that produce the activation and chemical selectivity of the molecules, which determines the conditions of synthesis. This information gives parameters for the reservoir structural and chemical optimization.

  7. Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth.

    PubMed

    Ramirez, Yulian P; Mladek, Ann C; Phillips, Roger M; Gynther, Mikko; Rautio, Jarkko; Ross, Alonzo H; Wheelhouse, Richard T; Sakaria, Jann N

    2015-01-01

    The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell-cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced antiglioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.

  8. Potential Application of Temozolomide in Mesenchymal Stem Cell-Based TRAIL Gene Therapy Against Malignant Glioma

    PubMed Central

    Kim, Seong Muk; Woo, Ji Sun; Jeong, Chang Hyun; Ryu, Chung Heon; Jang, Jae-Deog

    2014-01-01

    Because the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, it is one of the most promising candidates for cancer treatment. TRAIL-secreting human mesenchymal stem cells (MSC-TRAIL) provide targeted and prolonged delivery of TRAIL in glioma therapy. However, acquired resistance to TRAIL of glioma cells is a major problem to be overcome. We showed a potential therapy that used MSC-TRAIL combined with the chemotherapeutic agent temozolomide (TMZ). The antitumor effects of the combination with MSC-TRAIL and TMZ on human glioma cells were determined by using an in vitro coculture system and an in vivo experimental xenografted mouse model. Intracellular signaling events that are responsible for the TMZ-mediated sensitization to TRAIL-induced apoptosis were also evaluated. Treatment of either TRAIL-sensitive or -resistant human glioma cells with TMZ and MSC-TRAIL resulted in a significant enhancement of apoptosis compared with the administration of each agent alone. We demonstrated that TMZ effectively increased the sensitivity to TRAIL-induced apoptosis via extracellular signal-regulated kinase-mediated upregulation of the death receptor 5 and downregulation of antiapoptotic proteins, such as X-linked inhibitor of apoptosis protein and cellular FLICE-inhibitory protein. Subsequently, this combined treatment resulted in a substantial increase in caspase activation. Furthermore, in vivo survival experiments and bioluminescence imaging analyses showed that treatment using MSC-TRAIL combined with TMZ had greater therapeutic efficacy than did single-agent treatments. These results suggest that the combination of clinically relevant TMZ and MSC-TRAIL is a potential therapeutic strategy for improving the treatment of malignant gliomas. PMID:24436439

  9. Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level.

    PubMed

    Munoz, Jessian L; Rodriguez-Cruz, Vivian; Ramkissoon, Shakti H; Ligon, Keith L; Greco, Steven J; Rameshwar, Pranela

    2015-01-20

    Glioblastoma Multiforme (GBM), the most common and lethal adult primary tumor of the brain, showed a link between Sonic Hedgehog (SHH) pathway in the resistance to temozolomide (TMZ). PTCH1, the SHH receptor, can tonically represses signaling by endocytosis. We asked how the decrease in PTCH1 in GBM cells could lead to TMZ-resistance. TMZ resistant GBM cells have increased PTCH1 mRNA and reduced protein. Knockdown of Dicer, a Type III RNAase, indicated that miRNAs can explain the decreased PTCH1 in TMZ resistant cells. Computational studies, real-time PCR, reporter gene studies, western blots, target protector oligos and ectopic expression identified miR-9 as the target of PTCH1 in resistant GBM cells with concomitant activation of SHH signaling. MiR-9 mediated increases in the drug efflux transporters, MDR1 and ABCG2. MiR-9 was increased in the tissues from GBM patients and in an early passage GBM cell line from a patient with recurrent GBM but not from a naïve patient. Pharmacological inhibition of SHH signaling sensitized the GBM cells to TMZ. Taken together, miR-9 targets PTCH1 in GBM cells by a SHH-independent method in GBM cells for TMZ resistance. The identified pathways could lead to new strategies to target GBM with combinations of drugs. PMID:25595896

  10. Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells

    PubMed Central

    Park, Jae-Hyun; Ryu, Chung Heon; Kim, Mi Jin

    2015-01-01

    Objective Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-β) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-β on gliomas. Methods We engineered human MSCs to secret mouse IFN-β (MSC-IFN-β) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-β treatment. Results In vitro, the combination of MSC-IFN-β and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-β and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. Conclusion These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-β and TMZ could be considered as a new option for the treatment of malignant gliomas. PMID:26113958

  11. miR-487b-5p Regulates Temozolomide Resistance of Lung Cancer Cells Through LAMP2-Medicated Autophagy.

    PubMed

    Bao, Liang; Lv, Lei; Feng, Jinping; Chen, Yuyu; Wang, Xinhua; Han, Shuguang; Zhao, Hongqing

    2016-08-01

    Temozolomide (TMZ) is a standard agent used in the treatment of various types of cancers, including lung carcinoma, but TMZ resistance is common and accounts for many treatment failures. We investigated miRNA-487b-5p (miR-487b-5p) was highly expressed in A549 and H1299 cells which acquired TMZ resistance. Suppression of miR-487b-5p had overt effects on cellular proliferation and migration in the presence of TMZ. On the other hand, knockdown of miR-487b-5p resulted in increased survival and moderate tumor growth in vivo. In addition, the decreased cellular proliferation following miR-487b-5p suppression was linked to enhanced autophagy, evident by drastically increased levels of LC3-II, BECLIN1, and LAMP2 when miR-487b-5p was knocked down. Further analysis revealed that LAMP2 might be the target gene of miR-487b-5p. In conclusion, our study suggested that miR-487b-5p may be a potential biomarker of acquired TMZ resistance in lung cancer cells, and miR-487b-5p inhibition can be further explored as a chemotherapy target in the treatment of TMZ-resistant lung carcinoma.

  12. Hypofractionated Versus Standard Radiation Therapy With or Without Temozolomide for Older Glioblastoma Patients

    SciTech Connect

    Arvold, Nils D.; Aizer, Ayal A.; Chiocca, E. Antonio

    2015-06-01

    Purpose: Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ). Methods and Materials: We conducted a retrospective analysis of patients ≥65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis. Results: Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P<.001) and had worse baseline performance status (P<.001) than those receiving SRT. On multivariate analysis, older age (adjusted hazard ratio [AHR]: 1.06; 95% confidence interval [CI]: 1.01-1.10, P=.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P=.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P=.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P=.03; HRT: AHR: 3.92; 95% CI: 1.44-10.60, P=.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P=.82). Conclusions: With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall

  13. In Vitro Responsiveness of Glioma Cell Lines to Multimodality Treatment With Radiotherapy, Temozolomide, and Epidermal Growth Factor Receptor Inhibition With Cetuximab

    SciTech Connect

    Combs, Stephanie E. . E-mail: Stephanie.Combs@med.uni-heidelberg.de; Schulz-Ertner, Daniela; Roth, Wilfried; Herold-Mende, Christel; Debus, Juergen; Weber, Klaus-Josef

    2007-07-01

    Background: The majority of glioblastoma multiforme (GBM) cells express the epidermal growth factor receptor (EGFR). The present study evaluates the combination of temozolomide (TMZ), EGFR inhibition, and radiotherapy (RT) in GBM cell lines. Methods and Materials: Human GBM cell lines U87, LN229, LN18, NCH 82, and NCH 89 were treated with various combinations of TMZ, RT, and the monoclonal EGFR antibody cetuximab. Responsiveness of glioma cells to the combination treatment was measured by clonogenic survival. Results: Overall, double and triple combinations of RT, TMZ, and cetuximab lead to additive cytotoxic effects (independent toxicity). A notable exception was observed for U87 and LN 18 cell lines, where the combination of TMZ and cetuximab showed substantial antagonism. Interestingly, in these two cell lines, the combination of RT with cetuximab resulted in a substantial increase in cell killing over that expected for independent toxicity. The triple combination with RT, cetuximab, and TMZ was nearly able to overcome the antagonism for the TMZ/cetuximab combination in U87, however only marginally in LN18, GBM cell lines. Conclusion: It appears that EGFR expression is not correlated with cytotoxic effects exerted by cetuximab. Combination treatment with TMZ, cetuximab and radiation resulted in independent toxicity in three out of five cell lines evaluated, the antagonistic effect of the TMZ/cetuximab combination in two cell lines could indicate that TMZ preferentially kills cetuximab-resistant cells, suggesting for some cross-talk between toxicity mechanisms. Expression of EGFR was no surrogate marker for responsiveness to cetuximab, alone or in combination with RT and TMZ.

  14. Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe.

    PubMed

    Pérès, Elodie A; Gérault, Aurélie N; Valable, Samuel; Roussel, Simon; Toutain, Jérôme; Divoux, Didier; Guillamo, Jean-Sébastien; Sanson, Marc; Bernaudin, Myriam; Petit, Edwige

    2015-02-10

    Hypoxia-inducible genes may contribute to therapy resistance in glioblastoma (GBM), the most aggressive and hypoxic brain tumours. It has been recently reported that erythropoietin (EPO) and its receptor (EPOR) are involved in glioma growth. We now investigated whether EPOR signalling may modulate the efficacy of the GBM current treatment based on chemotherapy (temozolomide, TMZ) and radiotherapy (X-rays). Using RNA interference, we showed on glioma cell lines (U87 and U251) that EPOR silencing induces a G2/M cell cycle arrest, consistent with the slowdown of glioma growth induced by EPOR knock-down. In vivo, we also reported that EPOR silencing combined with TMZ treatment is more efficient to delay tumour recurrence and to prolong animal survival compared to TMZ alone. In vitro, we showed that EPOR silencing not only increases the sensitivity of glioma cells to TMZ as well as X-rays but also counteracts the hypoxia-induced chemo- and radioresistance. Silencing EPOR on glioma cells exposed to conventional treatments enhances senescence and induces a robust genomic instability that leads to caspase-dependent mitotic death by increasing the number of polyploid cells and cyclin B1 expression. Overall these data suggest that EPOR could be an attractive target to overcome therapeutic resistance toward ionising radiation or temozolomide.

  15. Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours

    PubMed Central

    von Bueren, A O; Bacolod, M D; Hagel, C; Heinimann, K; Fedier, A; Kordes, U; Pietsch, T; Koster, J; Grotzer, M A; Friedman, H S; Marra, G; Kool, M; Rutkowski, S

    2012-01-01

    Background: Tumours are responsive to temozolomide (TMZ) if they are deficient in O6-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. Methods: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1. Results: Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC50=1.7 μℳ), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O6-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry). Conclusion: A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient. PMID:22976800

  16. Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

    SciTech Connect

    Brachman, David G.; Pugh, Stephanie L.; Ashby, Lynn S.; Thomas, Theresa A.; Dunbar, Erin M.; Narayan, Samir; Robins, H. Ian; Bovi, Joseph A.; Rockhill, Jason K.; Won, Minhee; Curran, Walter P.

    2015-04-01

    Purpose: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

  17. Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line.

    PubMed

    Ashizawa, Tadashi; Akiyama, Yasuto; Miyata, Haruo; Iizuka, Akira; Komiyama, Masaru; Kume, Akiko; Omiya, Maho; Sugino, Takashi; Asai, Akira; Hayashi, Nakamasa; Mitsuya, Koichi; Nakasu, Yoko; Yamaguchi, Ken

    2014-07-01

    Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a median survival time of less than 2 years. Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. In particular, temozolomide (TMZ)-resistant (TMZ-R) GBM is very difficult to treat, and a novel approach to overcome resistance is eagerly awaited. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the current study, the efficacy of STX-0119 was evaluated against our established TMZ-resistant U87 cell line using quantitative PCR-based gene expression analysis, in vitro assay and animal experiments. The growth inhibitory effect of STX-0119 on U87 and TMZ-R U87 cells was moderate (IC₅₀, 34 and 45 µM, respectively). In particular, STX-0119 did not show significant inhibition of U87 tumor growth; however, it suppressed the growth of the TMZ-R U87 tumor in nude mice by more than 50%, and prolonged the median survival time compared to the control group. Quantitative PCR revealed that YKL-40, MAGEC1, MGMT, several EMT genes, mesenchymal genes and STAT3 target genes were upregulated, but most of those genes were downregulated by STX-0119 treatment. Furthermore, the invasive activity of TMZ-R U87 cells was significantly inhibited by STX-0119. YKL-40 levels in TMZ-R U87 cells and their supernatants were significantly decreased by STX-0119 administration. These results suggest that STX-0119 is an efficient therapeutic to overcome TMZ resistance in recurrent GBM tumors, and could be the next promising compound leading to survival prolongation, and YKL-40 may be a possible surrogate marker for STAT3 targeting.

  18. Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma

    PubMed Central

    Hong, David S.; Kurzrock, Razelle; Falchook, Gerald S.; Andresen, Corina; Kwak, Jennifer; Ren, Min; Xu, Lucy; George, Goldy C.; Kim, Kevin B.; Nguyen, Ly M.; O'Brien, James P.; Nemunaitis, John

    2015-01-01

    Objective and Methods In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1–5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. Results Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) ≥ 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD ≥ 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. Conclusion Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1–5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group. PMID:26503473

  19. Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells

    PubMed Central

    YU, ZHIYUN; ZHAO, GANG; LI, PENGLIANG; LI, YUNQIAN; ZHOU, GUANGTONG; CHEN, YONG; XIE, GUIFANG

    2016-01-01

    Glioblastoma is the most common and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas, but it is not curative. The difficulties in treating glioblastoma may be as a result of the presence of glioma stem cells (GSCs), which are a source of relapse and chemoresistance. Another reason may be that endogenous Akt kinase activity may be activated in response to clinically relevant concentrations of TMZ. Akt activation is correlated with the increased tumorigenicity, invasiveness and stemness of cancer cells and overexpression of an active form of Akt increases glioma cell resistance to TMZ. Mounting evidence has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of Akt and down-regulation of the PI3K/Akt pathway may enhance the cytotoxicity of TMZ. Metformin (MET), the first-line drug for treating diabetes, it has been proved that it reduces AKT activation and selectively kills cancer stem cells, but whether it can potentiate the cytotoxicity of TMZ for GSCs remains unknown. In the present study, the GSCs isolated from human glioma cell line U87 and Rat glioma cell line C6, in vitro treatment with TMZ either alone or with MET. The present study demonstrates that MET acts synergistically with TMZ in inhibiting GSCs proliferation and generating the highest apoptotic rates when compared to either drug alone. These findings implicate that GSCs cytotoxicity mediated by TMZ may be stimulated by MET, have a synergistic effect, but the definite mechanisms remain elusive. PMID:27073554

  20. Pharmacokinetics and antitumor efficacy of DSPE-PEG2000 polymeric liposomes loaded with quercetin and temozolomide: Analysis of their effectiveness in enhancing the chemosensitization of drug-resistant glioma cells

    PubMed Central

    HU, JUN; WANG, JUNJIE; WANG, GANG; YAO, ZHONGJUN; DANG, XIAOQIAN

    2016-01-01

    In the present study, a new type of DSPE-PEG2000 polymeric liposome for the brain-targeted delivery of poorly water-soluble anticancer drugs was successfully prepared and characterized. The nanoparticles were formed by the self-assembly of an amphiphilic polymer consisting of hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000). These nanoliposomes served as a safe delivery platform for the simultaneous delivery of quercetin (QUE) and temozolomide (TMZ) to rat brains. The 2-in-1 PEG2000-DSPE nanoliposomes containing QUE and TMZ (QUE/TMZ-NLs) were rapidly taken up by the U87 glioma cells in vitro, whereas at the same concentrations, the amounts of the free drugs taken up were minimal. The QUE/TMZ-NLs showed an enhanced potency in the U87 cells and the TMZ-resistant U87 cells (U87/TR cells), possibly due to the high intracellular drug concentration and the subsequent drug release. In vivo biodistribution experiments revealed a significant accumulation of QUE/TMZ-NLs in the brain, with significantly increased plasma concentrations of QUE and TMZ, as well as delayed clearance in our rat model of glioma. The results were not so significant for the QUE-loaded nanoliposomes (QUE-NLs) and free TMZ. The findings of our study establish the DSPE-PEG2000 polymeric liposome as a novel and effective nanocarrier for enhancing drug delivery to brain tumors. PMID:26782731

  1. Marked response of gliomatosis cerebri to temozolomide and whole brain radiotherapy.

    PubMed

    Mattox, Austin K; Lark, Amy L; Adamson, D Cory

    2012-05-01

    Gliomatosis cerebri (GC) represents an unfortunate, rare variant of glioma with a very poor prognosis. Given this lesion's rarity, little information exists on appropriate treatment options. The diffuse, infiltrative nature of GC precludes any surgical resection and limits therapy. Because of the improved survival seen with the use of temozolomide (TMZ) in malignant glioma, a rigorous systematic review of the published literature was performed to ascertain the benefit of TMZ in GC. We identified all GC cases in the literature where there was enough information to ascertain a clear response to a specific chemoradiotherapeutic treatment. In addition to our experience with a recent case, we have identified 61 patients with GC in the published literature who demonstrated a positive radiographic or clinic response after treatment. Statistical analysis of survival was performed by Kaplan-Meier analysis. A positive radiographic and clinical response was seen in patients ranging in age from 4 to 84 years. Overall median survival in patients diagnosed with GC who demonstrated a response after treatment was 25 months, with 1- and 2-year survival rates of 89% and 55%, respectively. The most common treatment regimens for responders included TMZ alone (26.2%), external whole-brain radiotherapy (WBRT) (26.2%), and concomitant TMZ and WBRT (20%). Our patient was treated with concomitant TMZ (150 mg/m(2)/day over 5 days) and WBRT (50 Gy) and has remained with a complete radiographic response after 36 months. In conclusion, patients with GC confirmed by surgical biopsy should be aggressively treated with concomitant TMZ and WBRT, as marked responses have been seen, and this appears to offer overall survival benefit.

  2. Phase I Study of Vorinostat in Combination with Temozolomide in Patients with High-Grade Gliomas: North American Brain Tumor Consortium Study 04-03

    PubMed Central

    Lee, Eudocia Q.; Puduvalli, Vinay K.; Reid, Joel M.; Kuhn, John G.; Lamborn, Kathleen R.; Cloughesy, Timothy F.; Chang, Susan M.; Drappatz, Jan; Yung, W. K. Alfred; Gilbert, Mark R.; Robins, H. Ian; Lieberman, Frank S.; Lassman, Andrew B.; McGovern, Renee M.; Xu, Jihong; Desideri, Serena; Ye, Xiabu; Ames, Matthew M.; Espinoza-Delgado, Igor; Prados, Michael D.; Wen, Patrick Y.

    2013-01-01

    Purpose A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). Experimental Design This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day × 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day × 5 days of the first cycle and 200 mg/m2/day × 5 days of the subsequent 28-day cycles. Results In Part 1, the MTD of vorinostat administered on days 1-7 and 15-21 of every 28 day cycle in combination with TMZ was 500 mg daily. Dose-limiting toxicities (DLTs) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In Part 2, the MTD of vorinostat on days 1-7 and 15-21 of every 28 day cycle combined with TMZ was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Conclusion Vorinostat in combination with temozolomide is well-tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. PMID:22923449

  3. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression

    PubMed Central

    Prados, Jose; Caba, Octavio; Cabeza, Laura; Berdasco, Maria; Gónzalez, Beatriz; Melguizo, Consolación

    2015-01-01

    Background The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated. Methods Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2’-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed. Results Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines. Conclusions These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma

  4. Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas.

    PubMed

    Ulasov, Ilya; Thaci, Bart; Sarvaiya, Purvaba; Yi, Ruiyang; Guo, Donna; Auffinger, Brenda; Pytel, Peter; Zhang, Lingjiao; Kim, Chung Kwon; Borovjagin, Anton; Dey, Mahua; Han, Yu; Baryshnikov, Anatoly Y; Lesniak, Maciej S

    2013-08-01

    Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy.

  5. Could the Anti-Chaperone VER155008 Replace Temozolomide for Glioma Treatment

    PubMed Central

    Shervington, Leroy; Patil, Harshada; Shervington, Amal

    2015-01-01

    Cancer inducible molecular chaperone HSP90 is of great importance as an anticancer target. Proteomic analysis showed that inhibiting HSP90 by the geldanamycin derivative, 17-AAG elevated the expression of the co-chaperone Hsp70. In this study we used HSP90 selective inhibitor 17-AAG and HSP70/90 dual inhibitor, VER155008 (VER) in U87-MG glioma cells. miRNAs microarray technology was used to evaluate the efficacy of these inhibitory drugs compared with temozolomide (TMZ), used as a standard treatment for glioma. Microarrays data identified 154 differentially expressed miRNAs using stringent or unstringent parameters. 16 miRNAs were overlapped between treatments, 13 upregulated and one downregulated miRNA were overlapped between TMZ and VER. The miRNA target prediction software was used for these overlapped miRNAs and identified 6 of the 13 upregulated miRNAs target methyltransferase genes. The IC50, together with Akt and HSP70 and 90 protein level data favour VER and TMZ to 17-AAG, however due to the selectivity of VER to cancer cells as a potent antichaperon, it may be more favourable to the standard TMZ. PMID:26185541

  6. HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma.

    PubMed

    Wang, Zhihao; Hu, Pengchao; Tang, Fang; Lian, Haiwei; Chen, Xiong; Zhang, Yingying; He, Xiaohua; Liu, Wanhong; Xie, Conghua

    2016-08-28

    Histone deacetylases are considered to be among the most promising targets in drug development for cancer therapy. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes involved in tumorigenesis through its deacetylase and ubiquitin-binding activities. Here, we report that HDAC6 is overexpressed in glioblastoma tissues and cell lines. Overexpression of HDAC6 promotes the proliferation and spheroid formation of glioblastoma cells. HDAC6 overexpression confers resistance to temozolomide (TMZ) mediated cell proliferation inhibition and apoptosis induction. Conversely, knockdown of HDAC6 inhibits cell proliferation, impairs spheroid formation and sensitizes glioblastoma cells to TMZ. The inhibition of HDAC6 deacetylase activity by selective inhibitors inhibits the proliferation of glioblastoma cells and induces apoptosis. HDAC6 selective inhibitors can sensitize glioblastoma cells to TMZ. Moreover, we showed that HDAC6 mediated EGFR stabilization might partly account for its oncogenic role in glioblastoma. TMZ resistant glioblastoma cells showed higher expression of HDAC6 and more activation of EGFR. HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of glioblastoma.

  7. Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

    PubMed Central

    Li, Xing-qi; Ouyang, Zhi-gang; Zhang, Sheng-hua; Liu, Hong; Shang, Yue; Li, Yi; Zhen, Yong-su

    2014-01-01

    Present work mainly evaluated the inhibitory effects of lidamycin (LDM), an enediyne antibiotic, on angiogenesis or glioma-induced angiogenesis in vitro and in vivo, especially its synergistic anti-angiogenesis with temozolomide (TMZ). LDM alone efficiently inhibited proliferations and induced apoptosis of rat brain microvessel endothelial cells (rBMEC). LDM also interrupted the tube formation of rat brain microvessel endothelial cells (rBMEC) and rat aortic ring spreading. The blockade of rBMEC invasion and C6 cell-induced rBMEC migration by LDM was associated with decrease of VEGF secretion in a co-culture system. TMZ dramatically potentiated the effects of LDM on anti-proliferation, apoptosis induction, and synergistically inhibited angiogenesis events. As determined by western blot and ELISA, the interaction of tumor cells and the rBMEC was markedly interrupted by LDM plus TMZ with synergistic regulations of VEGF induced angiogenesis signal pathway, tumor cell invasion/migration, and apoptosis signal pathway. Immunofluorohistochemistry of CD31 and VEGF showed that LDM plus TMZ resulted in synergistic decrease of microvessel density (MVD) and VEGF expression in human glioma U87 cell subcutaneous xenograft. This study indicates that the high efficacy of LDM and the synergistic effects of LDM plus TMZ against glioma are mediated, at least in part, by the potentiated anti-angiogenesis. PMID:24424202

  8. Unraveling the cytotoxic potential of Temozolomide loaded into PLGA nanoparticles

    PubMed Central

    2014-01-01

    Background Nanotechnology has received great attention since a decade for the treatment of different varieties of cancer. However, there is a limited data available on the cytotoxic potential of Temozolomide (TMZ) formulations. In the current research work, an attempt has been made to understand the anti-metastatic effect of the drug after loading into PLGA nanoparticles against C6 glioma cells. Nanoparticles were prepared using solvent diffusion method and were characterized for size and morphology. Diffusion of the drug from the nanoparticles was studied by dialysis method. The designed nanoparticles were also assessed for cellular uptake using confocal microscopy and flow cytometry. Results PLGA nanoparticles caused a sustained release of the drug and showed a higher cellular uptake. The drug formulations also affected the cellular proliferation and motility. Conclusion PLGA coated nanoparticles prolong the activity of the loaded drug while retaining the anti-metastatic activity. PMID:24410831

  9. Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death

    PubMed Central

    Marschall, V; Fulda, S

    2015-01-01

    Inhibitor of apoptosis (IAP) proteins are frequently expressed at high levels in cancer cells and represent attractive therapeutic targets. We previously reported that the Smac (second mitochondria-derived activator of caspases) mimetic BV6, which antagonizes IAP proteins, sensitizes glioblastoma cells to temozolomide (TMZ)-induced cell death in a nuclear factor-κB (NF-κB)-dependent manner. However, BV6-induced NF-κB target genes responsible for this synergistic interaction have remained elusive. Using whole-genome gene expression profiling, we here identify BV6-stimulated, NF-κB-dependent transcriptional upregulation of interferon-β (IFNβ) and IFN-mediated proapoptotic signaling as critical events that mediate BV6/TMZ-induced apoptosis. Knockdown of IFNβ significantly rescues cells from BV6/TMZ-induced cell death. Similarly, silencing of the corresponding receptor IFNα/β receptor (IFNAR) confers a significant protection against apoptosis, demonstrating that IFNβ and IFN signaling are required for BV6/TMZ-mediated cell death. Moreover, BV6 and TMZ cooperate to transcriptionally upregulate the proapoptotic B-cell lymphoma 2 family proteins Bax (Bcl-2-associated X protein) or Puma (p53-upregulated modulator of apoptosis). Knockdown of Bax or Puma significantly decreases BV6/TMZ-induced apoptosis, showing that both proteins are necessary for apoptosis. By identifying IFNβ as a key mediator of BV6/TMZ-induced apoptosis, our study provides novel insights into the underlying molecular mechanisms of Smac mimetic-mediated chemosensitization with important implications for the development of novel treatment strategies for glioblastoma. PMID:26379193

  10. MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment.

    PubMed

    He, Hua; Yao, Maojin; Zhang, Wenhao; Tao, Bangbao; Liu, Feili; Li, Shu; Dong, Yan; Zhang, Chenran; Meng, Yicheng; Li, Yuxin; Hu, Guohan; Luo, Chun; Zong, Hui; Lu, Yicheng

    2016-09-01

    Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.

  11. MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

    PubMed Central

    He, Hua; Yao, Maojin; Zhang, Wenhao; Tao, Bangbao; Liu, Feili; Li, Shu; Dong, Yan; Zhang, Chenran; Meng, Yicheng; Li, Yuxin; Hu, Guohan; Luo, Chun; Zong, Hui; Lu, Yicheng

    2016-01-01

    Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ. PMID:26189368

  12. Combination of temozolomide and Taxol exerts a synergistic inhibitory effect on Taxol‑resistant glioma cells via inhibition of glucose metabolism.

    PubMed

    Guan, Ding-Guo; Chen, Han-Min; Liao, Sheng-Fang; Zhao, Tian-Zhi

    2015-11-01

    Malignant gliomas, which comprise the most common type of primary malignant brain tumor, are associated with a poor prognosis and quality of life. Paclitaxel (Taxol) and temozolomide (TMZ) are Food and Drug Administration‑approved anticancer agents, which are known to have therapeutic applications in various malignancies. However, similar to other chemotherapeutic agents, the development of resistance to TMZ and Taxol is common. The aim of the present study was to investigate the regulation of glucose metabolism by TMZ and Taxol in glioma cells. The results demonstrated that glioma cells exhibit decreased glucose uptake and lactate production in response to treatment with TMZ; however, glucose metabolism was increased in response to Taxol treatment. Following analysis of TMZ‑ and Taxol‑resistant cell lines, it was reported that glucose metabolism was decreased in the TMZ‑resistant cells, but was increased in the Taxol‑resistant cells. Notably, a combination of TMZ and Taxol exerted synergistic inhibitory effects on Taxol‑resistant glioma cells. However, the synergistic phenotype was not observed following treatment with a combination of 5‑fluorouracil and Taxol. Furthermore, restoration of glucose metabolism by overexpression of glucose transporter 1 in Taxol‑resistant cells resulted in regained resistance to Taxol. Therefore, the present study proposes a novel mechanism accounting for the synergistic effects of Taxol and TMZ co‑treatment, which may contribute to the development of therapeutic strategies for overcoming chemoresistance in patients with cancer.

  13. Radiotherapy and temozolomide for anaplastic astrocytic gliomas

    PubMed Central

    Nayak, Lakshmi; Panageas, Katherine S.; Reiner, Anne S.; Huse, Jason T.; Pentsova, Elena; Braunthal, Stephanie G.; Abrey, Lauren E.; DeAngelis, Lisa M.

    2015-01-01

    We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m2), and six adjuvant 28-day cycles of either dose-dense (150 mg/m2, days 1–7, 15–21) or metronomic (50 mg/m2, days 1–28) temozolomide. Subsequently, maintenance RA (100 mg/m2, days 1–21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan–Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28–74), median KPS 90 (range 60–100). Extent of resection was gross-total in 35 %, subtotal 23 %, and biopsy 42 %. Histology was AA in 90 %, and AOA in 10 %. MGMT promoter methylation was methylated in 20 %, unmethylated in 50 %, and uninformative in 30 % of 30 tested. Median progression-free survival was 2.1 years (95 % CI 0.95–Not Reached), and overall survival 2.9 years (95 % CI 2.0–Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials. PMID:25920709

  14. Radiotherapy and temozolomide for anaplastic astrocytic gliomas.

    PubMed

    Nayak, Lakshmi; Panageas, Katherine S; Reiner, Anne S; Huse, Jason T; Pentsova, Elena; Braunthal, Stephanie G; Abrey, Lauren E; DeAngelis, Lisa M; Lassman, Andrew B

    2015-05-01

    We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m(2)), and six adjuvant 28-day cycles of either dose-dense (150 mg/m(2), days 1-7, 15-21) or metronomic (50 mg/m(2), days 1-28) temozolomide. Subsequently, maintenance RA (100 mg/m(2), days 1-21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan-Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28-74), median KPS 90 (range 60-100). Extent of resection was gross-total in 35%, subtotal 23%, and biopsy 42%. Histology was AA in 90%, and AOA in 10%. MGMT promoter methylation was methylated in 20%, unmethylated in 50%, and uninformative in 30% of 30 tested. Median progression-free survival was 2.1 years (95% CI 0.95-Not Reached), and overall survival 2.9 years (95 % CI 2.0-Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials. PMID:25920709

  15. Temozolomide-Induced Shrinkage of Invasive Pituitary Adenoma in Patient with Nelson's Syndrome: A Case Report and Review of the Literature

    PubMed Central

    Kurowska, Maria; Nowakowski, Andrzej; Zieliński, Grzegorz; Malicka, Joanna; Tarach, Jerzy S.; Maksymowicz, Maria; Denew, Piotr

    2015-01-01

    Introduction. Invasive tumours in Nelson's syndrome need aggressive therapy. Recent reports have documented the efficacy of temozolomide (TMZ) in the treatment of adenomas resistant to conventional management. Objective. The review of the literature concerning TMZ treatment of atypical corticotroph adenomas and a case study of 56-year-old woman who developed Nelson's syndrome. Treatment Proceeding. The patient with Cushing's disease underwent transsphenoidal adenomectomy followed by a 27-month-long period of remission. Due to a regrowth of the tumor, she underwent two reoperations followed by stereotactic radiotherapy. Because of treatment failures, bilateral adrenalectomy was performed. Then she developed Nelson's syndrome. A fourth transsphenoidal adenomectomy was performed, but there was a rapid recurrence. Five months later, she underwent a right frontotemporal craniotomy. Due to a rapid regrowth of the tumour, the patient did not receive gamma-knife therapy and was treated with cabergoline and somatostatin analogue for some time. Only TMZ therapy resulted in marked clinical, biochemical, and radiological improvement. To date, this is the first case of invasive corticotroph adenoma in Nelson's syndrome treated with temozolomide in Poland. Conclusion. In our opinion, temozolomide can be an effective treatment option of invasive adenomas in Nelson's syndrome. PMID:26221547

  16. Combined Delivery of Temozolomide and Anti-miR221 PNA Using Mesoporous Silica Nanoparticles Induces Apoptosis in Resistant Glioma Cells.

    PubMed

    Bertucci, Alessandro; Prasetyanto, Eko Adi; Septiadi, Dedy; Manicardi, Alex; Brognara, Eleonora; Gambari, Roberto; Corradini, Roberto; De Cola, Luisa

    2015-11-11

    Mesoporous silica nanoparticles (MSNPs), 100 nm in size, incorporating a Cy5 fluorophore within the silica framework, are synthesized and loaded with the anti-cancer drug temozolomide (TMZ), used in the treatment of gliomas. The surface of the particles is then decorated, using electrostatic interactions, with a polyarginine-peptide nucleic acid (R8-PNA) conjugate targeting the miR221 microRNA. The multi-functional nanosystem thus obtained is rapidly internalized into glioma C6 or T98G cells. The anti-miR activity of the PNA is retained, as confirmed by reverse transcription polymerase chain reaction (RT-PCR) measurements and induction of apoptosis is observed in temozolomide-resistant cell lines. The TMZ-loaded MSNPs show an enhanced pro-apoptotic effect, and the combined effect of TMZ and R8-PNA in the MSNPs shows the most effective induction of apoptosis (70.9% of apoptotic cells) thus far achieved in the temozolomide-resistant T98G cell line. PMID:26395266

  17. Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest

    PubMed Central

    Wang, Peng; Ye, Jing-An; Hou, Chong-Xian; Zhou, Dong; Zhan, Sheng-Quan

    2016-01-01

    Temozolomide (TMZ) is approved for use as first-line treatment for glioblastoma multiforme (GBM). However, GBM shows chemoresistance shortly after the initiation of treatment. In order to detect whether silencing of human protein phosphatase 1D magnesium dependent (PPM1D) gene could increase the effects of TMZ in glioma cells, glioma cells U87-MG were infected with lentiviral shRNA vector targeting PPM1D silencing. After PPM1D silencing was established, cells were treated with TMZ. The multiple functions of human glioma cells after PPM1D silencing and TMZ chemotherapy were detected by flow cytometry and MTT assay. Significantly differentially expressed genes were distinguished by microarray-based gene expression profiling and analyzed by gene pathway enrichment analysis and ontology assessment. Western blotting was used to establish the protein expression of the core genes. PPM1D gene silencing improves TMZ induced cell proliferation and induces cell apoptosis and cell cycle arrest. When PPM1D gene silencing combined with TMZ was performed in glioma cells, 367 genes were upregulated and 444 genes were downregulated compared with negative control. The most significant differential expression pathway was pathway in cancer and IGFR1R, PIK3R1, MAPK8 and EP300 are core genes in the network. Western blotting showed that MAPK8 and PIK3R1 protein expression levels were upregulated and RB1 protein expression was decreased. It was consistent with that detected in gene expression profiling. In conclusion, PPM1D gene silencing combined with TMZ eradicates glioma cells through cell apoptosis and cell cycle arrest. PIK3R1/AKT pathway plays a role in the multiple functions of glioma cells after PPM1D silencing and TMZ chemotherapy. PMID:27633132

  18. Comparison of long-term survival between temozolomide-based chemoradiotherapy and radiotherapy alone for patients with low-grade gliomas after surgical resection

    PubMed Central

    Gai, Xiu-juan; Wei, Yu-mei; Tao, Heng-min; An, Dian-zheng; Sun, Jia-teng; Li, Bao-sheng

    2016-01-01

    Purpose This study was designed to compare the survival outcomes of temozolomide-based chemoradiotherapy (TMZ + RT) vs radiotherapy alone (RT-alone) for low-grade gliomas (LGGs) after surgical resection. Patients and methods In this retrospective analysis, we reviewed postoperative records of 69 patients with LGGs treated with TMZ + RT (n=31) and RT-alone (n=38) at the Shandong Cancer Hospital Affiliated to Shandong University between June 2011 and December 2013. Patients in the TMZ + RT group were administered 50–100 mg oral TMZ every day until the radiotherapy regimen was completed. Results The median follow-up since surgery was 33 months and showed no significant intergroup differences (P=0.06). There were statistically significant intergroup differences in the progression-free survival rate (P=0.037), with 83.9% for TMZ-RT group and 60.5% for RT-alone group. The overall 2-year overall survival (OS) rate was 89.86%. Age distribution (≥45 years and <45 years) and resection margin (complete resection or not) were significantly associated with OS (P=0.03 and P=0.004, respectively). Conclusion Although no differences were found in the 2-year OS between the TMZ + RT and RT-alone groups, there was a trend toward increased 2-year progression-free survival in the TMZ + RT group. With better tolerability, concurrent TMZ chemoradiotherapy may be beneficial for postoperative patients with LGGs. Age distribution and surgical margin are likely potential indicators of disease prognosis. The possible differences in long-term survival between the two groups and the links between prognostic factors and long-term survival may be worthy of further investigation. PMID:27574452

  19. High expression of miR-9 in CD133+ glioblastoma cells in chemoresistance to temozolomide

    PubMed Central

    Munoz, Jessian L.; Rodriguez-Cruz, Vivian; Rameshwar, Pranela

    2016-01-01

    Glioblastoma Multiforme (GBM), a uniformly lethal stage IV astrocytoma, is currently treated with a combination of surgical and radiation therapy as well as Temozolomide (TMZ) chemotherapy. Resistance to TMZ is rapidly acquired by GBM cells and overcoming this resistance has been an area of signi?cant research. GBM 'cancer stem cells' (CSC) also known as 'cancer initiating cells' are often positively selected by CD133 expression and TMZ resistance. In this project, we selected GBM CSC from two cell lines based on CD133 expression. CD133+ and CD133− GBM cells showed comparable cell cycle status. The expression of genes within the Sonic Hedgehog Signaling pathway, PTCH1 (SHH receptor/basal signaling repressor) and Gli1 (effector transcription factor) were increased. The recent literature indicated a decreased in PTCH expression by miRNA and this was independent of SHH expression. We analyzed 5 potential PTCH-targeting miRNA and identi?ed an increase in miRNA-9-2. The CD133+ cells showed an increase in the Multiple Drug Resistance 1 gene (MDR1). Knockdown of Gli1 and MDR1 with siRNA enhanced TMZ induced cell death. Taken together, these studies show CD133+ GBM CSCs expressed greater levels of miR-9 and activation of the SHH/PTCH1/MDR1 axis. This axis has been shown to impart TMZ resistance. In the case of the CD133+ cells, the resistance is not acquires but seems to be inherent. Identi?cation of this pathway as well as the identi?cation of miR-9 may allow for the development of miRNA-targeted approach to Cancer Stem Cell therapy in GBM. PMID:27347493

  20. Do Glioma Patients Derive Any Therapeutic Benefit From Taking a Higher Cumulative Dose of Temozolomide Regimens?

    PubMed Central

    Sun, Hao; Du, Shasha; Liao, Guixiang; Xie, Xiao; Ren, Chen; Yuan, Ya Wei

    2015-01-01

    Abstract Temozolomide (TMZ) is an oral alkylating agent with established effects on the central nervous system of glioblastoma (GBM) patients. Clinical trials have demonstrated a significant impact on overall survival (OS) with TMZ. Ever since, several TMZ regimens have been designed to improve treatment efficacy by increasing the cumulative dose per cycle. We report a meta-analysis to systematically evaluate different treatment schedules of TMZ in GBM patients. All searches that were conducted in the Cochrane library, Science Direct, and PubMed Databases, and 3 randomized controlled trials (1141 patients) were included. OS and progression-free survival (PFS) were the primary outcomes to be pooled. Unexpectedly, this analysis did not reveal any OS or PFS advantage for the high cumulative dose (HCD) regimen compared with the normal cumulative dose regimen (1141 total patients; hazard ratio [HR] 1.07, 95% CI 0.94–1.22, P = 0.31). Then after analyzing the characteristics of the results from each trial, we found that the regimen with a higher peak concentration during a short-term period (daily doses ≥150 mg/m2/d within ≤7 days/cycle) always had a more superior clinical benefit. So we generated a new pooled HR of 1.10 with a 95% CI of 0.96–1.25 (P = 0.17), which prefers the high peak concentration schedule even without a significant difference. The adverse outcome also indicates a significant increased risk of leukopenia (risk ratio 1.59, 95% CI 1.03–2.46, P = 0.04) among the HCD group. Our study suggests that increasing the cumulative dose per cycle is not an ideal way to improve the efficacy of TMZ, and it will lead to increased risk for leukopenia. Future trials should be designed to examine schedules of higher peak concentration rather than the cumulative dose per cycle. PMID:25997057

  1. Transport of treosulfan and temozolomide across an in-vitro blood-brain barrier model.

    PubMed

    Linz, Ute; Hupert, Michelle; Santiago-Schübel, Beatrix; Wien, Sascha; Stab, Julia; Wagner, Sylvia

    2015-08-01

    In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood-brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in-vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors.

  2. Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models.

    PubMed

    Grossman, Rachel; Brastianos, Harry; Blakeley, Jaishri O; Mangraviti, Antonella; Lal, Bachchu; Zadnik, Patti; Hwang, Lee; Wicks, Robert T; Goodwin, Rory C; Brem, Henry; Tyler, Betty

    2014-01-01

    Anti-angiogenic agents, such as bevacizumab (BEV), can induce normalization of the blood brain barrier, which may influence the penetration and activity of a co-administered cytotoxic drug. However, it is unknown whether this effect is associated with a benefit in overall survival. This study employed intracranial human glioma models to evaluate the effect of BEV alone and in combination with temozolomide (TMZ) and/or radiation therapy (XRT) on overall survival. One hundred eight male athymic rats were intracranially injected with either U251 or U87 human glioma. Ten or eleven days after tumor inoculation, animals bearing U251 and U87, respectively, were treated with: TMZ alone (50 mg/kg for 5 consecutive days, P.O.), BEV alone (15 mg/kg, I.V.), a combination of TMZ and BEV, or a combination of TMZ, BEV, and a single fraction of XRT (20 Gy). Controls received no treatment. The U87 experiment was repeated and the relationship between survival and the extent of anti-angiogenesis via anti-laminin antibodies for the detection of blood vessels was assessed. In both U87 glioma experiments, all of the treatment groups had a statistically significant increase in survival as compared to the control groups. Also, for both U87 experiments the combination groups of TMZ and BEV had significantly better survival when compared to either treatment administered alone, with 75% of animals demonstrating long-term survival (LTS) (defined as animals alive 120 days after tumor implantation) in one experiment and 25% LTS in the repeat experiment. In the U251 glioma experiment, all treated groups (except BEV alone) had significantly improved survival as compared to controls with minimal statistical variance among groups. The percent vessel area was lowest in the group of animals treated with BEV alone. The addition of BEV to TMZ and/or XRT had variable effect on prolonging survival in the two human glioma models tested with reduced tumor vascularity in groups treated with BEV. These

  3. Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide

    PubMed Central

    Triscott, Joanna; Lee, Cathy; Hu, Kaiji; Fotovati, Abbas; Berns, Rachel; Pambid, Mary; Luk, Margaret; Kast, Richard E.; Kong, Esther; Toyota, Eric; Yip, Stephen; Toyota, Brian; Dunn, Sandra E.

    2012-01-01

    Glioblastomas (GBM) are associated with high rates of relapse. These brain tumors are often resistant to chemotherapies like temozolomide (TMZ) and there are very few treatment options available to patients. We recently reported that polo-like kinase-1 (PLK1) is associated with the proliferative subtype of GBM; which has the worst prognosis. In this study, we addressed the potential of repurposing disulfiram (DSF), a drug widely used to control alcoholism for the past six decades. DSF has good safety profiles and penetrates the blood-brain barrier. Here we report that DSF inhibited the growth of TMZ resistant GBM cells, (IC90=100 nM), but did not affect normal human astrocytes. At similar DSF concentrations, self-renewal was blocked by ~100% using neurosphere growth assays. Likewise the drug completely inhibited the self-renewal of the BT74 and GBM4 primary cell lines. Additionally, DSF suppressed growth and self-renewal of primary cells from two GBM tumors. These cells were resistant to TMZ, had unmethylated MGMT, and expressed high levels of PLK1. Consistent with its role in suppressing GBM growth, DSF inhibited the expression of PLK1 in GBM cells. Likewise, PLK1 inhibition with siRNA, or small molecules (BI-2536 or BI-6727) blocked growth of TMZ resistant cells. Our studies suggest that DSF has the potential to be repurposed for treatment of refractory GBM. PMID:23047041

  4. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo

    PubMed Central

    Yu, Zhiyun; Zhao, Gang; Xie, Guifang; Zhao, Liyan; Chen, Yong; Yu, Hongquan; Zhang, Zhonghua; Li, Cai; Li, Yunqian

    2015-01-01

    Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. The fast recurrence and multi-drug resistance are some of the key challenges in combating brain tumors. Glioma stem cells (GSCs) which are considered the source of relapse and chemoresistance, the need for more effective therapeutic options is overwhelming. In our present work, we found that combined treatment with temozolomide (TMZ) and metformin (MET) synergistically inhibited proliferation and induced apoptosis in both glioma cells and GSCs. Combination of TMZ and MET significantly reduced the secondary gliosphere formation and expansion of GSCs. We first demonstrated that MET effectively inhibited the AKT activation induced by TMZ, and a combination of both drugs led to enhanced reduction of mTOR, 4EBP1 and S6K phosphorylation. In addition, the combination of the two drugs was accompanied with a powerful AMP-activated protein kinase (AMPK) activation, while this pathway is not determinant. Xenografts performed in nude mice demonstrate in vivo demonstrated that combined treatment significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. In conclusion, TMZ in combination with MET synergistically inhibits the GSCs proliferation through downregulation of AKT-mTOR signaling pathway. The combined treatment of two drugs inhibits GSCs self-renewal capability and partly eliminates GSCs in vitro and in vivo. This combined treatment could be a promising option for patients with advanced GBM. PMID:26431379

  5. Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis

    PubMed Central

    Zhao, Qian; Qin, Qin; Sun, Jinglong; Han, Dan; Wang, Zhongtang; Teng, Junjie; Li, Baosheng

    2016-01-01

    Objective We performed a meta-analysis of randomized clinical trials to compare the efficacy of brain radiotherapy (RT) combined with temozolomide (TMZ) versus RT alone as first-line treatment for brain metastases (BM). Methods Medline, Embase, and Pubmed were used to search for relevant randomized controlled trials (RCTs). Two investigators reviewed the abstracts and independently rated the quality of trials and relevant data. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and adverse events. Results Seven studies were selected from the literature search. RT plus TMZ produced significant improvement in ORR with odds ratio (OR) of 2.27 (95% CI, 1.29 to 4.00; P = 0.005) compared with RT alone. OS and PFS were not significantly different between the two arms (OS: HR, 1.00; P = 0.959; PFS: HR, 0.73; P = 0.232). However, the RT plus TMZ arm was associated with significantly more grade 3 to 4 nausea and thrombocytopenia. Conclusion Concomitant RT and TMZ, compared to RT alone, significantly increases ORR in patients with BM, but yields increased toxicity and fails to demonstrate a survival advantage. PMID:26930609

  6. NF-κB is activated in response to temozolomide in an AKT-dependent manner and confers protection against the growth suppressive effect of the drug

    PubMed Central

    2012-01-01

    Background Most DNA-damaging chemotherapeutic agents activate the transcription factor nuclear factor κB (NF-κB). However, NF-κB activation can either protect from or contribute to the growth suppressive effects of the agent. We previously showed that the DNA-methylating drug temozolomide (TMZ) activates AKT, a positive modulator of NF-κB, in a mismatch repair (MMR) system-dependent manner. Here we investigated whether NF-κB is activated by TMZ and whether AKT is involved in this molecular event. We also evaluated the functional consequence of inhibiting NF-κB on tumor cell response to TMZ. Methods AKT phosphorylation, NF-κB transcriptional activity, IκB-α degradation, NF-κB2/p52 generation, and RelA and NF-κB2/p52 nuclear translocation were investigated in TMZ-treated MMR-deficient (HCT116, 293TLα-) and/or MMR-proficient (HCT116/3-6, 293TLα+, M10) cells. AKT involvement in TMZ-induced activation of NF-κB was addressed in HCT116/3-6 and M10 cells transiently transfected with AKT1-targeting siRNA or using the isogenic MMR-proficient cell lines pUSE2 and KD12, expressing wild type or kinase-dead mutant AKT1. The effects of inhibiting NF-κB on sensitivity to TMZ were investigated in HCT116/3-6 and M10 cells using the NF-κB inhibitor NEMO-binding domain (NBD) peptide or an anti-RelA siRNA. Results TMZ enhanced NF-κB transcriptional activity, activated AKT, induced IκB-α degradation and RelA nuclear translocation in HCT116/3-6 and M10 but not in HCT116 cells. In M10 cells, TMZ promoted NF-κB2/p52 generation and nuclear translocation and enhanced the secretion of IL-8 and MCP-1. TMZ induced RelA nuclear translocation also in 293TLα+ but not in 293TLα- cells. AKT1 silencing inhibited TMZ-induced IκB-α degradation and NF-κB2/p52 generation. Up-regulation of NF-κB transcriptional activity and nuclear translocation of RelA and NF-κB2/p52 in response to TMZ were impaired in KD12 cells. RelA silencing in HCT116/3-6 and M10 cells increased TMZ

  7. Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.

    PubMed

    D'Atri, S; Graziani, G; Lacal, P M; Nisticò, V; Gilberti, S; Faraoni, I; Watson, A J; Bonmassar, E; Margison, G P

    2000-08-01

    The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is important in cellular resistance to certain alkylating antitumor agents such as the methylating drug temozolomide (TMZ). To provide a more rational basis for clinical combinations with another commonly used drug, cisplatin, we assessed the modulation of MGMT protein and mRNA levels in the human leukemic cell line Jurkat after treatment with these agents. Cisplatin decreased MGMT activity in a time- and dose-dependent manner, with maximal suppression (50%) observed 24 h after treatment with 25 microM cisplatin. This was probably the result of decreased transcription of the MGMT gene, because there was an earlier nadir of MGMT mRNA levels after cisplatin treatment and neither cisplatin nor DNA reacted with cisplatin in vitro was able to inhibit MGMT activity in an in vitro assay. TMZ alone depleted MGMT activity in a time- and dose-dependent manner with almost complete loss of activity occurring immediately after treatment with 500 microM TMZ. Combinations of cisplatin (12.5 microM) and TMZ (250 microM) caused substantial and prolonged MGMT depletion with recovery to only 30% of pretreatment levels by 48 h. These results suggest that the clinical efficacy of TMZ and cisplatin may be improved by appropriate schedules of combinations of these agents.

  8. Nanoparticle-Delivered Antisense MicroRNA-21 Enhances the Effects of Temozolomide on Glioblastoma Cells.

    PubMed

    Ananta, Jeyarama S; Paulmurugan, Ramasamy; Massoud, Tarik F

    2015-12-01

    Glioblastoma (GBM) generally exhibits high IC50 values for its standard drug treatment, temozolomide (TMZ). MicroRNA-21 (miR-21) is an oncomiR overexpressed in GBM, thus controlling important aspects of glioma biology. We hypothesized that PLGA nanoparticles carrying antisense miR-21 to glioblastoma cells might beneficially knock down endogenous miR-21 prior to TMZ treatment. PLGA nanoparticles encapsulating antisense miR-21 were effective in intracellular delivery and sustained silencing (p < 0.01) of miR-21 function in U87 MG, LN229, and T98G cells. Prior antisense miR-21 delivery significantly reduced the number of viable cells (p < 0.001), and increased (1.6-fold) cell cycle arrest at G2/M phase upon TMZ treatment in U87 MG cells. There was overexpression of the miR-21 target genes PTEN (by 67%) and caspase-3 (by 15%) upon cotreatment. This promising PLGA nanoparticle-based platform for antisense miR-21 delivery to GBM is an effective cotherapeutic strategy in cell culture, warranting the need for further studies prior to future clinical translation. PMID:26559642

  9. Therapeutic interactions of autophagy with radiation and temozolomide in glioblastoma: evidence and issues to resolve.

    PubMed

    Koukourakis, Michael I; Mitrakas, Achilleas G; Giatromanolaki, Alexandra

    2016-03-01

    Glioblastoma is a unique model of non-metastasising disease that kills the vast majority of patients through local growth, despite surgery and local irradiation. Glioblastoma cells are resistant to apoptotic stimuli, and their death occurs through autophagy. This review aims to critically present our knowledge regarding the autophagic response of glioblastoma cells to radiation and temozolomide (TMZ) and to delineate eventual research directions to follow, in the quest of improving the curability of this incurable, as yet, disease. Radiation and TMZ interfere with the autophagic machinery, but whether cell response is driven to autophagy flux acceleration or blockage is disputable and may depend on both cell individuality and radiotherapy fractionation or TMZ schedules. Potent agents that block autophagy at an early phase of initiation or at a late phase of autolysosomal fusion are available aside to agents that induce functional autophagy, or even demethylating agents that may unblock the function of autophagy-initiating genes in a subset of tumours. All these create a maze, which if properly investigated can open new insights for the application of novel radio- and chemosensitising policies, exploiting the autophagic pathways that glioblastomas use to escape death. PMID:26889975

  10. Therapeutic interactions of autophagy with radiation and temozolomide in glioblastoma: evidence and issues to resolve

    PubMed Central

    Koukourakis, Michael I; Mitrakas, Achilleas G; Giatromanolaki, Alexandra

    2016-01-01

    Glioblastoma is a unique model of non-metastasising disease that kills the vast majority of patients through local growth, despite surgery and local irradiation. Glioblastoma cells are resistant to apoptotic stimuli, and their death occurs through autophagy. This review aims to critically present our knowledge regarding the autophagic response of glioblastoma cells to radiation and temozolomide (TMZ) and to delineate eventual research directions to follow, in the quest of improving the curability of this incurable, as yet, disease. Radiation and TMZ interfere with the autophagic machinery, but whether cell response is driven to autophagy flux acceleration or blockage is disputable and may depend on both cell individuality and radiotherapy fractionation or TMZ schedules. Potent agents that block autophagy at an early phase of initiation or at a late phase of autolysosomal fusion are available aside to agents that induce functional autophagy, or even demethylating agents that may unblock the function of autophagy-initiating genes in a subset of tumours. All these create a maze, which if properly investigated can open new insights for the application of novel radio- and chemosensitising policies, exploiting the autophagic pathways that glioblastomas use to escape death. PMID:26889975

  11. BMS-536924, an ATP-competitive IGF-1R/IR inhibitor, decreases viability and migration of temozolomide-resistant glioma cells in vitro and suppresses tumor growth in vivo.

    PubMed

    Zhou, Qiao

    2015-01-01

    Glioma is the most common type of primary brain tumor. Despite the combination of surgery, chemotherapy, and radiotherapy, the median survival duration of patients with malignant glioma is still very short. Temozolomide (TMZ) is the primary and most promising therapeutic drug for glioma; however, it is easy to develop acquired resistance during treatment. Activation of receptor tyrosine kinases (RTKs) has been identified to be involved in the acquisition of resistance toward many anticancer drugs. So inhibition of RTKs might be a promising therapeutic strategy for overcoming or attenuating acquired drug resistance. Here, we have investigated the anticancer activities of BMS-536924, an ATP-competitive IGF-1R/IR inhibitor in glioma, especially TMZ-resistant glioma, both in vitro and in vivo. We found that BMS-536924 could effectively reduce viability of both TMZ-sensitive and -resistant glioma cells. BMS-536924 induced dramatic apoptosis in TMZ-resistant cells, and it also dramatically inhibited migration of TMZ-resistant cells. Importantly, BMS-536924 significantly suppressed glioma tumor growth in vivo. This is the first report on anticancer activity of BMS-536924 in glioma. BMS-536924 is a promising compound in the therapy of glioma, especially of TMZ-resistant glioma, which might shed new light on glioma therapy.

  12. Temozolomide-Associated Bronchiolitis Obliterans Organizing Pneumonia Successfully Treated with High-Dose Corticosteroid

    PubMed Central

    Kim, Tae-Ok; Kang, Hyun-Wook; Chi, Su-Young; Ban, Hee-Jung; Kwon, Yong-Soo; Kim, Kyu-Sik; Kim, Yu-Il; Lim, Sung-Chul; Kim, Young-Chul

    2012-01-01

    Temozolomide is an oral alkylating agent with clinical activity against glioblastoma multiforme (GM). It is generally well-tolerated and has few pulmonary side effects. We report a case of temozolomide-associated brochiolitis obliterans organizing pneumonia (BOOP) requiring very high-dose corticosteroid treatment. A 56-yr-old woman presented with a 2-week history of exertional dyspnea. For the treatment of GM diagnosed 4 months previously, she had undergone surgery followed by chemoradiotherapy, and then planned adjuvant chemotherapy with temozolomide. After the 1st cycle, progressive dyspnea was gradually developed. Chest radiograph showed diffuse patchy peribronchovascular ground-glass opacities in both lungs. Conventional dose of methylprednisolone (1 mg/kg/day) was begun for the possibility of BOOP. Although transbronchial lung biopsy findings were compatible with BOOP, the patient's clinical course was more aggravated until hospital day 5. After the dose of methylprednisolone was increased (500 mg/day for 5 days) radiologic findings were improved dramatically. PMID:22468112

  13. Quality of life in low-grade glioma patients receiving temozolomide

    PubMed Central

    Liu, Raymond; Solheim, Karla; Polley, Mei-Yin; Lamborn, Kathleen R.; Page, Margaretta; Fedoroff, Anne; Rabbitt, Jane; Butowski, Nicholas; Prados, Michael; Chang, Susan M.

    2009-01-01

    The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy–Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients’ QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working. PMID:18713953

  14. Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas

    PubMed Central

    Ulasov, Ilya; Thaci, Bart; Sarvaiya, Purvaba; Yi, Ruiyang; Guo, Donna; Auffinger, Brenda; Pytel, Peter; Zhang, Lingjiao; Kim, Chung Kwon; Borovjagin, Anton; Dey, Mahua; Han, Yu; Baryshnikov, Anatoly Y; Lesniak, Maciej S

    2013-01-01

    Abstract Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy. Glioblastoma remains an incurable form of brain cancer. In this manuscript, we show that inhibition of MMP14 can potentiate the efficacy of current standard of care which includes chemo- and radiotherapy. PMID:24156018

  15. Erythropoietin Augments Survival of Glioma Cells After Radiation and Temozolomide

    SciTech Connect

    Hassouna, Imam; Sperling, Swetlana; Kim, Ella; Schulz-Schaeffer, Walter; Rave-Fraenk, Margret; Hasselblatt, Martin; Jelkmann, Wolfgang; Giese, Alf; Ehrenreich, Hannelore

    2008-11-01

    Purpose: Despite beneficial effects of irradiation/chemotherapy on survival of glioblastoma (GBM) patients, collateral damage to intact neural tissue leads to 'radiochemobrain' and reduced quality of life in survivors. For prophylactic neuroprotection, erythropoietin (EPO) is a promising candidate, provided that concerns regarding potential tumor promoting effects are alleviated. Methods and Materials: Human GBM-derived cell lines U87, G44, G112, and the gliosarcoma-derived line G28 were treated with EPO, with and without combinations of irradiation or temozolomide (TMZ). Responsiveness of glioma cells to EPO was measured by cell migration from spheroids, cell proliferation, and clonogenic survival. Implantation of U87 cells into brains of nude mice, followed 5 days later by EPO treatment (5,000 U/kg intraperitoneal every other day for 2 weeks) should reveal effects of EPO on tumor growth in vivo. Reverse transcriptase-polymerase chain reaction was performed for EPOR, HIF-1{alpha}, and epidermal growth factor receptor (EGFR)vIII in cell lines and 22 human GBM specimens. Results: EPO did not modulate basal glioma cell migration and stimulated proliferation in only one of four cell lines. Importantly, EPO did not enhance tumor growth in mouse brains. Preincubation of glioma cells with EPO for 3 h, followed by irradiation and TMZ for another 24 h, resulted in protection against chemoradiation-induced cytotoxicity in three cell lines. Conversely, EPO induced a dose-dependent decrease in survival of G28 gliosarcoma cells. In GBM specimens, expression of HIF-1{alpha} correlated positively with expression of EPOR and EGFRvIII. EPOR and EGFRvIII expression did not correlate. Conclusions: EPO is unlikely to appreciably influence basal glioma growth. However, concomitant use of EPO with irradiation/chemotherapy in GBM patients is not advisable.

  16. Targeting miR-381-NEFL axis sensitizes glioblastoma cells to temozolomide by regulating stemness factors and multidrug resistance factors

    PubMed Central

    Wang, Zeyou; Yang, Jing; Xu, Gang; Wang, Wei; Liu, Changhong; Yang, Honghui; Yu, Zhibin; Lei, Qianqian; Xiao, Lan; Xiong, Jing; Zeng, Liang; Xiang, Juanjuan; Ma, Jian; Li, Guiyuan; Wu, Minghua

    2015-01-01

    MicroRNA-381 (miR-381) is a highly expressed onco-miRNA that is involved in malignant progression and has been suggested to be a good target for glioblastoma multiforme (GBM) therapy. In this study, we employed two-dimensional fluorescence differential gel electrophoresis (2-D DIGE) and MALDI–TOF/TOF-MS/MS to identify 27 differentially expressed proteins, including the significantly upregulated neurofilament light polypeptide (NEFL), in glioblastoma cells in which miR-381 expression was inhibited. We identified NEFL as a novel target molecule of miR-381 and a tumor suppressor gene. In human astrocytoma clinical specimens, NEFL was downregulated with increased levels of miR-381 expression. Either suppressing miR-381 or enforcing NEFL expression dramatically sensitized glioblastoma cells to temozolomide (TMZ), a promising chemotherapeutic agent for treating GBMs. The mechanism by which these cells were sensitized to TMZ was investigated by inhibiting various multidrug resistance factors (ABCG2, ABCC3, and ABCC5) and stemness factors (ALDH1, CD44, CKIT, KLF4, Nanog, Nestin, and SOX2). Our results further demonstrated that miR-381 overexpression reversed the viability of U251 cells exhibiting NEFL-mediated TMZ sensitivity. In addition, NEFL-siRNA also reversed the proliferation rate of U251 cells exhibiting locked nucleic acid (LNA)-anti-miR-381-mediated TMZ sensitivity. Overall, the miR-381-NEFL axis is important for TMZ resistance in GBM and may potentially serve as a novel therapeutic target for glioma. PMID:25605243

  17. The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells.

    PubMed

    Lee, Seung Woo; Kim, Hyun-Kyung; Lee, Na-Hyeon; Yi, Hee-Yeon; Kim, Hong-Sug; Hong, Sung Hee; Hong, Yong-Kil; Joe, Young Ae

    2015-05-01

    Temozolomide (TMZ) is an alkylating agent used for the treatment of glioblastoma. The late autophagy inhibitor chloroquine (CQ) inhibits glioblastoma tumors in a p53-independent and p53-dependent manner. We addressed a possible beneficial effect of combination treatment with TMZ and CQ by examining the molecular and cellular mechanism of co-treatment. Combination treatment of U87 cell (wild type p53) with TMZ and CQ synergistically reduced cell proliferation and enhanced apoptosis, with increased sub-G1 hypodiploid cells and caspase activation. This effect was abolished by a pan-caspase inhibitor, Z-VAD-FMK. TMZ induced autophagy, and the addition of CQ further increased autophagic vacuoles. Inhibition of early stages of autophagy by Beclin 1 knockdown and 3-methyladenine pretreatment prevented the enhanced effect of the combination treatment. The combination treatment also upregulated p53 and phospho-p53 levels, whereas p53 knockdown or overexpression of mutant p53 abolished the combination effect. In contrast, combination therapy had no enhanced effect on U373 cell (mutant p53) proliferation and apoptosis within 3 d, although TMZ induced autophagy and co-treatment with CQ increased autophagic vacuole accumulation. However, long term combination treatment for 9-10 d effectively decreased clonal and cellular growth with increased G2-M arrest. This effect was also abolished by Beclin 1 knockdown. Our data support the beneficial effect of combination treatment with TMZ and CQ in glioma via differential autophagy-associated mechanisms, depending on p53 status. PMID:25681668

  18. The Effect of Chemoradiotherapy with SRC Tyrosine Kinase Inhibitor, PP2 and Temozolomide on Malignant Glioma Cells In Vitro and In Vivo

    PubMed Central

    Eom, Keun-Yong; Cho, Bong Jun; Choi, Eun Jung; Kim, Jin-Ho; Chie, Eui Kyu; Wu, Hong-Gyun; Kim, Il Han; Paek, Sun Ha; Kim, Jae-Sung; Kim, In Ah

    2016-01-01

    Purpose We investigated the effect of chemoradiotherapy with PP2 and temozolomide (TMZ) on malignant glioma cells using clonogenic assays and in vivo brain tumor model. Materials and Methods The effect of PP2 on radiosensitivity of U251 and T98G cells was investigated using clonogenic assays. The expression of E-cadherin, matrix metalloproteinases 2 (MMP2), Ephrin type-A receptor 2 (EphA2), and vascular endothelial growth factor (VEGF) was measured by Western blotting and an accumulation of γH2AX foci 6 hours after radiotherapy was measured after PP2 treatment. The effect of PP2 on migration, invasion, and vasculogenic mimicry formation (VMF) of U251 cells was evaluated. In an orthotopical brain tumor model with U251 cells, PP2 was injected intraperitoneally with or without oral TMZ before, during and after whole brain radiotherapy. Bioluminescence images were taken to visualize in vivo tumors and immunohistochemical staining of VEGF, CD31, EphA2, and hypoxia-inducible factor 1a was performed. Results PP2 increased radiosensitivity of U251 and T98G cells without decreasing survival of normal human astrocytes. Chemoradiotherapy with PP2 and TMZ resulted in increased accumulation of γH2AX foci. PP2 induced overexpression of E-cadherin and suppression of MMP2, VEGF, and EphA2. PP2 also compromised invasion, migration, and VMF of U251 cells. In brain tumors, chemoradiotherapy with PP2 and TMZ decreased tumor volume best, but not statistically significantly compared with chemoradiotherapy with TMZ. The expression of VEGF and CD31 was suppressed in PP2-treated tumors. Conclusion PP2 enhances radiosensitivity of malignant glioma cells and suppresses invasion and migration of U251 cells. Chemoradiotherapy with PP2 and TMZ resulted in non-significant tumor volume decrease. PMID:26044161

  19. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells.

    PubMed

    Ma, Jian; Yang, Yan-Ru; Chen, Wei; Chen, Mei-Hua; Wang, Hao; Wang, Xiao-Dan; Sun, Li-Li; Wang, Feng-Ze; Wang, De-Cai

    2016-08-01

    Although temozolomide (TMZ) is the most effective chemotherapy agent for glioma, chemotherapy resistance has limited its clinical use. Fluoxetine (FLT), which is widely used in cancer-related depression, has exhibited potent anticancer properties in different cancer cell types. The aim of this study was i) to evaluate the antitumor mechanism of FLT, and ii) to further evaluate the effects of a combination of FLT and TMZ on glioma cells. Glioma cell lines were exposed to FLT and/or TMZ. Cell viability and apoptosis were examined by CCK-8 assay, flow cytometry and caspase-3 activity assay, respectively. The expression of endoplasmic reticulum-stress (ERS) apoptosis-related proteins was measured using real-time PCR and western blotting. Synergism between the two drugs was evaluated by the combination index (CI) through CompuSyn software. FLT significantly and dose-dependently inhibited the proliferation of various glioma cell lines, and rat glioma C6 cells had a highly sensitive response to the addition of FLT. FLT treatment increased the early apoptosis rate, induced typical apoptotic morphology in the C6 cells and activated caspase-3 with no change in the mitochondrial membrane potential. Further study showed that FLT activated the ERS marker, CHOP. This induction was associated with activation of the PERK-eIF2α-ATF4 and ATF6 cascade. Concomitantly, GADD34, a downstream molecule of CHOP, was also increased. Combined FLT and TMZ treatment showed a synergistic cytotoxic effect in the C6 glioma cells. Knockdown of CHOP expression abolished the synergistic effect of FLT and TMZ in the C6 cells, which suggests that FLT may sensitize glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. These results revealed that FLT induced glioma cell apoptosis and sensitized glioma cells to TMZ through activation of the CHOP‑dependent apoptosis pathway. The present study provides a primary basis for using the combination of these drugs in patients with

  20. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells.

    PubMed

    Ma, Jian; Yang, Yan-Ru; Chen, Wei; Chen, Mei-Hua; Wang, Hao; Wang, Xiao-Dan; Sun, Li-Li; Wang, Feng-Ze; Wang, De-Cai

    2016-08-01

    Although temozolomide (TMZ) is the most effective chemotherapy agent for glioma, chemotherapy resistance has limited its clinical use. Fluoxetine (FLT), which is widely used in cancer-related depression, has exhibited potent anticancer properties in different cancer cell types. The aim of this study was i) to evaluate the antitumor mechanism of FLT, and ii) to further evaluate the effects of a combination of FLT and TMZ on glioma cells. Glioma cell lines were exposed to FLT and/or TMZ. Cell viability and apoptosis were examined by CCK-8 assay, flow cytometry and caspase-3 activity assay, respectively. The expression of endoplasmic reticulum-stress (ERS) apoptosis-related proteins was measured using real-time PCR and western blotting. Synergism between the two drugs was evaluated by the combination index (CI) through CompuSyn software. FLT significantly and dose-dependently inhibited the proliferation of various glioma cell lines, and rat glioma C6 cells had a highly sensitive response to the addition of FLT. FLT treatment increased the early apoptosis rate, induced typical apoptotic morphology in the C6 cells and activated caspase-3 with no change in the mitochondrial membrane potential. Further study showed that FLT activated the ERS marker, CHOP. This induction was associated with activation of the PERK-eIF2α-ATF4 and ATF6 cascade. Concomitantly, GADD34, a downstream molecule of CHOP, was also increased. Combined FLT and TMZ treatment showed a synergistic cytotoxic effect in the C6 glioma cells. Knockdown of CHOP expression abolished the synergistic effect of FLT and TMZ in the C6 cells, which suggests that FLT may sensitize glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. These results revealed that FLT induced glioma cell apoptosis and sensitized glioma cells to TMZ through activation of the CHOP‑dependent apoptosis pathway. The present study provides a primary basis for using the combination of these drugs in patients with

  1. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells

    PubMed Central

    Ma, Jian; Yang, Yan-Ru; Chen, Wei; Chen, Mei-Hua; Wang, Hao; Wang, Xiao-Dan; Sun, Li-Li; Wang, Feng-Ze; Wang, De-Cai

    2016-01-01

    Although temozolomide (TMZ) is the most effective chemotherapy agent for glioma, chemotherapy resistance has limited its clinical use. Fluoxetine (FLT), which is widely used in cancer-related depression, has exhibited potent anticancer properties in different cancer cell types. The aim of this study was i) to evaluate the antitumor mechanism of FLT, and ii) to further evaluate the effects of a combination of FLT and TMZ on glioma cells. Glioma cell lines were exposed to FLT and/or TMZ. Cell viability and apoptosis were examined by CCK-8 assay, flow cytometry and caspase-3 activity assay, respectively. The expression of endoplasmic reticulum-stress (ERS) apoptosis-related proteins was measured using real-time PCR and western blotting. Synergism between the two drugs was evaluated by the combination index (CI) through CompuSyn software. FLT significantly and dose-dependently inhibited the proliferation of various glioma cell lines, and rat glioma C6 cells had a highly sensitive response to the addition of FLT. FLT treatment increased the early apoptosis rate, induced typical apoptotic morphology in the C6 cells and activated caspase-3 with no change in the mitochondrial membrane potential. Further study showed that FLT activated the ERS marker, CHOP. This induction was associated with activation of the PERK-eIF2α-ATF4 and ATF6 cascade. Concomitantly, GADD34, a downstream molecule of CHOP, was also increased. Combined FLT and TMZ treatment showed a synergistic cytotoxic effect in the C6 glioma cells. Knockdown of CHOP expression abolished the synergistic effect of FLT and TMZ in the C6 cells, which suggests that FLT may sensitize glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. These results revealed that FLT induced glioma cell apoptosis and sensitized glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. The present study provides a primary basis for using the combination of these drugs in patients with

  2. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM.

    PubMed

    Tomicic, Maja T; Meise, Ruth; Aasland, Dorthe; Berte, Nancy; Kitzinger, Rebekka; Krämer, Oliver H; Kaina, Bernd; Christmann, Markus

    2015-10-20

    The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs. PMID:26418950

  3. Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide.

    PubMed

    Triscott, Joanna; Lee, Cathy; Hu, Kaiji; Fotovati, Abbas; Berns, Rachel; Pambid, Mary; Luk, Margaret; Kast, Richard E; Kong, Esther; Toyota, Eric; Yip, Stephen; Toyota, Brian; Dunn, Sandra E

    2012-10-01

    Glioblastomas (GBM) are associated with high rates of relapse. These brain tumors are often resistant to chemotherapies like temozolomide (TMZ) and there are very few treatment options available to patients. We recently reported that polo-like kinase-1 (PLK1) is associated with the proliferative subtype of GBM; which has the worst prognosis. In this study, we addressed the potential of repurposing disulfiram (DSF), a drug widely used to control alcoholism for the past six decades. DSF has good safety profiles and penetrates the blood-brain barrier. Here we report that DSF inhibited the growth of TMZ resistant GBM cells, (IC90=100 nM), but did not affect normal human astrocytes. At similar DSF concentrations, self-renewal was blocked by ~100% using neurosphere growth assays. Likewise the drug completely inhibited the self-renewal of the BT74 and GBM4 primary cell lines. Additionally, DSF suppressed growth and self-renewal of primary cells from two GBM tumors.These cells were resistant to TMZ, had unmethylated MGMT, and expressed high levels of PLK1. Consistent with its role in suppressing GBM growth, DSF inhibited the expression of PLK1 in GBM cells. Likewise, PLK1 inhibition with siRNA, or small molecules (BI-2536 or BI-6727) blocked growth of TMZ resistant cells. Our studies suggest that DSF has the potential to be repurposed for treatment of refractory GBM. PMID:23047041

  4. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM

    PubMed Central

    Aasland, Dorthe; Berte, Nancy; Kitzinger, Rebekka; Krämer, Oliver H.; Kaina, Bernd; Christmann, Markus

    2015-01-01

    The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs. PMID:26418950

  5. Double-salting out assisted liquid-liquid extraction (SALLE) HPLC method for estimation of temozolomide from biological samples.

    PubMed

    Jain, Darshana; Athawale, Rajani; Bajaj, Amrita; Shrikhande, Shruti

    2014-11-01

    The role of temozolomide (TMZ) in treatment of high grade gliomas, melanomas and other malignancies is being defined by the current clinical developmental trials. Temozolomide belongs to the group of alkylating agents and is prescribed to patients suffering from most aggressive forms of brain tumors. The estimation techniques for temozolomide from the extracted plasma or biological samples includes high-performance liquid chromatography with UV detection (HPLC-UV), micellar electrokinetic capillary chromatography (MKEC) and liquid chromatography coupled to mass spectroscopy (LC-MS). These methods suffer from disadvantages like low resolution, low sensitivity, low recovery or cost involvement. An analytical method possessing capacity to estimate low quantities of TMZ in plasma samples with high extraction efficiency (%) and high resolution with cost effectiveness needs to be developed. Cost effective, robust and low plasma component interfering HPLC method using salting out liquid-liquid extraction (SALLE) technique was developed and validated for estimation of drug from plasma samples. The extraction efficiency (%) with conventional LLE technique with methanol, ethyl acetate, dichloromethane and acetonitrile was found to be 5.99±2.45, 45.39±4.56, 46.04±1.14 and 46.23±3.67 respectively. Extraction efficiency (%) improved with SALLE where sodium chloride was used as an electrolyte and was found to be 6.80±5.56, 52.01±3.13, 62.69±2.11 and 69.20±1.18 with methanol, ethyl acetate, dichloromethane and acetonitrile as organic solvent. Upon utilization of two salts for extraction (double salting liquid-liquid extraction) the extraction efficiency (%) was further improved and was twice of LLE. It was found that double salting liquid-liquid extraction technique yielded extraction efficiency (%) of 11.71±5.66, 55.62±3.44, 77.28±2.89 and 87.75±0.89. Hence a method based on double SALLE was developed for quantification of TMZ demonstrating linearity in the range of

  6. Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma.

    PubMed

    Wu, Hao; Liu, Qiang; Cai, Tao; Chen, Yu-Dan; Wang, Zhi-Fei

    2015-10-01

    MicroRNA (miR)-146a is a negative regulator of nuclear factor-κB (NF-κB) signaling that affects tumor growth and survival. The present study was undertaken to determine whether the cytotoxicity of curcumin (diferuloylmethane), a natural polyphenolic compound isolated from turmeric (Curcuma longa Linn), in glioblastoma cells is mediated through upregulation of miR‑146a. Human U‑87 MG glioblastoma cells were treated with curcumin and temozolomide (TMZ) alone or in combination, and cell proliferation and apoptosis were assessed. The involvement of miR‑146a and NF‑κB signaling in curcumin‑mediated chemosensitization was explored. Curcumin exposure led to upregulation of miR‑146a in U‑87 MG cells. Combined curcumin and TMZ treatment significantly (P<0.05) inhibited U‑87 MG cell proliferation and induced apoptotic death, compared with each alone. Notably, curcumin‑mediated enhancement of TMZ‑induced apoptosis was blocked by depletion of miR‑146a. By contrast, miR‑146a overexpression enhanced apoptosis and suppressed NF‑κB activation in TMZ‑treated cells. Additionally, pharmacological inhibition of NF‑κB signaling significantly increased TMZ‑induced apoptosis. To the best of our knowledge, the present study provides the first evidence that upregulation of miR‑146a and inactivation of NF‑κB signaling mediates the sensitization of human glioblastoma cells to TMZ-induced apoptosis by curcumin. PMID:26239619

  7. Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase

    PubMed Central

    ARAI, HAJIME; YAMAUCHI, TAKAHIRO; UZUI, KANAKO; UEDA, TAKANORI

    2015-01-01

    The cytotoxicity of the monofunctional alkylator, temozolomide (TMZ), is known to be mediated by mismatch repair (MMR) triggered by O6-alkylguanine. By contrast, the cytotoxicity of bifunctional alkylators, including carmustine (BCNU) and melphalan (MEL), depends on interstrand crosslinks formed through O6-alkylguanine, which is repaired by nucleotide excision repair and recombination. O6-alkylguanine is removed by O6-methylguanine-DNA methyltransferase (MGMT). The aim of the present study was to evaluate the cytotoxicity of TMZ, BCNU and MEL in two different leukemic cell lines (HL-60 and MOLT-4) in the context of DNA repair. The transcript levels of MGMT, ERCC1, hMLH1 and hMSH2 were determined using reverse transcription-quantitative polymerase chain reaction. In addition, the proliferation was measured using the trypan blue exclusion assay. Drug sensitivity was found to vary between the two cell lines. Treatment of the cells with TMZ, BCNU or MEL in combination with O6-benzylguanine, an MGMT inhibitor, was demonstrated to sensitize the two cell lines to these agents. However, the extent of sensitization was not found to be correlated with the expression levels of MGMT transcripts. Furthermore, the drug sensitivity was also not associated with the transcript levels of ERCC1, hMLH1 and hMSH2. Thus, leukemic cells were sensitized to alkylating agents by the inhibition of MGMT. PMID:26622581

  8. Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas

    PubMed Central

    Li, Ming-Yang; Yang, Pei; Liu, Yan-Wei; Zhang, Chuan-Bao; Wang, Kuan-Yu; Wang, Yin-Yan; Yao, Kun; Zhang, Wei; Qiu, Xiao-Guang; Li, Wen-Bin; Peng, Xiao-Xia; Wang, Yong-Zhi; Jiang, Tao

    2016-01-01

    Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro, we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P < 0.0001). These findings were nearly consistent at the mRNA level across 3 independent cohorts. Multivariable analysis indicated that c-Met was an independent prognostic marker after adjusting for age, preoperative Karnofsky Performance Status (KPS) score, the extent of resection, radiotherapy, TMZ chemotherapy, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making. PMID:26879272

  9. Interactions of Nucleic Acid Bases with Temozolomide. Stacked, Perpendicular, and Coplanar Heterodimers.

    PubMed

    Kasende, Okuma Emile; Nziko, Vincent de Paul N; Scheiner, Steve

    2016-09-01

    Temozolomide (TMZ) was paired with each of the five nucleic acid bases, and the potential energy surface searched for all minima, in the context of dispersion-corrected density functional theory and MP2 methods. Three types of arrangements were observed, with competitive stabilities. Coplanar H-bonding structures, reminiscent of Watson-Crick base pairs were typically the lowest in energy, albeit by a small amount. Also very stable were perpendicular arrangements that included one or more H-bonds. The two monomers were stacked approximately parallel to one another in the third category, some of which contained weak and distorted H-bonds. Dispersion was found to be a dominating attractive force, largest for the stacked structures, and smallest for the coplanar dimers.

  10. A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.

    PubMed

    Song, Ye; Hu, Zheng; Long, Hao; Peng, Yuping; Zhang, Xi'an; Que, Tianshi; Zheng, Shihao; Li, Zhiyong; Wang, Gang; Yi, Liu; Liu, Zhen; Fang, Weiyi; Qi, Songtao

    2014-09-01

    HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-β were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, β-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-β signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-β signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.

  11. Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial

    PubMed Central

    Mao, Ying; Yao, Yu; Zhang, Li-Wei; Lu, Yi-Cheng; Chen, Zhong-Ping; Zhang, Jian-Min; Qi, Song-Tao; You, Chao; Wang, Ren-Zhi; Yang, Shu-Yuan; Zhang, Xiang; Wang, Ji-Sheng; Chen, Ju-Xiang; Yang, Qun-Ying; Shen, Hong; Li, Zhi-Yong; Wang, Xiang; Ma, Wen-Bin; Yang, Xue-Jun; Zhen, Hai-Ning; Zhou, Liang-Fu

    2015-01-01

    Background: The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. Methods: A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS). Results: The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively. Conclusions: Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen

  12. Long-Term Survival in Patients with Metastatic Melanoma Treated with DTIC or Temozolomide

    PubMed Central

    Kim, Christina; Lee, Christopher W.; Kovacic, Laurel; Shah, Amil; Klasa, Richard

    2010-01-01

    Background. Patients with metastatic melanoma typically have a poor outcome; however, a small proportion of patients achieve long-term survival (LTS). It is unclear how often LTS is related to sensitivity to chemotherapy. Methods. All patients with metastatic melanoma treated with either dacarbazine (DTIC) or temozolomide (TMZ) at the British Columbia Cancer Agency (BCCA) from January 1, 1988 to February 1, 2006 were identified through the BCCA pharmacy electronic database, which was then linked to the surveillance and outcomes unit to identify patients with LTS, defined as survival ≥18 months following chemotherapy. Results. In total, 397 patients were treated with either DTIC (n = 349) or TMZ (n = 48) and 43 patients (10.8%) were identified with LTS. Two additional patients with LTS were added prior to 1988 for a total of 45 patients. The 5-year overall and progression-free survival rates for patients with LTS were 33% and 16%, respectively. In total, 16% had a complete response (CR) to chemotherapy, which was the only factor identified that correlated with survival in the multivariate analysis. However, most patients with LTS had an incomplete response to chemotherapy. Conclusions. LTS occurs in select patients who achieve a CR to chemotherapy. However, this occurs in only a minority of patients and, in most cases, the longer survival is likely the result of indolent disease biology or host factors. PMID:20538743

  13. Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

    SciTech Connect

    Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd; Tran, David D.; Linette, Gerry; Jalalizadeh, Rohan; Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H.; Huang, Jiayi

    2014-11-15

    Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

  14. Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma

    PubMed Central

    Lou, Emil; Desjardins, Annick; Reardon, David A.; Lipp, Eric S.; Miller, Elizabeth; Herndon, James E.; McSherry, Frances; Friedman, Henry S.; Vredenburgh, James J.

    2015-01-01

    Lessons Learned Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy. Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. Background. Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. Methods. Patients received up to 4 cycles of TMZ at 200 mg/m2 per day on days 1–5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m2 or 340 mg/m2 depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. Results. Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial respons!e, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2–13.5 months). Conclusion. Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM. PMID:26025933

  15. TERT Promoter Mutations Lead to High Transcriptional Activity under Hypoxia and Temozolomide Treatment and Predict Poor Prognosis in Gliomas

    PubMed Central

    Meng, Lingxuan; Li, Zhonghua; Zhang, Xue; Wu, Anhua

    2014-01-01

    Objective This study explored the effects of telomerase reverse transcriptase (TERT) promoter mutations on transcriptional activity of the TERT gene under hypoxic and temozolomide (TMZ) treatment conditions, and investigated the status and prognostic value of these mutations in gliomas. Methods The effect of TERT promoter mutations on the transcriptional activity of the TERT gene under hypoxic and TMZ treatment conditions was investigated in glioma cells using the luciferase assay. TERT promoter mutations were detected in 101 glioma samples (grades I–IV) and 49 other brain tumors by sequencing. TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios from survival analysis of glioma patients were determined relative to the presence of TERT promoter mutations. Results Mutations in the TERT promoter enhanced gene transcription even under hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA expression. Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age. Conclusion TERT promoter mutations were specific to gliomas. TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. These findings demonstrate that TERT promoter mutations are novel prognostic markers for gliomas that can inform prospective therapeutic strategies. PMID:24937153

  16. Inhibition of Na(+)-K(+)-2Cl(-) cotransporter isoform 1 accelerates temozolomide-mediated apoptosis in glioblastoma cancer cells.

    PubMed

    Algharabil, Jehad; Kintner, Douglas B; Wang, Qiwei; Begum, Gulnaz; Clark, Paul A; Yang, Sung-Sen; Lin, Shih-Hua; Kahle, Kristopher T; Kuo, John S; Sun, Dandan

    2012-01-01

    The hallmark of apoptosis is a significant reduction in cell volume (AVD) resulting from loss of K(+)(i) and Cl(-)(i). Loss of cell volume and lowering of ionic strength of intracellular K(+) and Cl(-) occur before any other detectable characteristics of apoptosis. In the present study, temozolomide (TMZ) triggered loss of K(+)(i) and Cl(-)(i) and AVD in primary glioblastoma multiforme (GBM) cancer cells (GC) and GC cancer stem cells (GSC). We hypothesize that Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1) counteracts AVD during apoptosis in GBM cancer cells by regulating cell volume and Cl(-) homeostasis. NKCC1 protein was expressed in both GC and GSC and played an essential role in regulatory volume increase (RVI) in response to hypertonic cell shrinkage and isotonic cell shrinkage. Blocking NKCC1 activity with its potent inhibitor bumetanide abolished RVI. These cells maintained a basal [Cl(-)](i) (~ 68 mM) above the electrochemical equilibrium for Cl(-)(i). NKCC1 also functioned to replenish Cl(-)(i) levels following the loss of Cl(-)(i). TMZ-treated cells exhibited increased phosphorylation of NKCC1 and its up-stream novel Cl(-)/volume-sensitive regulatory kinase WNK1. Inhibition of NKCC1 activity with bumetanide accelerated AVD, early apoptosis, as well as activation of caspase-3 and caspase-8. Taken together, this study strongly suggests that NKCC1 is an essential mechanism in GBM cells to maintain K(+), Cl(-), and volume homeostasis to counteract TMZ-induced loss of K(+), Cl(-) and AVD. Therefore, blocking NKCC1 function augments TMZ-induced apoptosis in glioma cells.

  17. A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients

    PubMed Central

    Raizer, J. J.; Giglio, P.; Hu, J.; Groves, M.; Merrell, R.; Conrad, C.; Phuphanich, S.; Puduvalli, V. K.; Loghin, M.; Paleologos, N.; Yuan, Y.; Liu, D.; Rademaker, A.; Yung, W. K.; Vaillant, B.; Rudnick, J.; Chamberlain, M.; Vick, N.; Grimm, S.; Tremont-Lukats, I. W.; De Groot, J.; Aldape, K.; Gilbert, M. R.

    2016-01-01

    Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29–75) and median KPS was 90 (70–100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2–47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter. PMID:26476729

  18. Validation of the Effectiveness and Safety of Temozolomide during and after Radiotherapy for Newly Diagnosed Glioblastomas: 10-year Experience of a Single Institution

    PubMed Central

    Joo, Jin-Deok; Kim, Hansol; Kim, Young-Hoon; Han, Jung Ho

    2015-01-01

    This study was performed to validate the effectiveness and safety of concurrent chemoradiotherapy and adjuvant therapy with temozolomide for newly diagnosed glioblastoma multiforme as a standard treatment protocol. Between 2004 and 2011, patients newly diagnosed with glioblastoma who were treated with temozolomide during concurrent chemoradiotherapy and adjuvant chemotherapy were included from a single institution and analyzed retrospectively. The primary endpoint was overall survival, and the secondary endpoints were progression-free survival, response, and safety. A total of 71 patients were enrolled in this study. The response rate was 41% (29/71), and the tumor control rate was 80% (57/71). In the 67 patients who completed the concurrent chemoradiotherapy with temozolomide, the median overall survival was 19 months and the 1- and 2-yr overall survival rates were 78.3% and 41.7%, respectively. The median progression free survival was 9 months, and the 1- and 2-yr progression free survival rates were 33.8% and 14.3%, respectively. The mean duration of survival after progression of disease in salvage treatment group was 11.9 (1.3-53.2) months. Concurrent chemoradiotherapy with temozolomide resulted in grade 3 or 4 hematologic toxic effects in 2.8% of the patients. The current protocol of temozolomide during and after radiation therapy is both effective and safe and is still appropriate as the standard protocol for treatment of glioblastoma. An active salvage treatment might be required for a better prognosis. PMID:26539003

  19. Comparison of the effectiveness of whole-brain radiotherapy plus temozolomide versus whole-brain radiotherapy in treating brain metastases based on a systematic review of randomized controlled trials.

    PubMed

    Bai, Gui-Rong; An, Jin-Bing; Chu, Yang; Wang, Xiang-Yang; Li, Shu-Ming; Yan, Kai-Jing; Lü, Fu-Rong; Gu, Ning; Griffin, Amanda N; Sun, Bin-Yuan; Li, Wei; Wang, Guo-Cheng; Zhou, Shui-Ping; Sun, He; Liu, Chang-Xiao

    2016-01-01

    Temozolomide (TMZ) combination with whole-brain radiotherapy (WBRT) has been tested by many randomized controlled trials in the treatment of brain metastases (BMs) in China and other countries. We performed an up-to-date meta-analysis to determine (i) the log odds ratios (LORs) of objective response (ORR) and adverse effects (AEs) for all-grade, and (ii) the T value of mean overall survival in patients with BMs treated with WBRT combined with TMZ versus WBRT alone. PubMed, Chinese National Knowledge Infrastructure, and WanFang Data were searched for articles published up to 28 January 2015. Eligible studies were selected according to the PRISMA statement. ORR, AEs, and 95% confidence intervals were calculated using random-effects models. Eighteen studies were included in our analysis. A total of 1028 participants were enrolled. Summary LORs of ORR were 1.0239 (P<0.0001) on comparing WBRT plus TMZ with WBRT ORR (n=17). The overall mean difference of mean overall survival (n=17) between TMZ plus WBRT and WBRT was 2.2505 weeks (P=0.02185). There was a significant difference between WBRT plus TMZ and WBRT alone with a LOR of AEs for all-grade of (i) 0.923 for gastrointestinal toxicity and (ii) 0.7978 for myelosuppression. Sensitivity analysis and subgroup analysis were also performed. The 18 eligible randomized controlled trials demonstrated that the combination of WBRT and TMZ significantly improves the ORR and is statistically insignificant in prolonging the survival of patients with BMs. In addition, an increase in the incidence of gastrointestinal toxicity and myelosuppression was significant for all-grade. PMID:26426520

  20. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide.

    PubMed

    Chen, Chien-Min; Syu, Jhih-Pu; Way, Tzong-Der; Huang, Li-Jiau; Kuo, Sheng-Chu; Lin, Chung-Tien; Lin, Chih-Li

    2015-11-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti‑glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti‑proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell‑cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy‑mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B‑induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug‑resistant glioblastoma cells to the chemotherapeutic agent TMZ.

  1. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide

    PubMed Central

    CHEN, CHIEN-MIN; SYU, JHIH-PU; WAY, TZONG-DER; HUANG, LI-JIAU; KUO, SHENG-CHU; LIN, CHUNG-TIEN; LIN, CHIH-LI

    2015-01-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti-glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti-proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell-cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy-mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B-induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug-resistant glioblastoma cells to the chemotherapeutic agent TMZ. PMID:26329365

  2. Pine (Pinus morrisonicola Hayata) needle extracts sensitize GBM8901 human glioblastoma cells to temozolomide by downregulating autophagy and O(6)-methylguanine-DNA methyltransferase expression.

    PubMed

    Liao, Chia-Leng; Chen, Chien-Min; Chang, Yan-Zin; Liu, Guang-Yaw; Hung, Hui-Chih; Hsieh, Tung-Ying; Lin, Chih-Li

    2014-10-29

    Pine needle extracts of Pinus morrisonicola (Hayata) are commonly used as a functional health beverage. However, it remains unclear what the mechanism is underlying the antitumor activity of pine needle extract. The aims of present study were to investigate the anti-glioblastoma effects of pine needle extracts as well as its bioactive compounds. From three different solvent extracts of pine needles, the water extract displayed the strongest cytotoxicity effects on GBM8901 glioblastoma cells. The isolated compounds were identified as pinocembrin, chrysin, and tiliroside. Chrysin was the most active ingredient of pine needle extract for the induction of apoptosis and suppression of migration and invasion. It also markedly inhibited temozolomide (TMZ)-induced autophagy and O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Because both autophagy and MGMT overexpression have been implicated to TMZ-induced drug resistance in glioblastoma, our results showed that pine needle extract and chrysin may serve as a potential anticancer agent against glioblastoma, especially with regard to sensitizing glioblastoma cells resistant to TMZ.

  3. Comparison of Corticotropin-Releasing Factor, Dexamethasone and Temozolomide: Treatment Efficacy and Toxicity in U87 and C6 Intracranial Gliomas

    PubMed Central

    Moroz, Maxim A.; Huang, Ruimin; Kochetkov, Tatiana; Shi, Weiji; Thaler, Howard; de Stanchina, Elisa; Gamez, Idoia; Ryan, Robert P.; Blasberg, Ronald G.

    2011-01-01

    Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone (DEX) is an effective drug to treat brain edema, but is associated with well-described side effects. Corticorelin acetate (Xerecept) or human corticotrophin releasing factor (hCRF) is a comparatively new drug and was evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide. In vitro mono- and combination-treatments showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg/q12h) on survival of U87 intracranial xenograft-bearing animals [median survival: control 41 days (95% CI 25–61 d); “low-hCRF” 74.5 d (95% CI 41–88 d); “high-hCRF” >130 d (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with TMZ and TMZ + hCRF - treated animals, but with significant TMZ toxicity. C6-bearing animals showed no survival benefit, but similar treatment toxicities. The difference in hCRF-treatment response between U87- and C6-intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87-xenografts; no CRF-receptors were identified in C6-xenografts. HCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, with long-term survivors and only mild toxicity. HCRF therapeutic efficacy appears to be dependent on tumor hCRF-receptor expression. These results support further clinical assessment hCRF therapeutic efficacy and levels of CRFr expression in different human gliomas. PMID:21385926

  4. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid For Patients With Glioblastoma

    PubMed Central

    Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Fine, Howard A.; Camphausen, Kevin

    2015-01-01

    Purpose Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in pre-clinical models. We evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21–63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8–51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis results were significant for both OS and PFS. VPA levels were not correlated with grade 3/4 toxicity levels. Conclusions Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. PMID:26194676

  5. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

    SciTech Connect

    Krauze, Andra V.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Camphausen, Kevin

    2015-08-01

    Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

  6. MiR-203 sensitizes glioma cells to temozolomide and inhibits glioma cell invasion by targeting E2F3.

    PubMed

    Tang, Guodong; Wu, Jun; Xiao, Gelei; Huo, Lei

    2015-04-01

    Glioma is the most common malignant and fatal primary tumor in the central nervous system in adults. Recent data has suggested a profound role for microRNAs (miRs) in cancer progression. The present study demonstrated, via quantitative polymerase chain reaction (qPCR) analysis, that miR-203 expression was markedly lower in highly invasive U87MG glioma cells and glioma tissues. Wound healing and Transwell assays demonstrated that restoration of miR-203 expression inhibited U87MG cell migration and invasion. Restoration of miR-203 expression additionally sensitized the cells to temozolomide (TMZ) as determined by MTS assay. By contrast, miR-203 inhibition in A172 cells exerted opposite effects. Bioinformatic analysis combined with experimental analysis revealed that miR-203 directly targeted E2F3 via the conserved miR-203 target site within the E2F3 3'-untranslational region. E2F3 knockdown with specific small hairpin RNA also inhibited U87MG cell migration and invasion, and sensitized them to TMZ. Importantly, miR-203 and E2F3 showed inverse expression patterns in invasive glioma tissues, as demonstrated by qPCR and luciferase assay. These results suggested that miR-203 may function as a tumor suppressor in glioma progression and that the miR-203/E2F3 axis may be a novel candidate in the development of rational therapeutic strategies for glioma.

  7. Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma

    SciTech Connect

    Huang, Jiayi; DeWees, Todd A.; Badiyan, Shahed N.; Speirs, Christina K.; Mullen, Daniel F.; Fergus, Sandra; Tran, David D.; Linette, Gerry; Campian, Jian L.; Chicoine, Michael R.; Kim, Albert H.; Dunn, Gavin; Simpson, Joseph R.; Robinson, Clifford G.

    2015-08-01

    Purpose: Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. Methods and Materials: From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/μL within the first 3 months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. Results: Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2 months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46-11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V{sub 25Gy}) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V{sub 25Gy} <56% appeared to be the optimal threshold (OR: 2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). Conclusions: Female sex, older age, lower baseline TLC, and higher brain V{sub 25Gy} are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V{sub 25Gy} of brain below 56% may reduce the risk of ASL.

  8. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression

    PubMed Central

    Gao, Yong-tao; Chen, Xiao-bing; Liu, Hong-lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O6-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity. PMID:27595933

  9. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression.

    PubMed

    Gao, Yong-Tao; Chen, Xiao-Bing; Liu, Hong-Lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O(6)-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity. PMID:27595933

  10. Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression.

    PubMed

    Gao, Yong-Tao; Chen, Xiao-Bing; Liu, Hong-Lin

    2016-01-01

    MicroRNAs (miRNA) are believed to play an important role in glioblastoma multiforme (GBM)chemotherapy. Our study aims to investigate potential miRNA biomarkers in GBM. Sixty GBM patients, which were given temozolomide (TMZ) chemotherapy and recurrent radiotherapy, were recruited. miRNA array was performed in cancerous and in paired normal tissues. Microarray results were further validated by a quantitative real-time PCR in selected tissues and GBM cell lines. TMZ resistance cells were developed and cell proliferation along with colony formation assays was determined. Our study employed H2AX formation and flow cytometry to analyse the role of miRNA in DNA damage and apoptosis. Our study illustrated 16 miRNA in which 9 were up-regulated and 7 down-regulated. and their differential expression were demonstrated in a recurrent GBM tissue. Among them, miRNA-370-3p demonstrated the highest level of down- regulation in tissues and in TMZ resistance cells. miRNA-370-3p mimic increased its expression and sensitivity of GBM cells to TMZ by suppressing the self-reparative ability of tumour cell DNA. O(6)-methylguanine-DNA methyltransferase (MGMT) was identified as the direct target gene of miR-370-3p, and it was found to be inversely correlated with miR-370-3p expression in tissue samples obtained. Thus, our study demonstrated a critical clinical role of an up-regulated miR-370-3p expression in glioblastoma multiforme chemotherapy sensitivity.

  11. AKT2-knockdown suppressed viability with enhanced apoptosis, and attenuated chemoresistance to temozolomide of human glioblastoma cells in vitro and in vivo

    PubMed Central

    Cui, Yong; Lin, Jing; Zuo, Jianling; Zhang, Lei; Dong, Yan; Hu, Guohan; Luo, Chun; Chen, Juxiang; Lu, Yicheng

    2015-01-01

    The AKT2 kinase (protein kinase Bβ) is overexpressed in high-grade gliomas. Upregulation of the AKT2 gene has been previously observed in glioblastoma patients suffering from chemotherapy failure and tumor progress. In this study, we aimed to evaluate the effect of AKT2 on viability and chemoresistance in the human glioblastoma cell line U251. The U251 cell line was stably transfected with short hairpin RNA (shRNA) targeting AKT2. U251 cells underexpressing AKT2 were then examined for viability with temozolomide (TMZ) treatment, and tested for cell apoptosis both in vitro and in tumor-implanted mice. Next, expressions of several chemoresistance-related molecules were measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis. The results showed that the 50% inhibitory concentration (IC50) of AKT2 shRNA-transfected cells was significantly lower compared with Lenti-GFP-transfected and nontransfected controls and that the tumor growth of the AKT2-shRNA and TMZ combined-treated mice was obviously suppressed in either mass or volume. Concomitantly, the apoptosis of TMZ-treated tumor cells was significantly enhanced after knockdown of AKT2, as measured by flow cytometry and in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Furthermore, AKT2-inhibition in TMZ-treated glioblastoma U251 cells upregulated apoptotic effector caspase-3, whereas it downregulated antiapoptotic protein Bcl-2, DNA repairing protein MGMT, and drug efflux pump protein MRP1. Our study identified AKT2 as an important gene in presenting chemoresistance in glioblastoma, and a potential target to potentiate the clinical effect of chemotherapy in glioma treatment. PMID:26185456

  12. Phase II Pilot Study of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-Front Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Interim Analysis of Safety and Tolerability

    SciTech Connect

    Lai, Albert Filka, Emese; McGibbon, Bruce; Nghiemphu, Phioanh Leia; Graham, Carrie; Yong, William H.; Mischel, Paul; Liau, Linda M.; Bergsneider, Marvin; Pope, Whitney; Selch, Michael; Cloughesy, Tim

    2008-08-01

    Purpose: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. Methods and Materials: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m{sup 2} for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m{sup 2} for 5 days every 4 weeks and continuation of BV every 2 weeks. Results: For these 10 patients, toxicities were compiled until study discontinuation or up to {approx}40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. Conclusion: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.

  13. Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma

    PubMed Central

    Wen, Patrick Y.; Omuro, Antonio; Ahluwalia, Manmeet S.; Fathallah-Shaykh, Hassan M.; Mohile, Nimish; Lager, Joanne J.; Laird, A. Douglas; Tang, Jiali; Jiang, Jason; Egile, Coumaran; Cloughesy, Timothy F.

    2015-01-01

    Background This phase I study aimed to evaluate safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of voxtalisib (SAR245409, XL765), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, in combination with temozolomide (TMZ), with or without radiation therapy (RT), in patients with high-grade glioma. Methods Patients received voxtalisib 30–90 mg once daily (q.d.) or 20–50 mg twice daily (b.i.d.), in combination with 200 mg/m2 TMZ (n = 49), or voxtalisib 20 mg q.d. with 75 mg/m2 TMZ and RT (n = 5). A standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose. Patients were evaluated for adverse events (AEs), plasma pharmacokinetics, pharmacodynamic effects in skin biopsies, and tumor response. Results The maximum tolerated doses were 90 mg q.d. and 40 mg b.i.d. for voxtalisib in combination with TMZ. The most frequently reported treatment-related AEs were nausea (48%), fatigue (43%), thrombocytopenia (26%), and diarrhea (24%). The most frequently reported treatment-related grade ≥3 AEs were lymphopenia (13%), thrombocytopenia, and decreased platelet count (9% each). Pharmacokinetic parameters were similar to previous studies with voxtalisib monotherapy. Moderate inhibition of PI3K signaling was observed in skin biopsies. Best response was partial response in 4% of evaluable patients, with stable disease observed in 68%. Conclusions Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition. PMID:26019185

  14. A Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases: Radiation Therapy Oncology Group 0320

    SciTech Connect

    Sperduto, Paul W.; Wang, Meihua; Robins, H. Ian; Schell, Michael C.; Werner-Wasik, Maria; Komaki, Ritsuko; Souhami, Luis; Buyyounouski, Mark K.; Khuntia, Deepak; Demas, William; Shah, Sunjay A.; Nedzi, Lucien A.; Perry, Gad; Suh, John H.; Mehta, Minesh P.

    2013-04-01

    Background: A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. Methods and Materials: NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m{sup 2}/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m{sup 2}/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS. Results: After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). Conclusion: The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.

  15. Hepatic encephalopathy after treatment with temozolomide.

    PubMed

    Goldbecker, Annemarie; Tryc, Anita Blanka; Raab, Peter; Worthmann, Hans; Herrmann, Julian; Weissenborn, Karin

    2011-05-01

    Temozolomide in combination with radiation has been in use for more than 5 years for the therapy of glioblastoma. Known adverse effects concerning the gastrointestinal system are elevation of liver enzymes. We present the case of a patient treated with temozolomide who developed severe cholestatic liver damage and consecutive hepatic encephalopathy. Neurological symptoms were mistaken as being caused by focal brain damage for more than 9 months. After the correct diagnosis had been made and the treatment had been started, the patient's condition ameliorated. In conclusion, neurological deficits in patients with known brain lesion should not be attributed automatically to the pre-existing damage even if it is progressive but should be examined carefully, also including toxic and metabolic encephalopathies into the differential diagnosis. Furthermore, new side effects of drugs have to be considered. At least this case might lead to a closer monitoring of liver enzymes during temozolomide therapy.

  16. Addition of Bevacizumab to Standard Radiation Therapy and Daily Temozolomide Is Associated With Minimal Toxicity in Newly Diagnosed Glioblastoma Multiforme

    SciTech Connect

    Vredenburgh, James J.; Desjardins, Annick; Kirkpatrick, John P.; Reardon, David A.; Peters, Katherine B.; Herndon, James E.; Marcello, Jennifer; Bailey, Leighann; Threatt, Stevie; Sampson, John; Friedman, Allan; Friedman, Henry S.

    2012-01-01

    Purpose: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m{sup 2} daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. Results: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. Conclusions: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

  17. RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

    SciTech Connect

    Chinnaiyan, Prakash; Won, Minhee; Wen, Patrick Y.; Wendland, Merideth; Dipetrillo, Thomas A.; Corn, Benjamin W.; Mehta, Minesh P.

    2013-08-01

    Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.

  18. Glioma-associated endothelial cells are chemoresistant to temozolomide.

    PubMed

    Virrey, Jenilyn J; Golden, Encouse B; Sivakumar, Walavan; Wang, Weijun; Pen, Ligaya; Schönthal, Axel H; Hofman, Florence M; Chen, Thomas C

    2009-10-01

    Temozolomide is considered the standard of care and drug of choice for the treatment of initially diagnosed malignant gliomas. Although well tolerated, temozolomide still has limited clinical efficacy. Following drug treatment, patient prognosis still remains poor; tumor recurrence is almost universal. We hypothesized that this lack of effectiveness with temozolomide is because this drug does not target the glioma microenvironment, which is highly vascular in malignant gliomas. To test this hypothesis we analyzed the effects of temozolomide on the tumor vasculature in vitro and in vivo. We found that this drug did not affect the viability or proliferation rate of endothelial cells isolated from human glioma specimens, although temozolomide was highly cytotoxic to the glioma cell lines U87MG and U251. Furthermore, temozolomide did not inhibit the migration of these glioma-associated endothelial cells, a key mechanism responsible for tumor angiogenesis. In in vivo studies, using the intracranial glioma mouse model, temozolomide did not cause a pronounced effect on microvessel density. Our findings show that temozolomide has no apparent effect on the glioma vascular microenvironment. Thus combination therapy with anti-vascular agents may enhance temozolomide effectiveness as glioma therapeutic protocol.

  19. Effect of Bevacizumab Plus Temozolomide-Radiotherapy for Newly Diagnosed Glioblastoma with Different MGMT Methylation Status: A Meta-Analysis of Clinical Trials

    PubMed Central

    Du, Chigang; Ren, Junquan; Zhang, Rui; Xin, Tao; Li, Zhongmin; Zhang, Zhiti; Xu, Xinghua; Pang, Qi

    2016-01-01

    Background MGMT methylation status can influence the therapeutic effect and prognosis of glioblastoma (GBM). There are conflicting results from studies evaluating the efficacy of bevacizumab (BV) when it is combined with temozolomide (TMZ) and radiotherapy (RT) in patients diagnosed with GBM with different MGMT methylation status. Material/Methods Data were extracted from publications in PubMed, Embase, and The Cochrane Library, with the last search performed March 23, 2016. Data on overall survival (OS), progression-free survival (PFS), and MGMT methylation status were obtained. Results Data from 3 clinical trials for a total of 1443 subjects were used for this meta-analysis. MGMT methylated and unmethylated patients showed improved PFS in the BV group (pooled HRs, 0.769, 95% CIs 0.604–0.978, P=0.032; 0.675, 95%CIs 0.466–0.979, P=0.038). For patients with either type of GBM, BV did not improve the OS based on the pooled HRs 1.132 (95% CIs 0.876–1.462; P=0.345) for methylated and 1.018 (95% CIs 0.879–1.179; P=0.345) for unmethylated. Conclusions Bevacizumab combined with temozolomide-radiotherapy correlated with improved PFS for treatment of patients with different MGMT methylation status of newly diagnosed GBM. There was insufficient evidence to determine the synergistic effects of combining BV with TMZ and RT on improving survival in patients with different MGMT methylation status. PMID:27684457

  20. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide.

    PubMed

    Dresemann, Gregor; Weller, Michael; Rosenthal, Mark A; Wedding, Ulrich; Wagner, Wolfgang; Engel, Erik; Heinrich, Bernhard; Mayer-Steinacker, Regine; Karup-Hansen, Anders; Fluge, Oystein; Nowak, Anna; Mehdorn, Maximilian; Schleyer, Eberhard; Krex, Dietmar; Olver, Ian N; Steinbach, Joachim P; Hosius, Christian; Sieder, Christian; Sorenson, Greg; Parker, Richard; Nikolova, Zariana

    2010-02-01

    A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.

  1. Prediction of Response to Concurrent Chemoradiotherapy with Temozolomide in Glioblastoma: Application of Immediate Post-Operative Dynamic Susceptibility Contrast and Diffusion-Weighted MR Imaging

    PubMed Central

    Lee, Eun Kyoung; Yun, Tae Jin; Kang, Koung Mi; Kim, Tae Min; Lee, Se-Hoon; Park, Chul-Kee; Park, Sung-Hye; Kim, Il Han

    2015-01-01

    Objective To determine whether histogram values of the normalized apparent diffusion coefficient (nADC) and normalized cerebral blood volume (nCBV) maps obtained in contrast-enhancing lesions detected on immediate post-operative MR imaging can be used to predict the patient response to concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ). Materials and Methods Twenty-four patients with GBM who had shown measurable contrast enhancement on immediate post-operative MR imaging and had subsequently undergone CCRT with TMZ were retrospectively analyzed. The corresponding histogram parameters of nCBV and nADC maps for measurable contrast-enhancing lesions were calculated. Patient groups with progression (n = 11) and non-progression (n = 13) at one year after the operation were identified, and the histogram parameters were compared between the two groups. Receiver operating characteristic (ROC) analysis was used to determine the best cutoff value for predicting progression. Progression-free survival (PFS) was determined with the Kaplan-Meier method and the log-rank test. Results The 99th percentile of the cumulative nCBV histogram (nCBV C99) on immediate post-operative MR imaging was a significant predictor of one-year progression (p = 0.033). ROC analysis showed that the best cutoff value for predicting progression after CCRT was 5.537 (sensitivity and specificity were 72.7% and 76.9%, respectively). The patients with an nCBV C99 of < 5.537 had a significantly longer PFS than those with an nCBV C99 of ≥ 5.537 (p = 0.026). Conclusion The nCBV C99 from the cumulative histogram analysis of the nCBV from immediate post-operative MR imaging may be feasible for predicting glioblastoma response to CCRT with TMZ. PMID:26576125

  2. Polymer Nanocomposites Based Thermo-Sensitive Gel for Paclitaxel and Temozolomide Co-Delivery to Glioblastoma Cells.

    PubMed

    Xu, Yuanyuan; Shen, Ming; Sun, Ying; Gao, Pei; Duan, Yourong

    2015-12-01

    In this work, we have reported the preparation and optimization of paclitaxel (PTX) and temozolomide (TMZ) loaded monomethoxy (polyethylene glycol)-poly(D, L-lactide-co-glycolide) (mPEG-PLGA) nanocomposite which is a thermo-sensitive gel delivery system to glioblastoma. We utilized the orthogonal design and homogeneous design for the optimal drug-loaded nanoparticles (NPs) and composite gel prescription, respectively. The physicochemical characteristics of NPs and rheological properties of the gel were analyzed. Then the in vitro release of the gel was determined with a membrane-less diffusion system. Finally, the cytotoxic and apoptosis-inducing effects of the gel on the human malignant glioblastoma cell line U87 and C6 rat glioblastoma cell line were evaluated by MTT and flow cytometry apoptosis assay, respectively. The transmission electron microscopy (TEM) analysis revealed the optimized NPs with a relatively uniform diameter and distribution. The homogeneous design and rheological determination showed that the optimized gel prescription was 250 mg/mL Pluronic F127 (F127), 0.5% hydroxy propyl methylcellulose (HPMC-100M), 0.5% Pluronic F68 (F68), 0.5% sodium alginate (SA) and suitable NPs, which possessed the appropriate gelation behaviors: gelation temperature 28.01 degrees C, gelation time 127.1 s and corrosion speed 0.1892 g/cm2 x hr; and rheological properties: suitable elasticity modulus, viscosity modulus and low phase angle. The in vitro results suggested that the PTX and TMZ were sustainedly released from nanoparticles or the composite gel, and the release and elimination time greatly prolonged; and the composite gel possessed much higher growth-inhibiting effect and apoptosis-inducing rate in U87 and C6 cells than other formulations. These findings demonstrated that the optimal gel was a promising delivery system for the interstitial chemotherapy to glioblastoma. PMID:26682412

  3. MicroRNA-93 promotes the malignant phenotypes of human glioma cells and induces their chemoresistance to temozolomide

    PubMed Central

    Chen, Rui; Liu, Huan; Cheng, Quan; Jiang, Bing; Peng, Renjun; Zou, Qin; Yang, Wenren; Yang, Xiaosheng; Wu, Xiaobing; Chen, Zigui

    2016-01-01

    ABSTRACT MicroRNAs (miRNAs), a class of small non-coding RNAs, can induce mRNA degradation or repress translation by binding to the 3′-untranslated region (UTR) of its target mRNA. Recently, some specific miRNAs, e.g. miR-93, have been found to be involved in pathological processes by targeting some oncogenes or tumor suppressors in glioma. However, the regulatory mechanism of miR-93 in the biological behaviors and chemoresistance of glioma cells remains unclear. In the present study, in situ hybridization and real-time RT-PCR data indicated that miR-93 was significantly upregulated in glioma patients (n=43) compared with normal brain tissues (n=8). Moreover, the upregulated miR-93 level was significantly associated with the advanced malignancy. We also found that upregulation of miR-93 promoted the proliferation, migration and invasion of glioma cells, and that miR-93 was involved in the regulation of cell cycle progression by mediating the protein levels of P21, P27, P53 and Cyclin D1. P21 was further identified as a direct target of miR-93. Knockdown of P21 attenuated the suppressive effects of miR-93 inhibition on cell cycle progression and colony formation. In addition, inhibition of miR-93 enhanced the chemosensitization of glioma cells to temozolomide (TMZ). Based on these above data, our study demonstrates that miR-93, upregulated in glioma, promotes the proliferation, cell cycle progression, migration and invasion of human glioma cells and suppresses their chemosensitivity to TMZ. Therefore, miR-93 may become a promising diagnostic marker and therapeutic target for glioma. PMID:27185265

  4. Organized Pneumonia Secondary to Increasing Doses of Temozolomide

    PubMed Central

    Consuegra Vanegas, Angélica; Matachana Martínez, María; Cordero Lorenzana, Lourdes; Vidal García, Iria; Montero Martínez, Carmen

    2015-01-01

    Surgery, radiotherapy (RT), and chemotherapy have a role in the control of tumor growth, progression, and recurrence in high-grade gliomas. Temozolomide has been incorporated as the main chemotherapy agent for managing these tumors. Here, we present a case of a patient who developed a severe organizing pneumonia after increasing doses of temozolomide for a high-grade glioma. PMID:26487994

  5. Temozolomide-perillyl alcohol conjugate induced reactive oxygen species accumulation contributes to its cytotoxicity against non-small cell lung cancer

    PubMed Central

    Song, Xingguo; Xie, Li; Wang, Xingwu; Zeng, Qian; Chen, Thomas C.; Wang, Weijun; Song, Xianrang

    2016-01-01

    Temozolomide-perillyl alcohol conjugate (TMZ − POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and TMZ-resistant gliomas. In a current study we had demonstrated how TMZ − POH also exhibited its cytotoxicity against non-small cell lung cancer (NSCLC), the most common type of lung cancer, as evidence from cell/tumor proliferation inhibition, G2/M arrest, DNA damage and mitochondrial apoptosis. Importantly, TMZ − POH’s cytotoxicity is closely related to reactive oxygen species (ROS) accumulation because it can be reversed by two ROS scavengers, catalase (CAT) and N-acetyl-L-cysteine (NAC). TMZ − POH induces mitochondrial transmembrane potential (MTP) decrease and ROS accumulation, in turn activates mitogen-activated protein kinase (MAPKs) signaling and mitochondrial apoptosis, and then exerts its cytotoxicity, thus proposing TMZ − POH as a potential therapeutic candidate for NSCLC. PMID:26949038

  6. Radiologic response to radiation therapy concurrent with temozolomide for progressive simple dysembryoplastic neuroepithelial tumor.

    PubMed

    Morr, Simon; Qiu, Jingxin; Prasad, Dheerendra; Mechtler, Laszlo L; Fenstermaker, Robert A

    2016-07-01

    Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment.

  7. Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma

    PubMed Central

    Butowski, Nicholas; Chang, Susan M.; Lamborn, Kathleen R.; Polley, Mei–Yin; Pieper, Russell; Costello, Joseph F.; Vandenberg, Scott; Parvataneni, Rupa; Nicole, Angelina; Sneed, Patricia K.; Clarke, Jennifer; Hsieh, Emily; Costa, Bruno M.; Reis, Rui M.; Hristova-Kazmierski, Maria; Nicol, Steven J.; Thornton, Donald E.; Prados, Michael D.

    2011-01-01

    This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m2 daily during RT and then adjuvantly at 200 mg/m2 daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotininb and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials. PMID:21896554

  8. Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

    PubMed

    Butowski, Nicholas; Chang, Susan M; Lamborn, Kathleen R; Polley, Mei-Yin; Pieper, Russell; Costello, Joseph F; Vandenberg, Scott; Parvataneni, Rupa; Nicole, Angelina; Sneed, Patricia K; Clarke, Jennifer; Hsieh, Emily; Costa, Bruno M; Reis, Rui M; Hristova-Kazmierski, Maria; Nicol, Steven J; Thornton, Donald E; Prados, Michael D

    2011-12-01

    This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

  9. [Influenza vaccine and adjuvant].

    PubMed

    Nakayama, Tetsuo

    2011-01-01

    Adjuvant is originated from the Latin word "adjuvare" which means "help" in English to enhance the immunological responses when given together with antigens. The beginning of adjuvant was mineral oil which enhanced the immune response when it was given with inactivated Salmonella typhimurium. Aluminium salt was used to precipitate diphtheria toxoid and increased level of antibody response was demonstrated when administered with alum-precipitated antigens. Since 1930, aluminium salt has been used as DTaP (diphtheria-tetanus-acellular pertussis vaccine) adjuvant. Many candidates were tested for adjuvant activity but only aluminum salt is allowed to use for human vaccines. New adjuvant MF59, oil-in-water emulsion type, was developed for influenza vaccine for elderly (Fluad) and series of AS adjuvant are used for hepatitis B, pandemic flue, and human papiloma virus vaccines. Oil-adjuvanted influenza pandemic vaccines induced higher antibody response than alum-adjuvanted vaccine with higher incidence of adverse events, especially for local reactions. Alum-adjuvanted whole virion inactivated H5N1 vaccine was developed in Japan, and it induced relatively well immune responses in adults. When it applied for children, febrile reaction was noted in approximately 60% of the subjects, with higher antibodies. Recent investigation on innate immunity demonstrates that adjuvant activity is initiated from the stimulation on innate immunity and/or inflammasome, resulting in cytokine induction and antigen uptake by monocytes and macrophages. The probable reason for high incidence of febrile reaction should be investigated to develop a safe and effective influenza vaccine.

  10. NKG2D- and T-cell receptor-dependent lysis of malignant glioma cell lines by human γδ T cells: Modulation by temozolomide and A disintegrin and metalloproteases 10 and 17 inhibitors

    PubMed Central

    Chitadze, Guranda; Lettau, Marcus; Luecke, Stefanie; Wang, Ting; Janssen, Ottmar; Fürst, Daniel; Mytilineos, Joannis; Wesch, Daniela; Oberg, Hans-Heinrich; Held-Feindt, Janka; Kabelitz, Dieter

    2016-01-01

    ABSTRACT The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) and UL-16 binding protein (ULBP) family members expressed on tumor cells with the corresponding NKG2D receptor triggers cytotoxic effector functions in NK cells and γδ T cells. However, as a mechanism of tumor immune escape, NKG2D ligands (NKG2DLs) can be released from the cell surface. In this study, we investigated the NKG2DL system in different human glioblastoma (GBM) cell lines, the most lethal brain tumor in adults. Flow cytometric analysis and ELISA revealed that despite the expression of various NKG2DLs only ULBP2 is released as a soluble protein via the proteolytic activity of “a disintegrin and metalloproteases” (ADAM) 10 and 17. Moreover, we report that temozolomide (TMZ), a chemotherapeutic agent in clinical use for the treatment of GBM, increases the cell surface expression of NKG2DLs and sensitizes GBM cells to γδ T cell-mediated lysis. Both NKG2D and the T-cell receptor (TCR) are involved. The cytotoxic activity of γδ T cells toward GBM cells is strongly enhanced in a TCR-dependent manner by stimulation with pyrophosphate antigens. These data clearly demonstrate the complexity of mechanisms regulating NKG2DL expression in GBM cells and further show that treatment with TMZ can increase the immunogenicity of GBM. Thus, TMZ might enhance the potential of the adoptive transfer of ex vivo expanded γδ T cells for the treatment of malignant glioblastoma. PMID:27141377

  11. MGMT Gene Promoter Methylation as a Potent Prognostic Factor in Glioblastoma Treated With Temozolomide-Based Chemoradiotherapy: A Single-Institution Study

    SciTech Connect

    Kim, Young Suk; Kim, Se Hoon; Cho, Jaeho; Kim, Jun Won; Chang, Jong Hee; Kim, Dong Suk; Lee, Kyu Sung; Suh, Chang-Ok

    2012-11-01

    Purpose: Recently, cells deficient in O{sup 6}-methylguanine-DNA methyltransferase (MGMT) were found to show increased sensitivity to temozolomide (TMZ). We evaluated whether hypermethylation of MGMT was associated with survival in patients with glioblastoma multiforme (GBM). Methods and Materials: We retrospectively analyzed 93 patients with histologically confirmed GBM who received involved-field radiotherapy with TMZ from 2001 to 2008. The median age was 58 years (range, 24-78 years). Surgical resection was total in 39 patients (42%), subtotal in 30 patients (32%), and partial in 17 patients (18%); only a biopsy was performed in 7 patients (8%). Postoperative radiotherapy began within 3 weeks of surgery in 87% of the patients. Radiotherapy doses ranged from 50 to 74 Gy (median, 70 Gy). MGMT gene methylation was determined in 78 patients; MGMT was unmethylated in 43 patients (55%) and methylated in 35 patients (45%). The median follow-up period was 22 months (range, 3-88 months) for all patients. Results: The median overall survival (OS) was 22 months, and progression-free survival (PFS) was 11 months. MGMT gene methylation was an independently significant prognostic factor for both OS (p = 0.002) and PFS (p = 0.008) in multivariate analysis. The median OS was 29 months for the methylated group and 20 months for the unmethylated group. In 35 patients with methylated MGMT genes, the 2-year and 5-year OS rates were 54% and 31%, respectively. Six patients with combined prognostic factors of methylated MGMT genes, age {<=}50 years, and total/subtotal resections are all alive 38 to 77 months after operation, whereas the median OS in 8 patients with unmethylated MGMT genes, age >50 years, and less than subtotal resection was 13.2 months. Conclusion: We confirmed that MGMT gene methylation is a potent prognostic factor in patients with GBM. Our results suggest that early postoperative radiotherapy and a high total/subtotal resection rate might further improve the

  12. EGFR inhibition in glioma cells modulates Rho signaling to inhibit cell motility and invasion and cooperates with temozolomide to reduce cell growth.

    PubMed

    Ramis, Guillem; Thomàs-Moyà, Elena; Fernández de Mattos, Silvia; Rodríguez, José; Villalonga, Priam

    2012-01-01

    Enforced EGFR activation upon gene amplification and/or mutation is a common hallmark of malignant glioma. Small molecule EGFR tyrosine kinase inhibitors, such as erlotinib (Tarceva), have shown some activity in a subset of glioma patients in recent trials, although the reported data on the cellular basis of glioma cell responsiveness to these compounds have been contradictory. Here we have used a panel of human glioma cell lines, including cells with amplified or mutant EGFR, to further characterize the cellular effects of EGFR inhibition with erlotinib. Dose-response and cellular growth assays indicate that erlotinib reduces cell proliferation in all tested cell lines without inducing cytotoxic effects. Flow cytometric analyses confirm that EGFR inhibition does not induce apoptosis in glioma cells, leading to cell cycle arrest in G(1). Interestingly, erlotinib also prevents spontaneous multicellular tumour spheroid growth in U87MG cells and cooperates with sub-optimal doses of temozolomide (TMZ) to reduce multicellular tumour spheroid growth. This cooperation appears to be schedule-dependent, since pre-treatment with erlotinib protects against TMZ-induced cytotoxicity whereas concomitant treatment results in a cooperative effect. Cell cycle arrest in erlotinib-treated cells is associated with an inhibition of ERK and Akt signaling, resulting in cyclin D1 downregulation, an increase in p27(kip1) levels and pRB hypophosphorylation. Interestingly, EGFR inhibition also perturbs Rho GTPase signaling and cellular morphology, leading to Rho/ROCK-dependent formation of actin stress fibres and the inhibition of glioma cell motility and invasion.

  13. Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial.

    PubMed

    Khasraw, Mustafa; Lee, Adrian; McCowatt, Sally; Kerestes, Zoltan; Buyse, Marc E; Back, Michael; Kichenadasse, Ganessan; Ackland, Stephen; Wheeler, Helen

    2016-05-01

    Newly diagnosed glioblastoma multiforme with unmethylated MGMT promoter has a poor prognosis, with a median survival of 12 months. This phase II study investigated the efficacy and safety of combining the selective integrin inhibitor cilengitide with a combination of metronomic temozolomide and procarbazine for these patients. Eligible patients (newly diagnosed, histologically confirmed supratentorial glioblastoma with unmethylated MGMT promoter) were entered into this multicentre study. Cilengitide (2000 mg IV twice weekly) was commenced 1 week prior to radiotherapy combined with daily temozolomide (60 mg/m(2)) and procarbazine (50 or 100 mg) and, after 4 weeks' break, followed by six adjuvant cycles of temozolomide (50-60 mg/m(2)) and procarbazine (50 or 100 mg) on days 1-20, every 28 days. Cilengitide was continued for up to 12 months or until disease progression or unacceptable toxicity. The primary endpoint for efficacy was a 12-month overall survival rate of 65 %. Twenty-nine patients completed study treatment. Sixteen patients survived for 12 months or more, an overall survival rate of 55 %. The median overall survival was 14.5 months (95 % CI 11.1-19.6) and the median progression-free survival was 7.4 months (95 % CI 6.1-8). Cilengitide combined with metronomic temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did not improve survival compared with historical data and does not warrant further investigation. PMID:26935578

  14. [Evaluation of stability of temozolomide in solutions after opening the capsule].

    PubMed

    Kodawara, Takaaki; Mizuno, Tomoyuki; Taue, Hiromi; Hashida, Tohru; Yano, Ikuko; Katsura, Toshiya; Inui, Ken-Ichi

    2009-03-01

    We evaluated the stability of temozolomide, an alkylating agent, in solutions after opening the capsule. First, we established an analytical method for determination of temozolomide concentration by HPLC. The calibration curve for temozolomide was linear between 0.5-20 microg/ml (r=0.999). We then evaluated the stability of temozolomide in each buffer solution (pH 2-9) for 30 min. Temozolomide was decomposed pH-dependently between pH 7 and 9, and completely decomposed at pH 9. Temozolomide in several drinking water samples and beverages was decomposed according to their pH values. We also examined the time-dependent degradation of temozolomide in different pH solutions. Temozolomide started to decompose at 5 min in alkaline and neutral solutions, whereas 90% of temozolomide remained intact in acidic solution at 60 min. These results indicate that the stability of temozolomide after opening the capsule is affected by pH of solvents, and temozolomide is almost stable in acidic solutions. PMID:19252393

  15. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

    PubMed

    Farace, Cristiano; Oliver, Jaime Antonio; Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  16. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells

    PubMed Central

    Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell–microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  17. Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma.

    PubMed

    Ney, Douglas E; Carlson, Julie A; Damek, Denise M; Gaspar, Laurie E; Kavanagh, Brian D; Kleinschmidt-DeMasters, B K; Waziri, Allen E; Lillehei, Kevin O; Reddy, Krishna; Chen, Changhu

    2015-03-01

    Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1 cm margin (PTV1) to 60 Gy and to the T2 abnormality with a 1 cm margin (PTV2) to 30 Gy in 10 daily fractions over 2 weeks. Concurrent temozolomide (75 mg/m(2) daily) and bevacizumab (10 mg/kg) was administered followed by adjuvant temozolomide (200 mg/m(2)) on a standard 5/28 day cycle and bevacizumab (10 mg/kg) every 2 weeks for 6 months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1 cm(3) and the median PTV2 volume was 342.6 cm(3). Six-month progression-free survival (PFS) was 90 %, with median follow-up of 15.9 months. The median PFS was 14.3 months, with a median overall survival (OS) of 16.3 months. Grade 4 hematologic toxicity included neutropenia (10 %) and thrombocytopenia (17 %). Grades 3/4 non-hematologic toxicity included fatigue (13 %), wound dehiscence (7 %) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50 % of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90 % 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis. PMID:25524817

  18. Liposome encapsulated of temozolomide for the treatment of glioma tumor: preparation, characterization and evaluation.

    PubMed

    Gao, Jinhua; Wang, Zhonglan; Liu, Honghai; Wang, Longmei; Huang, Guihua

    2015-06-01

    Temozolomide plays a critical role in curing glioma at present. The purpose of this work was to develop a suitable drug delivery system which could prolong the half-life, improve the brain targeting, and reduce the systemic effect of the drug. Temozolomide-liposomes were formulated by the method of proliposomes. They were found to be relatively uniform in size of 156.70 ± 11.40 nm with a narrow polydispersity index (PI) of 0.29 ± 0.04. The average drug entrapment efficiency and loading capacity were 35.45 ± 1.48% and 2.81 ± 0.20%, respectively. The pH of temozolomide-liposomes was 6.46. In vitro release studies were conducted by a dynamic dialysis. The results showed that temozolomide released slowly from liposomes compared with the solution group. The release behavior of temozolomide-liposomes was in line with First-order kinetics and Weibull equation. The pharmacokinetics study was evaluated by pharmacokinetics parameters. The t(1/2β) and MRT of temozolomide-liposomes were 3.57 times and 1.27 times greater than that of temozolomide solution. The Cmax and AUC values of temozolomide-liposomes were 1.10 times and 1.55 times greater than that of temozolomide solution. The results of pharmacokinetics study showed temozolomide-liposomes prolonged the in vivo circulation time and increased AUC. Furthermore, the biodistribution in mice showed that temozolomide-liposomes preferentially decreased the accumulation of temozolomide in heart and lung and increased the drug concentration in brain after i.v. injection, which implied that temozolomide-liposomes improved the therapeutic effect in the brain and reduced the toxicity in lung and heart. PMID:26193943

  19. MiR-143 acts as a tumor suppressor by targeting N-RAS and enhances temozolomide-induced apoptosis in glioma.

    PubMed

    Wang, Lin; Shi, Zhu-Mei; Jiang, Cheng-Fei; Liu, Xue; Chen, Qiu-Dan; Qian, Xu; Li, Dong-Mei; Ge, Xin; Wang, Xie-Feng; Liu, Ling-Zhi; You, Yong-Ping; Liu, Ning; Jiang, Bing-Hua

    2014-07-30

    Therapeutic applications of microRNAs (miRNAs) in RAS-driven glioma were valuable, but their specific roles and functions have yet to be fully elucidated. Here, we firstly report that miR-143 directly targets the neuroblastoma RAS viral oncogene homolog (N-RAS) and functions as a tumor-suppressor in glioma. Overexpression of miR-143 decreased the expression of N-RAS, inhibited PI3K/AKT, MAPK/ERK signaling, and attenuated the accumulation of p65 in nucleus of glioma cells. In human clinical specimens, miR-143 was downregulated where an adverse with N-RAS expression was observed. Furthermore, overexpression of miR-143 decreased glioma cell migration, invasion, tube formation and slowed tumor growth and angiogenesis in a manner associated with N-RAS downregulation in vitro and in vivo. Finally, miR-143 also sensitizes glioma cells to temozolomide (TMZ),the first-line drug for glioma treatment. Taken together, for the first time, our results demonstrate that miR-143 plays a significant role in inactivating the RAS signaling pathway through the inhibition of N-RAS, which may provide a novel therapeutic strategy for treatment of glioma and other RAS-driven cancers.

  20. Mechanisms of Action of Adjuvants

    PubMed Central

    Awate, Sunita; Babiuk, Lorne A.; Mutwiri, George

    2013-01-01

    Adjuvants are used in many vaccines, but their mechanisms of action are not fully understood. Studies from the past decade on adjuvant mechanisms are slowly revealing the secrets of adjuvant activity. In this review, we have summarized the recent progress in our understanding of the mechanisms of action of adjuvants. Adjuvants may act by a combination of various mechanisms including formation of depot, induction of cytokines and chemokines, recruitment of immune cells, enhancement of antigen uptake and presentation, and promoting antigen transport to draining lymph nodes. It appears that adjuvants activate innate immune responses to create a local immuno-competent environment at the injection site. Depending on the type of innate responses activated, adjuvants can alter the quality and quantity of adaptive immune responses. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity, help in rational design of vaccines against various diseases, and can inform on adjuvant safety. PMID:23720661

  1. Outcomes in Newly Diagnosed Elderly Glioblastoma Patients after Concomitant Temozolomide Administration and Hypofractionated Radiotherapy

    PubMed Central

    Nguyen, Ludovic T.; Touch, Socheat; Nehme-Schuster, Hélène; Antoni, Delphine; Eav, Sokha; Clavier, Jean-Baptiste; Bauer, Nicolas; Vigneron, Céline; Schott, Roland; Kehrli, Pierre; Noël, Georges

    2013-01-01

    This study aimed to analyze the treatment and outcomes of older glioblastoma patients. Forty-four patients older than 70 years of age were referred to the Paul Strauss Center for chemotherapy and radiotherapy. The median age was 75.5 years old (range: 70–84), and the patients included 18 females and 26 males. The median Karnofsky index (KI) was 70%. The Charlson indices varied from 4 to 6. All of the patients underwent surgery. O6-methylguanine–DNA methyltransferase (MGMT) methylation status was determined in 25 patients. All of the patients received radiation therapy. Thirty-eight patients adhered to a hypofractionated radiation therapy schedule and six patients to a normofractionated schedule. Neoadjuvant, concomitant and adjuvant chemotherapy regimens were administered to 12, 35 and 20 patients, respectively. At the time of this analysis, 41 patients had died. The median time to relapse was 6.7 months. Twenty-nine patients relapsed, and 10 patients received chemotherapy upon relapse. The median overall survival (OS) was 7.2 months and the one- and two-year OS rates were 32% and 12%, respectively. In a multivariate analysis, only the Karnofsky index was a prognostic factor. Hypofractionated radiotherapy and chemotherapy with temozolomide are feasible and acceptably tolerated in older patients. However, relevant prognostic factors are needed to optimize treatment proposals. PMID:24202340

  2. Modern Vaccine Adjuvant/Formulation—Session 9: Adjuvants

    PubMed Central

    Dalençon, François

    2013-01-01

    The Session 9 of the Modern Vaccine Adjuvant/Formulation meeting pointed out the permanent need for vaccine improvement and for adjuvant development. Indeed, the increasing use of recombinant subunit vaccines for both parenteral and mucosal vaccination necessitates the development of improved adjuvants. This session dealt with strategies for the development of new vaccine adjuvants with respect to the availability of new molecules targeting specifically the receptors of the systemic or mucosal immune system. PMID:23938771

  3. Vaccines, adjuvants and autoimmunity.

    PubMed

    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.

  4. Laser vaccine adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C

    2014-01-01

    Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines. PMID:25424797

  5. Decitabine nanoconjugate sensitizes human glioblastoma cells to temozolomide.

    PubMed

    Cui, Yi; Naz, Asia; Thompson, David H; Irudayaraj, Joseph

    2015-04-01

    In this study, we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) based nanoconjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells than that with the free drug. After synthesis, the highly efficient uptake process and intracellular dynamics of this nanoconjugate were monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nanovector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing positive feedback to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to the excellent internalization and endolysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than that of free drug molecules. Hence, the synthesized nanoconjugate and temozolomide could act in synergy to deliver a more potent and long-term antiproliferative effect against malignant GBM cells.

  6. Decitabine Nano-conjugate Sensitizing Human Glioblastoma Cells to Temozolomide

    PubMed Central

    Cui, Yi; Naz, Asia; Thompson, David H.; Irudayaraj, Joseph

    2015-01-01

    In this study we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) based nano-conjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells. After synthesis, the highly efficient uptake process and intracellular dynamics of this nano-conjugate was monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nano-vector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing a “positive feedback” to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to excellent internalization and endo-lysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than free drug molecules. Hence, the synthesized nano-conjugate and temozolomide could act in synergy to deliver a more potent and long-term anti-proliferation effect against malignant GBM cells. PMID:25751281

  7. Adjuvants for allergy vaccines.

    PubMed

    Moingeon, Philippe

    2012-10-01

    Allergen-specific immunotherapy is currently performed via either the subcutaneous or sublingual routes as a treatment for type I (IgE dependent) allergies. Aluminum hydroxide or calcium phosphate are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts in the absence of any immunopotentiator. Adjuvants to be included in the future in products for allergen specific immunotherapy should ideally enhance Th1 and CD4+ regulatory T cell responses. Imunomodulators impacting dendritic or T cell functions to induce IL10, IL12 and IFNγ production are being investigated in preclinical allergy models. Such candidate adjuvants encompass synthetic or biological immunopotentiators such as glucocorticoids, 1,25-dihydroxy vitamin D3, selected probiotic strains (e.g., Lactobacillus and Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4 (monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 (CpGs) ligands. Furthermore, the use of vector systems such as mucoadhesive particules, virus-like particles or liposomes are being considered to enhance allergen uptake by tolerogenic antigen presenting cells present in mucosal tissues.

  8. Vaccine Potentiation by Combination Adjuvants

    PubMed Central

    Levast, Benoît; Awate, Sunita; Babiuk, Lorne; Mutwiri, George; Gerdts, Volker; van Drunen Littel-van den Hurk, Sylvia

    2014-01-01

    Adjuvants are crucial components of vaccines. They significantly improve vaccine efficacy by modulating, enhancing, or extending the immune response and at the same time reducing the amount of antigen needed. In contrast to previously licensed adjuvants, current successful adjuvant formulations often consist of several molecules, that when combined, act synergistically by activating a variety of immune mechanisms. These “combination adjuvants” are already registered with several vaccines, both in humans and animals, and novel combination adjuvants are in the pipeline. With improved knowledge of the type of immune responses needed to successfully induce disease protection by vaccination, combination adjuvants are particularly suited to not only enhance, but also direct the immune responses desired to be either Th1-, Th2- or Th17-biased. Indeed, in view of the variety of disease and population targets for vaccine development, a panel of adjuvants will be needed to address different disease targets and populations. Here, we will review well-known and new combination adjuvants already licensed or currently in development—including ISCOMs, liposomes, Adjuvant Systems Montanides, and triple adjuvant combinations—and summarize their performance in preclinical and clinical trials. Several of these combination adjuvants are promising having promoted improved and balanced immune responses. PMID:26344621

  9. Carbohydrate-based immune adjuvants

    PubMed Central

    Petrovsky, Nikolai; Cooper, Peter D

    2011-01-01

    The role for adjuvants in human vaccines has been a matter of vigorous scientific debate, with the field hindered by the fact that for over 80 years, aluminum salts were the only adjuvants approved for human use. To this day, alum-based adjuvants, alone or combined with additional immune activators, remain the only adjuvants approved for use in the USA. This situation has not been helped by the fact that the mechanism of action of most adjuvants has been poorly understood. A relative lack of resources and funding for adjuvant development has only helped to maintain alum’s relative monopoly. To seriously challenge alum’s supremacy a new adjuvant has many major hurdles to overcome, not least being alum’s simplicity, tolerability, safety record and minimal cost. Carbohydrate structures play critical roles in immune system function and carbohydrates also have the virtue of a strong safety and tolerability record. A number of carbohydrate compounds from plant, bacterial, yeast and synthetic sources have emerged as promising vaccine adjuvant candidates. Carbohydrates are readily biodegradable and therefore unlikely to cause problems of long-term tissue deposits seen with alum adjuvants. Above all, the Holy Grail of human adjuvant development is to identify a compound that combines potent vaccine enhancement with maximum tolerability and safety. This has proved to be a tough challenge for many adjuvant contenders. Nevertheless, carbohydrate-based compounds have many favorable properties that could place them in a unique position to challenge alum’s monopoly over human vaccine usage. PMID:21506649

  10. Adjuvant therapy of melanoma.

    PubMed

    Agarwala, S S; Kirkwood, J M

    1998-06-01

    Patients with AJCC Stage IIB and III melanoma have a poor 5-year survival rate which has been the driving force behind attempts to find an effective adjuvant therapy for this stage of disease that would effectively reduce relapse and improve survival. Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum, and levamisole have not been successful in achieving this goal, nor have trials with chemotherapy in the adjuvant setting, including high-dose chemotherapy with autologous bone marrow transplantation. The recent Eastern Cooperative Oncology Group (ECOG) 1684 study showed significant improvement in relapse-free and overall survival with high doses of alpha interferon (IFNalpha) given for 1 year. Lower dosages of IFNalpha have to date been unsuccessful in impacting upon long-term survival. Recent data with vaccines have been encouraging, and the GM2-KLH vaccine is the focus of ongoing intergroup study comparing this treatment with IFNalpha in resected Stage IIB and III melanoma. The various regimens are reviewed in this article. PMID:9588723

  11. Molecular signatures of vaccine adjuvants.

    PubMed

    Olafsdottir, Thorunn; Lindqvist, Madelene; Harandi, Ali M

    2015-09-29

    Mass vaccination has saved millions of human lives and improved the quality of life in both developing and developed countries. The emergence of new pathogens and inadequate protection conferred by some of the existing vaccines such as vaccines for tuberculosis, influenza and pertussis especially in certain age groups have resulted in a move from empirically developed vaccines toward more pathogen tailored and rationally engineered vaccines. A deeper understanding of the interaction of innate and adaptive immunity at molecular level enables the development of vaccines that selectively target certain type of immune responses without excessive reactogenicity. Adjuvants constitute an imperative element of modern vaccines. Although a variety of candidate adjuvants have been evaluated in the past few decades, only a limited number of vaccine adjuvants are currently available for human use. A better understanding of the mode of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in shaping a desired immune response. Recent advancement in systems biology powered by the emerging cutting edge omics technology has led to the identification of molecular signatures rapidly induced after vaccination in the blood that correlate and predict a later protective immune response or vaccine safety. This can pave ways to prospectively determine the potency and safety of vaccines and adjuvants. This review is intended to highlight the importance of big data analysis in advancing our understanding of the mechanisms of actions of adjuvants to inform rational development of future human vaccines. PMID:25989447

  12. Resveratrol sensitizes glioblastoma-initiating cells to temozolomide by inducing cell apoptosis and promoting differentiation.

    PubMed

    Li, Hao; Liu, Yaodong; Jiao, Yumin; Guo, Anchen; Xu, Xiaoxue; Qu, Xianjun; Wang, Shuo; Zhao, Jizong; Li, Ye; Cao, Yong

    2016-01-01

    Glioblastoma-initiating cells play crucial roles in the origin, growth, and recurrence of glioblastoma multiforme. The elimination of glioblastoma-initiating cells is believed to be a key strategy for achieving long-term survival of glioblastoma patients due to the highly resistant property of glioblastoma-initiating cells to temozolomide. Resveratrol, a naturally occurring polyphenol, has been widely studied as a promising candidate for cancer prevention and treatment. Whether resveratrol could enhance the sensitivity of glioblastoma-initiating cells to temozolomide therapy has not yet been reported. Here, using patient-derived glioblastoma-initiating cell lines, we found that resveratrol sensitized glioblastoma-initiating cells to temozolomide both in vitro and in vivo. Furthermore, we showed that resveratrol enhanced glioblastoma-initiating cells to temozolomide-induced apoptosis through DNA double-stranded breaks/pATM/pATR/p53 pathway activation, and promoted glioblastoma-initiating cell differentiation involving p-STAT3 inactivation. Our results propose that temozolomide and resveratrol combination strategy may be effective in the management of glioblastoma patients, particularly for those patients who have been present with a high abundance of glioblastoma-initiating cells in their tumors and show slight responsiveness to temozolomide.

  13. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  14. Mucosal adjuvants: Opportunities and challenges.

    PubMed

    Zeng, Lingbin

    2016-09-01

    Most pathogens access the body via mucosal surfaces. Mucosal vaccination is a highly effective and recommended method to prevent mucosally transmitted infections. Compared with immunization via intramuscular injection, mucosal immunization offers remarkable advantages, including non-invasiveness, low costs and reduced risk of transmission of blood-borne diseases, which make it more acceptable to human beings, especially to young children. However, only few mucosal vaccines are licensed for human, which is mainly due to the deficiency of safe and effective mucosal adjuvants. Adjuvants, as important components of most vaccines, are essential to enhance immunity and induce immune memory. The development of mucosal adjuvants, unfortunately, has been severely hampered by research strategies based on empiric trials and non-comprehensive methods for safety evaluation. Therefore, changing the research and development strategies of mucosal adjuvant field from empiricism based discovery to rational design based invention is highly demanded. The change of strategies mainly depends upon clarification of mechanism of mucosal adjuvant activity though a combination of life science, information science and materials science. PMID:27159278

  15. Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide.

    PubMed

    Goldwirt, Lauriane; Beccaria, Kevin; Carpentier, Alexandre; Idbaih, Ahmed; Schmitt, Charlotte; Levasseur, Camille; Labussiere, Marianne; Milane, Aline; Farinotti, Robert; Fernandez, Christine

    2015-04-01

    Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.

  16. The ultrastructure of tomatine adjuvant.

    PubMed

    Yang, Ya-Wun; Sheikh, Nadeem A; Morrow, W J W

    2002-12-01

    The tomatine adjuvant, consisting of tomatine, n-octyl-beta-D-glucopyranoside, phosphatidylethanolamine, cholesterol, and ovalbumin, has recently been shown to potentiate the immunogenicity of protein antigen and elicit cytotoxic T-lymphocyte responses in immunized animals. The physicochemical properties of tomatine adjuvant have not been characterized. The aim of this study was to examine the microstructure of this complex formulation, as directly related to its physicochemical properties. To elucidate the micromorphology of this system, the tomatine adjuvant was separated by isopycnic ultracentrifugation, followed by freeze fracturing and examination by transmission and scanning electron microscopy. The adjuvant mixture was shown to be composed of several micro- and nano-structures. The major fraction obtained from isopycnic separation was shown to consist of flaky needle-like microcrystals, approximately 80-160 nm in width and 2-4 microm in length. The tomatine crystals alone in 0.9% NaCl, on the other hand, were shown to be elongated hollow tubular crystals of hundreds of nanometers up to a few microns in length, along which n-octyl-beta-glucopyranoside was speculated to serve as a seeding microtemplate for gel crystallization of protein complexes. Indented marks within the gel phase were observed in the freeze fractured replicas of the adjuvant, suggesting that protein complexes may have been crystallized or precipitated within the gels. Several other forms of micro- and nano-structures were also observed, showing multiple-dispersion features with gel characteristics. The presence of gel crystalline and multiple-dispersed phases is postulated to contribute to the sustained immunopotentiation effect of tomatine adjuvant.

  17. Safety and Efficacy of Stereotactic Radiosurgery and Adjuvant Bevacizumab in Patients With Recurrent Malignant Gliomas

    SciTech Connect

    Cuneo, Kyle C.; Vredenburgh, James J.; Sampson, John H.; Reardon, David A.; Desjardins, Annick; Peters, Katherine B.; Friedman, Henry S.; Willett, Christopher G.; Kirkpatrick, John P.

    2012-04-01

    Purpose: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. Methods and Materials: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. Results: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17-0.82) and 0.45 (CI 0.21-0.97). KPS >70 and age <50 years were significantly associated with improved survival. Conclusions: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant

  18. MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM

    PubMed Central

    Stojcheva, Nina; Schechtmann, Gennadi; Sass, Steffen; Roth, Patrick; Florea, Ana-Maria; Stefanski, Anja; Stühler, Kai; Wolter, Marietta; Müller, Nikola S.; Theis, Fabian J.; Weller, Michael; Reifenberger, Guido; Happold, Caroline

    2016-01-01

    Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells. Using microarray-based miRNA expression profiling of parental and TMZ-resistant cultures of three human glioma cell lines, we identified a set of differentially expressed miRNA candidates. From these, we selected miR-138 for further functional analyses as this miRNA was not only upregulated in TMZ-resistant versus parental cells, but also showed increased expression in vivo in recurrent glioblastoma tissue samples after TMZ/RT→TMZ treatment. Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype. Altered sensitivity to apoptosis played only a minor role in this resistance mechanism. Instead, we identified the induction of autophagy to be regulated downstream of the miR-138/BIM axis and to promote cell survival following TMZ exposure. Our data thus define miR-138 as a glioblastoma cell survival-promoting miRNA associated with resistance to TMZ therapy in vitro and with tumor progression in vivo. PMID:26887050

  19. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  20. Adjuvant therapy of malignant melanoma.

    PubMed

    Molife, R; Hancock, B W

    2002-10-01

    High risk surgically resected melanoma is associated with a less than 50% 5-year survival. Adjuvant therapy is an appropriate treatment modality in this setting, and is more likely to be effective as the tumour burden here is small. Clinical observations of spontaneous tumour regressions and a highly variable rate of disease progression suggest a role of the immune system in the natural history of melanoma. Biological agents have therefore been the subjects of numerous adjuvant studies. Early, randomised controlled trials (RCTs) of Bacillus Calmette-Guerin (BCG), levamisole, Corynebacterium parvum, chemotherapy, isolated limb perfusion (ILP), radiotherapy, transfer factor (TF), megestrol acetate and vitamin A yielded largely negative results. Current trials focus on vaccines and the interferons. To date the latter is the only therapy to have shown a significant benefit in the prospective randomised controlled phase III setting. This report represents a systematic review of studies in adjuvant therapy in melanoma. Data from ongoing studies is awaited before a role for adjuvant agents in high risk melanoma is confirmed. PMID:12399001

  1. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)

    PubMed Central

    Kirson, Eilon D; Schneiderman, Rosa S; Dbalý, Vladimír; Tovaryš, František; Vymazal, Josef; Itzhaki, Aviran; Mordechovich, Daniel; Gurvich, Zoya; Shmueli, Esther; Goldsher, Dorit; Wasserman, Yoram; Palti, Yoram

    2009-01-01

    Background The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. Methods Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. Results The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months. Conclusion These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity. PMID:19133110

  2. [Adjuvants in modern medicine and veterinary].

    PubMed

    Kozlov, V G; Ozherelkov, S V; Sanin, A V; Kozhevnikova, T N

    2014-01-01

    The review is dedicated to immunologic adjuvants--various natural and synthetics substances that are added to vaccines for stimulation of specific immune response, but they do not induce specific response themselves. Critically important is the selection of the correct adjuvants, for which mechanisms of effect on immune system are studied the most. The majority of these mechanisms as well as physical-chemical and biological features of modern adjuvants are analyzed in the review. The problem of safety of adjuvants, types of immune response induced by adjuvants of various nature, excipients that are being verified or already in use in modern medicine and veterinary are also examined.

  3. Vaccine adjuvants as potential cancer immunotherapeutics.

    PubMed

    Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J

    2016-07-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  4. Vaccine adjuvants as potential cancer immunotherapeutics

    PubMed Central

    Temizoz, Burcu; Kuroda, Etsushi

    2016-01-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund’s adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  5. Advances and challenges in mucosal adjuvant technology.

    PubMed

    Newsted, Daniel; Fallahi, Firouzeh; Golshani, Ashkan; Azizi, Ali

    2015-05-15

    Adjuvants play attractive roles in enhancement of immune response during vaccination; however, due to several challenges, only a limited number of adjuvants are licensed by health authorities. The lack of an effective mucosal adjuvant is even more significant as none of the licensed adjuvants revealed a strong enhancement in immune system after mucosal administration. Over the past two decades, several mucosal adjuvants have been developed to deliver antigens to the target cells in the mucosal immune system and increase specific immune responses. However, the safety and efficacy of these adjuvants for testing in human trials is still an important issue, requiring further study. In this article, we briefly review the challenges associated with most common mucosal adjuvants and discuss potential strategies for targeting the mucosal immune system.

  6. Improving vaccine delivery using novel adjuvant systems.

    PubMed

    Pichichero, Michael E

    2008-01-01

    Adjuvants have been common additions to vaccines to help facilitate vaccine delivery. With advancements in vaccine technology, several adjuvants which activate immune specific responses have emerged. Available data show these adjuvants elicit important immune responses in both healthy and immunocompromised populations, as well as the elderly. Guidelines for the use and licensure of vaccine adjuvants remain under discussion. However, there is a greater understanding of the innate and adaptive immune response, and the realization of the need for immune specific adjuvants appears to be growing. This is a focused review of four adjuvants currently in clinical trial development: ASO4, ASO2A, CPG 7907, and GM-CSF. The vaccines including these adjuvants are highly relevant today, and are expected to reduce the disease burden of cervical cancer, hepatitis B and malaria. PMID:18398303

  7. Adjuvant therapy for endometrial cancer

    PubMed Central

    DeLeon, Maria C.; Ammakkanavar, Natraj R.

    2014-01-01

    Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID:24761218

  8. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

  9. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    PubMed

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease. PMID:27353036

  10. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    PubMed

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

  11. New dry powders for inhalation containing temozolomide-based nanomicelles for improved lung cancer therapy.

    PubMed

    Rosière, Rémi; Gelbcke, Michel; Mathieu, Véronique; Van Antwerpen, Pierre; Amighi, Karim; Wauthoz, Nathalie

    2015-09-01

    Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10-7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomide-loaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F

  12. New dry powders for inhalation containing temozolomide-based nanomicelles for improved lung cancer therapy.

    PubMed

    Rosière, Rémi; Gelbcke, Michel; Mathieu, Véronique; Van Antwerpen, Pierre; Amighi, Karim; Wauthoz, Nathalie

    2015-09-01

    Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10-7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomide-loaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F

  13. Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system.

    PubMed

    Sarganas, Giselle; Orzechowski, Hans D; Klimpel, Andreas; Thomae, Michael; Kauffmann, Wolfgang; Herbst, Hermann; Bronder, Elisabeth; Garbe, Edeltraut

    2012-05-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity. PMID:22394496

  14. Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system

    PubMed Central

    Sarganas, Giselle; Orzechowski, Hans D.; Klimpel, Andreas; Thomae, Michael; Kauffmann, Wolfgang; Herbst, Hermann; Bronder, Elisabeth; Garbe, Edeltraut

    2012-01-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity. PMID:22394496

  15. Adjuvant progestagens for endometrial cancer

    PubMed Central

    Martin-Hirsch, Pierre PL; Bryant, Andrew; Keep, Sarah L; Kitchener, Henry C; Lilford, Richard

    2014-01-01

    Background Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. Objectives To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. Selection criteria Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses.. Main results Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). Authors’ conclusions There

  16. A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

    PubMed Central

    Larkin, J M G; Hughes, S A; Beirne, D A; Patel, P M; Gibbens, I M; Bate, S C; Thomas, K; Eisen, T G; Gore, M E

    2006-01-01

    Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m−2 days 1–5 every 28 days and lomustine 60 mg m–2 on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted. PMID:17146474

  17. A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma.

    PubMed

    Larkin, J M G; Hughes, S A; Beirne, D A; Patel, P M; Gibbens, I M; Bate, S C; Thomas, K; Eisen, T G; Gore, M E

    2007-01-15

    Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m(-2) days 1-5 every 28 days and lomustine 60 mg m(-2) on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted. PMID:17146474

  18. Adjuvants: Classification, Modus Operandi, and Licensing

    PubMed Central

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations. PMID:27274998

  19. Vaccine adjuvants: putting innate immunity to work.

    PubMed

    Coffman, Robert L; Sher, Alan; Seder, Robert A

    2010-10-29

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.

  20. Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma

    PubMed Central

    Pirzkall, Andrea; McGue, Colleen; Saraswathy, Suja; Cha, Soonmee; Liu, Raymond; Vandenberg, Scott; Lamborn, Kathleen R.; Berger, Mitchel S.; Chang, Susan M.; Nelson, Sarah J.

    2009-01-01

    To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT. Postsurgical MRI indicated that 18 patients had gross total and 14 subtotal resections. Twenty-one patients showed reduced diffusion, and 25 patients showed new or increased CE. In eight patients (25%), the new CE was confined to areas of postsurgical reduced diffusion. In the other 17 patients (53%), new CE was found to be indicative of tumor growth or a combination of tumor growth and surgical injury. Higher perfusion and creatine within nonenhancing tumor in the presurgery MR were associated with subsequent tumor growth. High levels of choline and reduced diffusion in pre-RT CE suggested active metabolism and tumor cell proliferation. Median survival was 14.6 months in patients with interim tumor growth and 24 months in patients with no growth. Increased volume or new onset of CE between surgery and RT was attributed to tumor growth in 53% of patients and was associated with shorter survival. This suggests that reducing the time between surgery and adjuvant therapy may be important. The acquisition of metabolic and physiologic imaging data prior to adjuvant therapy may also be valuable in assessing regions of new CE and nonenhancing tumor. PMID:19229057

  1. Profile of capecitabine/temozolomide combination in the treatment of well-differentiated neuroendocrine tumors

    PubMed Central

    Kotteas, Elias A; Syrigos, Konstantinos N; Saif, Muhammad Wasif

    2016-01-01

    Neuroendocrine tumors are a rare and heterogeneous group of tumors with a variety of primary origins and variable aggressiveness. Platinum-based chemotherapy has been the cornerstone of treatment for the poorly differentiated tumors. However, well-differentiated neuroendocrine tumors are quite chemoresistant and therapy options are limited. Octreotide analogs and tyrosine kinase inhibitors are widely acceptable treatments due to substantial efficacy and tolerable toxicity. On the contrary, monotherapy or combinations of the only approved cytotoxic agent streptozocin with other drugs have been almost abandoned because of excessive toxic events. In recent years, the combination of capecitabine and temozolomide has emerged as the most promising and efficacious treatment. The oral route of administration and the substantial improvement in the outcomes with manageable toxicity are the major advantages. We reviewed the current literature and presented the profile of the capecitabine/temozolomide combination in the management of well-differentiated neuroendocrine tumors. PMID:26929640

  2. Nimotuzumab enhances temozolomide-induced growth suppression of glioma cells expressing mutant EGFR in vivo.

    PubMed

    Nitta, Yusuke; Shimizu, Saki; Shishido-Hara, Yukiko; Suzuki, Kaori; Shiokawa, Yoshiaki; Nagane, Motoo

    2016-03-01

    A mutant form of epidermal growth factor receptor (EGFR), EGFRvIII, is common in glioblastoma (GBM) and confers enhanced tumorigenic activity and drug resistance. Nimotuzumab, an anti-EGFR antibody, has shown preclinical and clinical activity to GBM, but its specific activity against EGFRvIII has not been fully investigated. Human glioma U87MG or LNZ308 cells overexpressing either wild-type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both. Expression and phosphorylation status of molecules were determined by Western blot analysis. Methylation status of promoter region of O(6) -methylguanine-DNA methyltransferase (MGMT) was detected by methylation-specific PCR. Antitumor activity was tested using nude mice bearing either subcutaneous or intracerebral xenografts along with analyses of EGFR phosphorylation status, proliferation, apoptosis, and vessel density. Nimotuzumab treatment resulted in reduction of EGFRvIII tyrosine phosphorylation with a decrease in Akt phosphorylation that was greater than that of wtEGFR. Correspondingly, antitumor effects, growth suppression and survival elongation, were more significant in mice bearing either subcutaneous or intracerebral tumor expressing EGFRvIII than in those expressing wtEGFR. These effects were markedly increased when temozolomide was combined with nimotuzumab. The post-treatment recurrent brain tumors exhibited a decrease in expression of the mismatch repair (MMR) proteins, MSH6 and MLH1, but their methylated MGMT status did not changed. Nimotuzumab has in vivo antitumor activity against GBM, especially those expressing EGFRvIII, when combined with temozolomide. This could provide a basis for preselection of patients with GBM by EGFR status who might benefit from the nimotuzumab and temozolomide combination therapy. PMID:26778701

  3. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures.

    PubMed

    Oh, Djin-Ye; Dowling, David J; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T; Sauld, John F; Pettengill, Matthew; Kho, Alvin T; Pollack, Henry J; Steen, Hanno; Levy, Ofer

    2016-06-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  4. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures*

    PubMed Central

    Oh, Djin-Ye; Dowling, David J.; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T.; Sauld, John F.; Pettengill, Matthew; Kho, Alvin T.; Pollack, Henry J.; Steen, Hanno; Levy, Ofer

    2016-01-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  5. A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide

    PubMed Central

    Pojo, Marta; Gonçalves, Céline S.; Xavier-Magalhães, Ana; Oliveira, Ana Isabel; Gonçalves, Tiago; Correia, Sara; Rodrigues, Ana J.; Costa, Sandra; Pinto, Luísa; Pinto, Afonso A.; Lopes, José M.; Reis, Rui M.; Rocha, Miguel; Sousa, Nuno; Costa, Bruno M.

    2015-01-01

    Glioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma. PMID:25762636

  6. Adjuvants are Key Factors for the Development of Future Vaccines: Lessons from the Finlay Adjuvant Platform

    PubMed Central

    Pérez, Oliver; Romeu, Belkis; Cabrera, Osmir; González, Elizabeth; Batista-Duharte, Alexander; Labrada, Alexis; Pérez, Rocmira; Reyes, Laura M.; Ramírez, Wendy; Sifontes, Sergio; Fernández, Nelson; Lastre, Miriam

    2013-01-01

    The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs), AFPL (proteoliposome), and AFCo (cochleate), were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed. PMID:24348475

  7. Immunological adjuvants: a role for liposomes.

    PubMed

    Gregoriadis, G

    1990-03-01

    Recent technological advances have resulted in the production of safe subunit and synthetic small peptide vaccines. These vaccines are weakly or non-immunogenic and cannot, therefore, be used effectively in the absence of immunological adjuvants (agents that can induce strong immunity to antigens). Owing to the toxicity of adjuvants, only one (aluminium salts) has hitherto been licensed for use in humans, and it is far from ideal. In this article, Gregory Gregoriadis discusses the use of liposomes as an alternative safe, versatile, universal adjuvant that can induce humoral- and cell-mediated immunity to antigens when administered parenterally or enterally. PMID:2186746

  8. Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling.

    PubMed

    Riganti, Chiara; Salaroglio, Iris C; Pinzòn-Daza, Martha L; Caldera, Valentina; Campia, Ivana; Kopecka, Joanna; Mellai, Marta; Annovazzi, Laura; Couraud, Pierre-Olivier; Bosia, Amalia; Ghigo, Dario; Schiffer, Davide

    2014-02-01

    Low delivery of many anticancer drugs across the blood-brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma.

  9. Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: A case report

    PubMed Central

    Alshami, Jad; Guiot, Marie-Christine; Owen, Scott; Kavan, Petr; Gibson, Neil; Solca, Flavio; Cseh, Agnieszka; Reardon, David A.; Muanza, Thierry

    2015-01-01

    There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical trial of afatinib (20–40 mg daily for 28 days) plus temozolomide (50 mg/m2 every 21/28 days). Next-generation sequencing analysis of the brain tumor specimen was performed. At the last assessment, 63 treatment cycles had been completed and the patient had survived for ~5 years since recurrence. Significant disease regression was observed after 5 cycles and was maintained during long-term follow-up. Adverse events were consistent with the known tolerability profile of afatinib and were managed by treatment interruption/dose reduction. The patient had several epidermal growth factor receptor (EGFR) aberrations, including gene amplification and EGFRvIII positivity. Three somatic mutations were identified, including an unprecedented extracellular-domain substitution (D247Y). The patient has survived ~6-fold longer than normally expected in patients with recurrent GBM. The complex EGFR genotype may underlie sustained response to afatinib plus temozolomide. PMID:26423602

  10. The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain.

    PubMed

    Jackson, Sadhana; Anders, Nicole M; Mangraviti, Antonella; Wanjiku, Teresia M; Sankey, Eric W; Liu, Ann; Brem, Henry; Tyler, Betty; Rudek, Michelle A; Grossman, Stuart A

    2016-02-01

    The blood-brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60-90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 µg/g, P < 0.05). A similar trend was noted in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders.

  11. The effect of regadenoson-induced transient disruption of the blood–brain barrier on temozolomide delivery to normal rat brain

    PubMed Central

    Jackson, Sadhana; Anders, Nicole M.; Mangraviti, Antonella; Wanjiku, Teresia M.; Sankey, Eric W.; Liu, Ann; Brem, Henry; Tyler, Betty; Rudek, Michelle A.

    2016-01-01

    The blood–brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60–90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 μg/g, P <0.05). A similar trend was noted in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60 % higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders. PMID:26626489

  12. Novel Adjuvants and Immunomodulators for Veterinary Vaccines.

    PubMed

    Heegaard, Peter M H; Fang, Yongxiang; Jungersen, Gregers

    2016-01-01

    Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the vaccine is becoming a reality with our increased understanding of innate and adaptive immune activation. This will allow future vaccines to induce immune reactivity having adequate specificity as well as protective and recallable immune effector mechanisms in appropriate body compartments, including mucosal surfaces. Here we describe these new developments and, when possible, relate new immunological knowledge to the many years of experience with traditional, empirical adjuvants. Finally, some protocols are given for production of emulsion (oil-based) and liposome-based adjuvant/antigen formulations.

  13. Extended Adjuvant Therapy for Breast Cancer

    Cancer.gov

    An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

  14. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Cancer.gov

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  15. Combined radiotherapy and chemotherapy for high-grade brain tumours

    NASA Astrophysics Data System (ADS)

    Barazzuol, Lara

    Glioblastoma (GBM) is the most common primary brain tumour in adults and among the most aggressive of all tumours. For several decades, the standard care of GBM was surgical resection followed by radiotherapy alone. In 2005, a landmark phase III clinical trial coordinated by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) demonstrated the benefit of radiotherapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy. With TMZ, the median life expectancy in optimally managed patients is still only 12-14 months, with only 25% surviving 24 months. There is an urgent need for new therapies in particular in those patients whose tumour has an unmethylated methylguanine methyltransferase gene (MGMT) promoter, which is a predictive factor of benefit from TMZ. In this dissertation, the nature of the interaction between TMZ and radiation is investigated using both a mathematical model, based on in vivo population statistics of survival, and in vitro experimentation on a panel of human GBM cell lines. The results show that TMZ has an additive effect in vitro and that the population-based model may be insufficient in predicting TMZ response. The combination of TMZ with particle therapy is also investigated. Very little preclinical data exists on the effects of charged particles on GBM cell lines as well as on the concomitant application of chemotherapy. In this study, human GBM cells are exposed to 3 MeV protons and 6 MeV alpha particles in concomitance with TMZ. The results suggest that the radiation quality does not affect the nature of the interaction between TMZ and radiation, showing reproducible additive cytotoxicity. Since TMZ and radiation cause DNA damage in cancer cells, there has been increased attention to the use of poly(ADP-ribose) polymerase (PARP) inhibitors. PARP is a family of enzymes that play a key role in the repair of DNA breaks. In this study, a novel PARP inhibitor, ABT-888

  16. Applications of nanomaterials as vaccine adjuvants

    PubMed Central

    Zhu, Motao; Wang, Rongfu; Nie, Guangjun

    2014-01-01

    Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials’ physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants. PMID:25483497

  17. Adjuvant therapy after surgical stone management.

    PubMed

    Ferrandino, Michael N; Monga, Manoj; Preminger, Glenn M

    2009-01-01

    The aim of this article was to review the most widely researched adjuvant medical therapies for the surgical management of urolithiasis. Articles were identified and reviewed from PubMed and Medline databases with MeSH headings focusing on the various surgical treatments of urolithiasis and adjuvant therapy. Additional articles were retrieved from references and conference proceedings. Surgical treatments reviewed included shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy. Adjuvant therapy was considered medical or complementary therapy as an adjunct to these surgical interventions. Adjuvant therapy for the surgical management of urolithiasis has been documented to increase stone-free rates, reduce stone remission rates, prevent renal damage, and decrease postoperative morbidity. A variety of agents have been studied, ranging from antioxidants to alpha-blockers and to alkalinizing agents. Additionally, there is increasing interest in complementary adjuvant therapy (ie, acupuncture). Adjuvant therapy is a fertile area for research in the surgical management of urolithiasis. The optimal agents have yet to be determined and therefore further investigation is warranted and necessary.

  18. Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant chemotherapy part of standard of care in low-grade glioma.

    PubMed

    van den Bent, Martin J

    2014-12-01

    The long-term follow-up of the RTOG 9802 trial that compared 54 Gy of radiotherapy (RT) with the same RT followed by adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy in high-risk low-grade glioma shows a major increase in survival after adjuvant PCV chemotherapy. Median overall survival increased from 7.8 years to 13.3 years, with a hazard ratio of death of 0.59 (log rank: P = .002). This increase in survival was observed despite the fact that 77% of patients who progressed after RT alone received salvage chemotherapy. With this outcome, RT + PCV is now to be considered standard of care for low-grade glioma requiring postsurgical adjuvant treatment. Unfortunately, studies on molecular correlates associated with response are still lacking. This is now the third trial showing benefit from the addition of PCV to RT in grade II or III diffuse glioma. The optimal parameter for selecting patients for adjuvant PCV has not yet been fully elucidated, but several candidate markers have so far emerged. It is still unclear whether temozolomide can replace PCV and whether initial management with chemotherapy only is a safe initial treatment. Potentially, that may adversely affect overall survival, but concerns for delayed RT-induced neurotoxicity may limit acceptance of early RT in patients with expected long term survival. The current evidence supports that in future trials, grades II and III tumors with similar molecular backgrounds should be combined, and trials should focus on molecular glial subtype regardless of grade.

  19. Adjuvant effects of saponins on animal immune responses*

    PubMed Central

    Rajput, Zahid Iqbal; Hu, Song-hua; Xiao, Chen-wen; Arijo, Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines, ISCOMs (immunostimulating complexes), Freund’s complete adjuvant, Freund’s incomplete adjuvant, alums, bacterial toxins etc., are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed. PMID:17323426

  20. Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

    SciTech Connect

    Narayana, Ashwatha Golfinos, John G.; Fischer, Ingeborg; Raza, Shahzad; Kelly, Patrick M.D.; Parker, Erik; Knopp, Edmond A.; Medabalmi, Praveen; Zagzag, David; Eagan, Patricia; Gruber, Michael L.

    2008-10-01

    Introduction: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has shown promise in the treatment of patients with recurrent high-grade glioma. The purpose of this study is to test the feasibility of using bevacizumab with chemoradiation in the primary management of high-grade glioma. Methods and Materials: Fifteen patients with high-grade glioma were treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 mg/kg on Days 14 and 28 and temozolomide 75 mg/m{sup 2}. Subsequently, bevacizumab 10 mg/kg was continued every 2 weeks with temozolomide 150 mg/m{sup 2} for 12 months. Changes in relative cerebral blood volume, perfusion-permeability index, and tumor volume measurement were measured to assess the therapeutic response. Immunohistochemistry for phosphorylated VEGF receptor 2 (pVEGFR2) was performed. Results: Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation therapy. Four Grade III/IV nonhematologic toxicities were seen. Radiographic responses were noted in 13 of 14 assessable patients (92.8%). The pVEGFR2 staining was seen in 7 of 8 patients (87.5%) at the time of initial diagnosis. Six patients have experienced relapse, 3 at the primary site and 3 as diffuse disease. One patient showed loss of pVEGFR2 expression at relapse. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively. Conclusion: Use of antiangiogenic therapy with radiation and temozolomide in the primary management of high-grade glioma is feasible. Perfusion imaging with relative cerebral blood volume, perfusion-permeability index, and pVEGFR2 expression may be used as a potential predictor of therapeutic response. Toxicities and patterns of relapse need to be monitored closely.

  1. Metronomic temozolomide as second line treatment for metastatic poorly differentiated pancreatic neuroendocrine carcinoma.

    PubMed

    De Divitiis, C; von Arx, C; Grimaldi, A M; Cicala, D; Tatangelo, F; Arcella, A; Romano, G M; Simeone, E; Iaffaioli, R V; Ascierto, P A; Tafuto, S

    2016-01-01

    Neuroendocrine Neoplasms (NEN) are a group of heterogeneous malignancies derived from neuroendocrine cell compartment, with different roles in both endocrine and nervous system. Most NETs have gastroentero-pancreatic (GEP) origin, arising in the foregut, midgut, or hindgut. The 2010 WHO classification divides GEP-NETs into two main subgroups, neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), according with Ki-67 levels. NET are tumors with low (<20 %) Ki-67 value, and NECs, including small cell lung carcinomas and Merkel Cell carcinomas, are all NETs with high Ki-67 levels (>20 %-G3). Poorly differentiated neuroendocrine carcinomas (NEC) are usually treated with cisplatin-based chemotherapy regimens. Here we present a case of a patient with pancreatic NEC progressing after cisplatin and etoposide, treated with temozolomide as palliative, second line treatment. According with the poor Performance Status (PS = 2) and to reduce the toxicity of the treatment was chosen an intermittent dosing regimen of metronomic temozolomide (75 mg/m(2)/day-one-week-on/on-week-off). MGMT resulted methylated. On July 2014 the patient started the treatment. On August 2014 the patient obtained a significant clinical benefit (PS = 0) and the total body CT scan performed on October 2014 showed a RECIST partial response on all the sites of disease. No drug-related side effects were reported by the patient. After 18 months of therapy the treatment continues without significant toxicity, and with further remission of the metastases. Treatment with metronomic "one-week-on/on-week-off" Temozolomide can be considered a good treatment option in patients with poor performance status, affected by pNEC with MGMT methylation. PMID:27142424

  2. Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma.

    PubMed

    Das, Arabinda; Cheng, Ron Ron; Hilbert, Megan L T; Dixon-Moh, Yaenette N; Decandio, Michele; Vandergrift, William Alex; Banik, Naren L; Lindhorst, Scott M; Cachia, David; Varma, Abhay K; Patel, Sunil J; Giglio, Pierre

    2015-01-01

    Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the

  3. Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma

    PubMed Central

    Das, Arabinda; Cheng, Ron Ron; Hilbert, Megan L.T.; Dixon-Moh, Yaenette N.; Decandio, Michele; Vandergrift, William Alex; Banik, Naren L.; Lindhorst, Scott M.; Cachia, David; Varma, Abhay K.; Patel, Sunil J.; Giglio, Pierre

    2015-01-01

    Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the

  4. Relapse of herpes encephalitis induced by temozolomide-based chemoradiation in a patient with malignant glioma.

    PubMed

    Okada, Masaki; Miyake, Keisuke; Shinomiya, Aya; Kawai, Nobuyuki; Tamiya, Takashi

    2013-02-01

    The authors report on a case of concurrent herpes simplex encephalitis (HSE) and malignant glioma. The co-occurrence of HSE and malignant glioma is very rare, but it can occur during glioma treatment. Both radiotherapy and chemoradiation with temozolomide can induce viral reactivation, leading to HSE relapse. Careful observation for HSE is necessary when administering chemoradiation to patients with a history of HSE. Antiviral therapy for HSE must be initiated immediately, and the chemoradiation for glioma should be stopped; however, it is not clear what antitumor therapy is optimal when HSE co-occurs during the treatment of glioma.

  5. Beyond antigens and adjuvants: formulating future vaccines.

    PubMed

    Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J

    2016-03-01

    The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines.

  6. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    NASA Astrophysics Data System (ADS)

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

    Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.

  7. Oil-based emulsion vaccine adjuvants.

    PubMed

    Schijns, Virgil E J C; Strioga, Marius; Ascarateil, Stephane

    2014-01-01

    Vaccine adjuvants are critical components in experimental and licensed vaccines used in human and veterinary medicine. When aiming to evoke an immune response to a purified antigen, the administration of antigen alone is often insufficient, unless the antigen contains microbial structures or has a natural particulate structure. In most cases, the rationale to use an adjuvant is obvious to the experimental immunologist or the professional vaccinologist, who is familiar with the nature of the antigen, and the aim of the vaccine to elicit a specific antibody response and/or a specific type of T cell response. In this unit, we describe protocols to formulate antigens with oil-based emulsions. Such emulsions represent a major prototype adjuvant category that is frequently used in experimental preclinical vaccines, as well as veterinary and human vaccines.

  8. Adjuvants and vector systems for allergy vaccines.

    PubMed

    Moingeon, Philippe; Lombardi, Vincent; Saint-Lu, Nathalie; Tourdot, Sophie; Bodo, Véronique; Mascarell, Laurent

    2011-05-01

    Allergen-specific immunotherapy represents a curative treatment of type I allergies. Subcutaneous immunotherapy is conducted with allergens adsorbed on aluminum hydroxide or calcium phosphate particles, whereas sublingual immunotherapy relies on high doses of soluble allergen without any immunopotentiator. There is a potential benefit of adjuvants enhancing regulatory and Th1 CD4+T cell responses during specific immunotherapy. Molecules affecting dendritic cells favor the induction of T regulatory cell and Th1 responses and represent valid candidate adjuvants for allergy vaccines. Furthermore, the interest in viruslike particles and mucoadhesive particulate vector systems, which may better address the allergen(s) to tolerogenic antigen-presenting cells, is documented.

  9. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.

    PubMed

    Cives, M; Ghayouri, M; Morse, B; Brelsford, M; Black, M; Rizzo, A; Meeker, A; Strosberg, J

    2016-09-01

    The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

  10. Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor

    PubMed Central

    Thearle, Marie S.; Bruce, Jeffrey N.; Isaacson, Steven R.; Lee, Yoomi

    2010-01-01

    Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted. PMID:19960369

  11. [ADJUVANTED INFLUENZA VACCINES: DATA FROM DIRECT COMPARATIVE STUDIES].

    PubMed

    Chernikova, M I; Vasiliev, Yu M

    2015-01-01

    Vaccines are the cornerstone of influenza control, however available vaccines are subject to certain limitations. Adjuvanted vaccines are a promising approach, however available adjuvants have a suboptimal effectiveness and safety profile. Data from direct comparative trials are necessary for selection of optimal adjuvants among currently available and search for novel safe and effective adjuvants for next generation influenza vaccines. Data from published direct comparative studies of adjuvants for influenza vaccines are summarized, a lack of such studies is noted, especially those using adequate methods and designs and comparing adjuvants of major groups (nature/source and mechanism of action). Several promising approaches of adjuvant research and development could be identified: chitosan-based adjuvants, oil-in-water emulsions and multi-component formulations (depot + immune modulating components).

  12. Outlining novel cellular adjuvant products for therapeutic vaccines against cancer.

    PubMed

    Tefit, Josianne Nitcheu; Serra, Vincent

    2011-08-01

    Despite the library of new adjuvants available for use in vaccines, we remain, at present, almost reliant on aluminum-based compounds for clinical use. The increasing use of recombinant subunit vaccines, however, makes the need for improved adjuvant of particular interest. Adjuvants are crucial components of all cancer vaccines whether they are composed of whole cells, proteins or peptides. For the purposes of this article, cellular adjuvant products are defined as adjuvants associated with cellular or T-cell immunity. Several pharmaceutical companies are developing new adjuvants or immune enhancers for the treatment of cancers such as melanoma and non-small-cell lung carcinoma. Several products are being developed and have entered clinical trials either alone or in combination. In this article, we discuss recent adjuvant development and novel cellular adjuvant products for therapeutic cancer vaccines.

  13. Phase II trial of temozolomide and reirradiation using conformal 3D-radiotherapy in recurrent brain gliomas

    PubMed Central

    2014-01-01

    Purpose This phase II trial was designed to assess the response rate, survival benefits and toxicity profile of temozolomide, and brain reirradiation using conformal radiotherapy (RT) for treatment of recurrent high grade glioma. Design Open-label phase II trial. Patients Twenty-nine patients had been enrolled in the study between February 2006 and June 2009. Patients had to show unequivocal evidence of tumour recurrence on gadolinium-enhanced magnetic resonance imaging (MRI) after failing conventional RT with or without temozolomide and surgery for initial disease. Histology included recurrent anaplastic astrocytoma, glioblastoma multiforme. Interventions Patients were treated by temozolomide at a dose of 200 mg/m2/day for chemonaïve patients, and at a dose of 150 mg/m2/day to previously treated patients, for 4-5 cycles. Then, patients underwent reirradiation by conformal RT at a dose of 30-40 Gy by conventional fractionation. Main outcome measures The primary end point of the study was response. The secondary end points included survival benefit. Results All the 29 patients were treated with temozolomide and reirradiation. Two patients achieved complete remission (CR), 4 achieved partial remission (PR), with an overall objective response rate of 20.6%, and further 10 patients had stable disease (SD), with a SD rate of 34.4%. The mean progression free survival (PFS) was 10.1 months, and the mean overall survival (OS) was 11.4 months. Additionally, treatment significantly improved quality of life (QOL). Treatment was tolerated well with mild grade 1, 2 nausea/vomiting in 40% of cycles, and mild grade 1, 2 haematological toxicities (neutropenia/thrombocytoprnia) in 8.6% of cycles. Conclusions Temozolomide and conformal RT had an anti-tumor activity in recurrent high grade glioma, and represented a good treatment hope for patients with recurrent brain glioma. PMID:25333019

  14. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  15. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Adjuvants for pesticide chemicals. 582.99...

  16. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide chemicals. 182.99...

  17. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  18. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 182.99...

  19. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 582.99...

  20. Gaps in knowledge and prospects for research of adjuvanted vaccines.

    PubMed

    Seder, Robert; Reed, Steven G; O'Hagan, Derek; Malyala, Padma; D'Oro, Ugo; Laera, Donatello; Abrignani, Sergio; Cerundolo, Vincenzo; Steinman, Lawrence; Bertholet, Sylvie

    2015-06-01

    A panel of researchers working in different areas of adjuvanted vaccines deliberated over the topic, "Gaps in knowledge and prospects for research of adjuvanted vaccines" at, "Enhancing Vaccine Immunity and Value" conference held in July 2014. Several vaccine challenges and applications for new adjuvant technologies were discussed.

  1. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 582.99...

  2. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 182.99...

  3. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 582.99...

  4. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 582.99...

  5. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) SUBSTANCES GENERALLY RECOGNIZED AS SAFE General Provisions § 182.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 182.99...

  6. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 182.99...

  7. Adjuvant Chemotherapy in Rectal Cancer after Chemoradiotherapy.

    PubMed

    Boustani, J; Caubet, M; Bosset, J-F

    2016-02-01

    The aim of this overview was to investigate whether adjuvant chemotherapy has a favourable effect on the outcome of patients with rectal cancer who had preoperative (chemo)radiotherapy. A review of randomised clinical trials that allocated patients between fluorouracil-based and observation or between fluorouracil-based and oxaliplatin-based adjuvant chemotherapy after preoperative (chemo)radiotherapy was carried out, including their corresponding meta-analyses. None of the five randomised trials has shown a significant benefit of fluorouracil-based adjuvant chemotherapy for overall survival or disease-free survival. Also, the three corresponding meta-analyses failed to show a benefit of adjuvant treatment. Of three randomised trials - two phase III and one phase II with a 3-year disease-free survival end point - two showed a small benefit of adding oxaliplatin to fluorouracil, one failed. The corresponding meta-analyses showed that the pooled difference was not significant. In conclusion, the use of postoperative 5-fluorouracil-based chemotherapy with or without oxaliplatin in patients with rectal cancer after preoperative (chemo)radiotherapy is not scientifically proven.

  8. Adjuvants for peptide-based cancer vaccines.

    PubMed

    Khong, Hiep; Overwijk, Willem W

    2016-01-01

    Cancer therapies based on T cells have shown impressive clinical benefit. In particular, immune checkpoint blockade therapies with anti-CTLA-4 and anti-PD-1/PD-L1 are causing dramatic tumor shrinkage and prolonged patient survival in a variety of cancers. However, many patients do not benefit, possibly due to insufficient spontaneous T cell reactivity against their tumors and/or lacking immune cell infiltration to tumor site. Such tumor-specific T cell responses could be induced through anti-cancer vaccination; but despite great success in animal models, only a few of many cancer vaccine trials have demonstrated robust clinical benefit. One reason for this difference may be the use of potent, effective vaccine adjuvants in animal models, vs. the use of safe, but very weak, vaccine adjuvants in clinical trials. As vaccine adjuvants dictate the type and magnitude of the T cell response after vaccination, it is critical to understand how they work to design safe, but also effective, cancer vaccines for clinical use. Here we discuss current insights into the mechanism of action and practical application of vaccine adjuvants, with a focus on peptide-based cancer vaccines. PMID:27660710

  9. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-08-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  10. Induction of lupus autoantibodies by adjuvants

    USGS Publications Warehouse

    Satoh, M.; Kuroda, Y.; Yoshida, H.; Behney, K.M.; Mizutani, A.; Akaogi, J.; Nacionales, D.C.; Lorenson, T.D.; Rosenbauer, R.J.; Reeves, W.H.

    2003-01-01

    Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNF?? production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines. ?? 2003 Elsevier Ltd. All rights reserved.

  11. Vitamins as influenza vaccine adjuvant components.

    PubMed

    Quintilio, Wagner; de Freitas, Fábio Alessandro; Rodriguez, Dunia; Kubrusly, Flavia Saldanha; Yourtov, Dimitri; Miyaki, Cosue; de Cerqueira Leite, Luciana Cezar; Raw, Isaias

    2016-10-01

    A number of adjuvant formulations were assayed in mice immunized with 3.75 µg of A/California/7/2009 (H1N1) pdm09 influenza vaccine with vitamins A, D and/or E in emulsions or B2 and/or B9 combined with Bordetella pertussis MPLA and/or alum as adjuvants. Squalene was used as positive control, as well as MPLA with alum. The immune response was evaluated by a panel of tests, including a hemagglutination inhibition (HAI) test, ELISA for IgG, IgG1, and IgG2a and IFN-γ, IL-2, IL-6 and IL-10 quantification in splenocyte culture supernatant after stimulus with influenza antigen. Immunological memory was evaluated using a 1/10 dose booster 60 days after the first immunization followed by assessment of the response by HAI, IgG ELISA, and determination of the antibody affinity index. The highest increases in HAI, IgG1 and IgG2a titers were obtained with the adjuvant combinations containing vitamin E, or the hydrophilic combinations containing MPLA and alum or B2 and alum. The IgG1/IgG2a ratio indicates that the response to the combination of B2 with alum would have more Th2 character than the combination of MPLA with alum. In an assay to investigate the memory response, a significant increase in HAI titer was observed with a booster vaccine dose at 60 days after immunization with vaccines containing MPLA with alum or B2 with alum. Overall, of the 27 adjuvant combinations, MPLA with alum and B2 with alum were the most promising adjuvants to be evaluated in humans. PMID:27449155

  12. Vitamins as influenza vaccine adjuvant components.

    PubMed

    Quintilio, Wagner; de Freitas, Fábio Alessandro; Rodriguez, Dunia; Kubrusly, Flavia Saldanha; Yourtov, Dimitri; Miyaki, Cosue; de Cerqueira Leite, Luciana Cezar; Raw, Isaias

    2016-10-01

    A number of adjuvant formulations were assayed in mice immunized with 3.75 µg of A/California/7/2009 (H1N1) pdm09 influenza vaccine with vitamins A, D and/or E in emulsions or B2 and/or B9 combined with Bordetella pertussis MPLA and/or alum as adjuvants. Squalene was used as positive control, as well as MPLA with alum. The immune response was evaluated by a panel of tests, including a hemagglutination inhibition (HAI) test, ELISA for IgG, IgG1, and IgG2a and IFN-γ, IL-2, IL-6 and IL-10 quantification in splenocyte culture supernatant after stimulus with influenza antigen. Immunological memory was evaluated using a 1/10 dose booster 60 days after the first immunization followed by assessment of the response by HAI, IgG ELISA, and determination of the antibody affinity index. The highest increases in HAI, IgG1 and IgG2a titers were obtained with the adjuvant combinations containing vitamin E, or the hydrophilic combinations containing MPLA and alum or B2 and alum. The IgG1/IgG2a ratio indicates that the response to the combination of B2 with alum would have more Th2 character than the combination of MPLA with alum. In an assay to investigate the memory response, a significant increase in HAI titer was observed with a booster vaccine dose at 60 days after immunization with vaccines containing MPLA with alum or B2 with alum. Overall, of the 27 adjuvant combinations, MPLA with alum and B2 with alum were the most promising adjuvants to be evaluated in humans.

  13. New generation adjuvants--from empiricism to rational design.

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability.

  14. New generation adjuvants--from empiricism to rational design.

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. PMID:26022561

  15. In vitro evaluation of combined temozolomide and radiotherapy using X  rays and high-linear energy transfer radiation for glioblastoma.

    PubMed

    Barazzuol, Lara; Jena, Raj; Burnet, Neil G; Jeynes, Jonathan C G; Merchant, Michael J; Kirkby, Karen J; Kirkby, Norman F

    2012-05-01

    High-linear energy transfer radiation offers superior biophysical properties over conventional radiotherapy and may have a great potential for treating radioresistant tumors, such as glioblastoma. However, very little pre-clinical data exists on the effects of high-LET radiation on glioblastoma cell lines and on the concomitant application of chemotherapy. This study investigates the in vitro effects of temozolomide in combination with low-energy protons and α particles. Cell survival, DNA damage and repair, and cell growth were examined in four human glioblastoma cell lines (LN18, T98G, U87 and U373) after treatment with either X rays, protons (LET 12.91 keV/μm), or α particles (LET 99.26 keV/μm) with or without concurrent temozolomide at clinically-relevant doses of 25 and 50 μM. The relative biological effectiveness at 10% survival (RBE(10)) increased as LET increased: 1.17 and 1.06 for protons, and 1.84 and 1.68 for α particles in the LN18 and U87 cell lines, respectively. Temozolomide administration increased cell killing in the O(6)-methylguanine DNA methyltransferase-methylated U87 and U373 cell lines. In contrast, temozolomide provided no therapeutic enhancement in the methylguanine DNA methyltransferase-unmethylated LN18 and T98G cell lines. In addition, the residual number of γ-H2AX foci at 24 h after treatment with radiation and concomitant temozolomide was found to be lower than or equal to that expected by DNA damage with either of the individual treatments. Kinetics of foci disappearance after X-ray and proton irradiation followed similar time courses; whereas, loss of γ-H2AX foci after α particle irradiation occurred at a slower rate than that by low-LET radiation (half-life 12.51-16.87 h). The combination of temozolomide with different radiation types causes additive rather than synergistic cytotoxicity. Nevertheless, particle therapy combined with chemotherapy may offer a promising alternative with the additional benefit of superior

  16. Patterns and Timing of Recurrence After Temozolomide-Based Chemoradiation for Glioblastoma

    SciTech Connect

    Milano, Michael T.; Okunieff, Paul; Donatello, Rosemary S.; Mohile, Nimish A.; Sul, Joohee; Walter, Kevin A.; Korones, David N.

    2010-11-15

    Purpose: To determine recurrence patterns of glioblastoma treated with temozolomide-based chemoradiation. Methods: Pretreatment and serial posttreatment magnetic resonance imaging scans of 54 patients were retrospectively evaluated. Central recurrence (i.e., local progression) and the development of new (i.e., interval appearance of discrete enhancing lesion) in-field, marginal, and distant recurrences were assessed, with the pattern of recurrence of individual lesions defined relative to the 95% isodose line (D{sub 95}). Distant recurrences were defined as lesions completely outside D{sub 95}, marginal recurrences crossed D{sub 95}, and in-field recurrences were completely inside D{sub 95}. Results: At a median follow-up of 17 months, 39 of 54 (72%) patients developed recurrent glioblastoma. Among these 39 patients, central recurrence occurred in 80% (at a median of 7 months from diagnosis); new in-field recurrence developed in 33% (at a median of 14 months); marginal recurrences developed in 15% (at a median of 18 months); and distant recurrences developed in 20% (at a median of 11 months). The actuarial rates of central, new in-field, marginal, distant, and any new recurrences at 1-year were 46%, 15%, 3%, 14%, and 25% respectively, whereas at 2 years, the rates were 68%, 60%, 32%, 28%, and 66%, reflecting an increasing probability of new lesions developing at later time points. Ten patients developed subependymal recurrences, of whom 7 developed multiple subependymal lesions. Conclusions: Whereas central recurrence of glioblastoma treated with radiation and temozolomide predominates and persists over time, new in-field, marginal, and distant recurrences commonly develop, particularly at later time points in patients with longer survival.

  17. Psychosocial and Physical Effects of Adjuvant Chemotherapy

    PubMed Central

    Hislop, Thomas Gregory; Elwood, J. Mark; Waxler-Morrison, Nancy; Ragaz, Joseph; Skippen, Diane Hazel; Turner, I.D.

    1991-01-01

    Breast cancer patients younger than 55 completed a questionnaire on psychosocial factors and physical side effects shortly after diagnosis and 9 to 15 months after diagnosis. Those who had used adjuvant chemotherapy were more likely than those who had not to report physical side effects; there was little difference in psychosocial factors. Recent users were more likely than ex-users to report physical side effects, difficulties with domestic chores, and improvement in psychosocial factors. PMID:21229020

  18. Inflammatory responses following intramuscular and subcutaneous immunization with aluminum-adjuvanted or non-adjuvanted vaccines.

    PubMed

    Kashiwagi, Yasuyo; Maeda, Mika; Kawashima, Hisashi; Nakayama, Tetsuo

    2014-06-01

    Aluminum-adjuvanted vaccines are administered through an intramuscular injection (IM) in the US and EU, however, a subcutaneous injection (SC) has been recommended in Japan because of serious muscle contracture previously reported following multiple IMs of antibiotics. Newly introduced adjuvanted vaccines, such as the human papillomavirus (HPV) vaccines, have been recommended through IM. In the present study, currently available vaccines were evaluated through IM in mice. Aluminum-adjuvanted vaccines induced inflammatory nodules at the injection site, which expanded into the intra-muscular space without any muscle degeneration or necrosis, whereas non-adjuvanted vaccines did not. These nodules consisted of polymorph nuclear neutrophils with some eosinophils within the initial 48h, then monocytes/macrophages 1 month later. Inflammatory nodules were observed 6 months after IM, had decreased in size, and were absorbed 12 months after IM, which was earlier than that after SC. Cytokine production was examined in the injected muscular tissues and AS04 adjuvanted HPV induced higher IL-1β, IL-6, KC, MIP-1, and G-CSF levels in muscle tissues than any other vaccine, but similar serum cytokine profiles were observed to those induced by the other vaccines. Currently available vaccines did not induce muscular degeneration or fibrotic scar as observed with muscle contracture caused by multiple IMs of antibiotics in the past.

  19. Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study

    PubMed Central

    Heimberger, Amy B.; Sun, Wei; Hussain, S. Farzana; Dey, Mahua; Crutcher, Lamonne; Aldape, Ken; Gilbert, Mark; Hassenbusch, Samuel J.; Sawaya, Raymond; Schmittling, Bob; Archer, Gary E.; Mitchell, Duane A.; Bigner, Darell D.; Sampson, John H.

    2008-01-01

    Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemo-therapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery. PMID:18079360

  20. Utility of adjuvant systemic therapy in melanoma

    PubMed Central

    Eggermont, A. M. M.; Testori, A.; Marsden, J.; Hersey, P.; Quirt, I.; Petrella, T.; Gogas, H.; MacKie, R. M.; Hauschild, A.

    2009-01-01

    The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing. PMID:19617295

  1. Adjuvant and neoadjuvant treatment in pancreatic cancer

    PubMed Central

    Herreros-Villanueva, Marta; Hijona, Elizabeth; Cosme, Angel; Bujanda, Luis

    2012-01-01

    Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes “standard” adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients. PMID:22529684

  2. Recent Advances of Vaccine Adjuvants for Infectious Diseases

    PubMed Central

    Nguyen, Minh Trang

    2015-01-01

    Vaccines are the most effective and cost-efficient method for preventing diseases caused by infectious pathogens. Despite the great success of vaccines, development of safe and strong vaccines is still required for emerging new pathogens, re-emerging old pathogens, and in order to improve the inadequate protection conferred by existing vaccines. One of the most important strategies for the development of effective new vaccines is the selection and usage of a suitable adjuvant. Immunologic adjuvants are essential for enhancing vaccine potency by improvement of the humoral and/or cell-mediated immune response to vaccine antigens. Thus, formulation of vaccines with appropriate adjuvants is an attractive approach towards eliciting protective and long-lasting immunity in humans. However, only a limited number of adjuvants is licensed for human vaccines due to concerns about safety and toxicity. We summarize current knowledge about the potential benefits of adjuvants, the characteristics of adjuvants and the mechanisms of adjuvants in human vaccines. Adjuvants have diverse modes of action and should be selected for use on the basis of the type of immune response that is desired for a particular vaccine. Better understanding of current adjuvants will help exploring new adjuvant formulations and facilitate rational design of vaccines against infectious diseases. PMID:25922593

  3. The Microarray Gene Profiling Analysis of Glioblastoma Cancer Cells Reveals Genes Affected by FAK Inhibitor Y15 and Combination of Y15 and Temozolomide

    PubMed Central

    Huang, Grace; Ho, Baotran; Conroy, Jeffrey; Liu, Song; Qiang, Hu; Golubovskaya, Vita

    2013-01-01

    Focal adhesion is known to be highly expressed and activated in glioma cells. Recently, we demonstrated that FAK autophosphorylation inhibitor, Y15 significantly decreased tumor growth of DBTRG and U87 cells, especially in combination with temozolomide. In the present report, we performed gene expression analysis in these cells to reveal genes affected by Y15, temozolomide and combination of Y15 and temozolomide. We tested the effect of Y15 on gene expression by Illumina Human HT12v4 microarray assay and detected 8087 and 6555 genes, which were significantly either up- or down-regulated by Y15-treatment in DBTRG and U87 cells, respectively (p<0.05). Moreover, DBTRG and U87 cells treated with Y15 changed expression of 1332 and 462 genes more than 1.5 fold, p<0.05, respectively and had 237 common genes affected by Y15. The common genes up-regulated by Y15 included GADD45A, HSPA6 (heat-shock 70); DUSP1, DUSP 5 (dual-phosphatase 5); CDKN1A (p21) and common down-regulated genes included kinesins, such as KIF11, 14, 20A, 20B; topoisomerase II, TOP2A; cyclin F; cell cycle protein: BUB1; PARP1, POLA1. In addition, we detected genes affected by temozolomide and by combination of Y15 and temozolomide treatment in U87 cells. Among genes up-regulated by Y15 and temozolomide more significantly than by each agent alone were: COX7B; interferon, gamma-inducible transcript: IFI16; DDIT4; GADD45G and down-regulated: KIF3A, AKT1; ABL; JAK1, GLI3 and ALDH1A3. Thus, microarray gene expression analysis can be effective in establishing genes affected in response to FAK inhibitor alone and in response to combination of Y15 with temozolomide that is important for glioblastoma therapy. PMID:23387973

  4. A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

    SciTech Connect

    Den, Robert B.; Kamrava, Mitchell; Sheng, Zhi; Werner-Wasik, Maria; Dougherty, Erin; Marinucchi, Michelle; Lawrence, Yaacov R.; Hegarty, Sarah; Hyslop, Terry; Andrews, David W.; Glass, Jon; Friedman, David P.; Green, Michael R.; Camphausen, Kevin; Dicker, Adam P.

    2013-02-01

    Purpose: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m{sup 2}) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

  5. Phase I Study Of The Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, In Combination With Temozolomide in Patients with Advanced Solid Tumors

    PubMed Central

    Plummer, Ruth; Jones, Christopher; Middleton, Mark; Wilson, Richard; Evans, Jeffrey; Olsen, Anna; Curtin, Nicola; Boddy, Alan; McHugh, Peter; Newell, David; Harris, Adrian; Johnson, Patrick; Steinfeldt, Heidi; Dewji, Raz; Wang, Diane; Robson, Lesley; Calvert, Hilary

    2009-01-01

    Purpose One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. PARP-1 is a nuclear enzyme involved in base excision repair, one of the 5 major repair pathways. PARP inhibitors are emerging as a new class of agents which can potentiate chemo and radiotherapy. The paper reports safety, efficacy, pharmacokinetic and pharmacodynamic results of the First-in-Class trial of a PARP inhibitor, AG-014699, combined with temozolomide in adults with advanced malignancy. Experimental Design Initially patients with solid tumors received escalating doses of AG-014699 with 100 mg/m2 temozolomide daily x 5 q 28 to establish the PARP-inhibitory dose (PID). Subsequently AG-014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumours were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single strand breaks (SSB), response and toxicity were evaluated. Results 33 patients were enrolled. PARP inhibition was seen at all doses, PID was 12 mg/m2 based on 74 -97% inhibition of PBL PARP activity. Recommended doses were AG014699 12 mg/m2 and temozolomide 200 mg/m2. Mean tumor PARP inhibition at 5 hours was 92% (range 46 - 97%). No toxicity attributable to AG014699 alone was observed. AG014699 demonstrated linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA SSB and encouraging evidence of activity was seen. Conclusions The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments demonstrating proof of principle of the mode of action of this new class of agents. PMID:19047122

  6. Phase II Trial of Pre-Irradiation and Concurrent Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendrogliomas and Mixed Anaplastic Oligoastrocytomas: Long Term Results of RTOG BR0131

    PubMed Central

    Vogelbaum, Michael A.; Hu, Chen; Peereboom, David M.; Macdonald, David R.; Giannini, Caterina; Suh, John H.; Jenkins, Robert B.; Laack, Nadia N.; Brachman, David G.; Shrieve, Dennis C.; Souhami, Luis; Mehta, Minesh P.

    2015-01-01

    BACKGROUND We report on the long-term results of a phase II study of pre-irradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma (MOA). METHODS Pre-RT temozolomide was given for up to 6 cycles. RT with concurrent temozolomide was administered to patients with less than a complete radiographic response. RESULTS Forty eligible patients were entered and 32 completed protocol treatment. With a median follow-up time of 8.7 years (range: 1.1 to 10.1), median progression-free survival (PFS) is 5.8 years (95% C.I. 2.0, NR) and median overall survival (OS) has not been reached (5.9, NR). 1p/19q data are available in 37 cases; 23 tumors had codeletion while 14 tumors had no loss or loss of only 1p or 19q (non-codeleted). In codeleted patients, 9 patients have progressed and 4 have died; neither median PFS nor OS have been reached and two patients who received only pre-RT temozolomide and no RT have remained progression-free for over 7 years. 3-year PFS and 6-year OS are 78% (95% CI: 61-95%) and 83% (95% CI: 67-98%), respectively. Codeleted patients show a trend towards improved 6-year survival when compared to the codeleted procarbazine/CCNU/vincristrine (PCV) and RT cohort in RTOG 9402 (67%, 95% CI:55-79%). For non-codeleted patients, median PFS and OS are 1.3 and 5.8 years, respectively. CONCLUSIONS These updated results suggest that the regimen of dose intense, pre-RT temozolomide followed by concurrent RT/temozolomide has significant activity, particularly in patients with 1p/19q codeleted AOs and MAOs. PMID:26088460

  7. PTEN loss compromises homologous recombination repair in astrocytes: implications for GBM therapy with temozolomide or PARP inhibitors

    PubMed Central

    McEllin, Brian; Camacho, Cristel V.; Mukherjee, Bipasha; Hahm, Brandon; Tomimatsu, Nozomi; Bachoo, Robert M.; Burma, Sandeep

    2010-01-01

    Glioblastoma multiforme (GBM) are lethal brain tumors that are highly resistant to therapy. The only meaningful improvement in therapeutic response came from use of the SN1-type alkylating agent, temozolomide, in combination with ionizing radiation (IR). However, no genetic markers that might predict a better response to DNA alkylating agents have been identified in GBMs, except for loss of O6-methylguanine-DNA methyltransferase (MGMT) via promoter methylation. In this study, using genetically defined primary murine astrocytes as well as human glioma lines, we show that loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) confers sensitivity to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), a functional analog of temozolomide. We find that MNNG induces replication-associated DNA double-strand breaks (DSBs) that are inefficiently repaired in PTEN-deficient astrocytes and trigger apoptosis. Mechanistically, this is because PTEN-null astrocytes are compromised in homologous recombination (HR), which is important for the repair of replication-associated DSBs. Our results suggest that reduced levels of Rad51 paralogs in PTEN-null astrocytes might underlie the HR deficiency of these cells. Importantly, the HR deficiency of PTEN-null cells renders them sensitive to the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 due to synthetic lethality. In sum, our results tentatively suggest that patients with PTEN-null GBMs (about 36%) may especially benefit from treatment with DNA alkylating agents such as temozolomide. Significantly, our results also provide a rational basis for treating the sub-group of patients who are PTEN deficient with PARP inhibitors in addition to the current treatment regimen of radiation and temozolomide. PMID:20530668

  8. B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells

    PubMed Central

    Krumm, Andrea; Merz, Stephanie; Switzeny, Olivier Jérôme; Christmann, Markus; Loquai, Carmen; Kaina, Bernd

    2014-01-01

    In the treatment of metastatic melanoma, a highly therapy-refractory cancer, alkylating agents are used and, for the subgroup of BRAFV600E cancers, the B-Raf inhibitor vemurafenib. Although vemurafenib is initially beneficial, development of drug resistance occurs leading to tumor relapse, which necessitates the requirement for combined or sequential therapy with other drugs, including genotoxic alkylating agents. This leads to the question whether vemurafenib and alkylating agents act synergistically and whether chronic vemurafenib treatment alters the melanoma cell response to alkylating agents. Here we show that a) BRAFV600E melanoma cells are killed by vemurafenib, driving apoptosis, b) BRAFV600E melanoma cells are neither more resistant nor sensitive to temozolomide/fotemustine than non-mutant cells, c) combined treatment with vemurafenib plus temozolomide or fotemustine has an additive effect on cell kill, d) acquired vemurafenib resistance of BRAFV600E melanoma cells does not affect MGMT, MSH2, MSH6, PMS2 and MLH1, nor does it affect the resistance to temozolomide and fotemustine, e) metastatic melanoma biopsies obtained from patients prior to and after vemurafenib treatment did not show a change in the MGMT promoter methylation status and MGMT expression level. The data suggest that consecutive treatment with vemurafenib and alkylating drugs is a reasonable strategy for metastatic melanoma treatment. PMID:25557167

  9. Adjuvant chemotherapy for rectal cancer: Is it needed?

    PubMed Central

    Milinis, Kristijonas; Thornton, Michael; Montazeri, Amir; Rooney, Paul S

    2015-01-01

    Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies. PMID:26677436

  10. Treatment of newly diagnosed malignant glioma in the elderly people: new trials that impact therapy.

    PubMed

    Chamberlain, M C

    2013-12-01

    Glioblastoma (GB), World Health Organization Grade 4 glioma, is the most common malignant primary brain tumour with an annual incidence of 12,943 cases in the United States . It is a tumour of the elderly people with a median age of onset of 64 years, although children and young adults are also affected. GB is associated with a poor prognosis; despite best treatment, most community-based patients will not survive 1 year . Cures are rare and overall survival rates at 2 and 5 years are 26-48% and 12%, respectively, in highly selected, contemporary, clinical trial eligible patients . For protocol eligible US patients, the median survival is 16-17 months, which is partly a reflection of improved supportive care, recognition of pseudoprogression, exclusion of patients undergoing biopsy only and availability of bevacizumab at recurrence . Initial treatment for patients with high performance [Karnofsky Performance Status (KPS) > 60 and age < 71 years) consists of maximal safe surgical resection followed by adjuvant focal, external beam radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy and post-RT TMZ for 6 months . TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . The current standard treatment is based upon a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomised, phase 3 trial of 573 patients with newly diagnosed GB (age 19-71 years and World Health Organization Performance Status ≤ 2) that compared RT alone [total dose 60 Gray (Gy)] to TMZ chemotherapy in combination with RT (total 60 Gy), followed by 6 months of post-RT TMZ (4,6,8).

  11. Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

    SciTech Connect

    Patel, Shilpen; DiBiase, Steven; Meisenberg, Barry; Flannery, Todd; Patel, Ashish; Dhople, Anil; Cheston, Sally; Amin, Pradip

    2012-02-01

    Purpose: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. Methods and Materials: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were given tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status {>=}60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m{sup 2} divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m{sup 2} increments until the MTD was reached. When {>=}2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m{sup 2}. A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. Results: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m{sup 2}. One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m{sup 2}. Conclusions: The MTD of tamoxifen was 100 mg/m{sup 2} when given concurrently with temozolomide 75 mg/m{sup 2} and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.

  12. Phase I study of temozolomide in combination with thiotepa and carboplatin with autologous hematopoietic cell rescue in patients with malignant brain tumors with minimal residual disease.

    PubMed

    Egan, G; Cervone, K A; Philips, P C; Belasco, J B; Finlay, J L; Gardner, S L

    2016-04-01

    Recurrence of malignant brain tumors results in a poor prognosis with limited treatment options. High-dose chemotherapy with autologous hematopoietic cell rescue (AHCR) has been used in patients with recurrent malignant brain tumors and has shown improved outcomes compared with standard chemotherapy. Temozolomide is standard therapy for glioblastoma and has also shown activity in patients with medulloblastoma/primitive neuro-ectodermal tumor (PNET), particularly those with recurrent disease. Temozolomide was administered twice daily on days -10 to -6, followed by thiotepa 300 mg/m(2) per day and carboplatin dosed using the Calvert formula or body surface area on days -5 to -3, with AHCR day 0. Twenty-seven patients aged 3-46 years were enrolled. Diagnoses included high-grade glioma (n=12); medulloblastoma/PNET (n=9); central nervous system (CNS) germ cell tumor (n=4); ependymoma (n=1) and spinal cord PNET (n=1). Temozolomide doses ranged from 100 mg/m(2) per day to 400 mg/m(2) per day. There were no toxic deaths. Prolonged survival was noted in several patients including those with recurrent high-grade glioma, medulloblastoma and CNS germ cell tumor. Increased doses of temozolomide are feasible with AHCR. A phase II study using temozolomide, carboplatin and thiotepa with AHCR for children with recurrent malignant brain tumors is being conducted through the Pediatric Blood and Marrow Transplant Consortium. PMID:26726947

  13. Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO).

    PubMed

    Brandes, A A; Tosoni, A; Cavallo, G; Bertorelle, R; Gioia, V; Franceschi, E; Biscuola, M; Blatt, V; Crinò, L; Ermani, M

    2006-11-01

    The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.

  14. On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives.

    PubMed

    Pellegrino, Paolo; Clementi, Emilio; Radice, Sonia

    2015-10-01

    Adjuvants are compounds incorporated into vaccines to enhance immunogenicity and the development of these molecules has become an expanding field of research in the last decades. Adding an adjuvant to a vaccine antigen leads to several advantages, including dose sparing and the induction of a more rapid, broader and strong immune response. Several of these molecules have been approved, including aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), virosomes and AS04. Adjuvants have recently been implicated in the new syndrome named "ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants", which describes an umbrella of clinical conditions including post-vaccination adverse reactions. Recent studies implicate a web of mechanisms in the development of vaccine adjuvant-induced autoimmune diseases, in particular, in those associated with aluminium-based compounds. Fewer and unsystematised data are instead available about other adjuvants, despite recent evidence indicating that vaccines with different adjuvants may also cause specific autoimmune adverse reactions possible towards different pathogenic mechanisms. This topic is of importance as the specific mechanism of action of each single adjuvant may have different effects on the course of different diseases. Herein, we review the current evidence about the mechanism of action of currently employed adjuvants and discuss the mechanisms by which such components may trigger autoimmunity. PMID:26031899

  15. Rational design of small molecules as vaccine adjuvants.

    PubMed

    Wu, Tom Y-H; Singh, Manmohan; Miller, Andrew T; De Gregorio, Ennio; Doro, Francesco; D'Oro, Ugo; Skibinski, David A G; Mbow, M Lamine; Bufali, Simone; Herman, Ann E; Cortez, Alex; Li, Yongkai; Nayak, Bishnu P; Tritto, Elaine; Filippi, Christophe M; Otten, Gillis R; Brito, Luis A; Monaci, Elisabetta; Li, Chun; Aprea, Susanna; Valentini, Sara; Calabrό, Samuele; Laera, Donatello; Brunelli, Brunella; Caproni, Elena; Malyala, Padma; Panchal, Rekha G; Warren, Travis K; Bavari, Sina; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M

    2014-11-19

    Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants.

  16. [Adjuvant drug therapies for breast cancer].

    PubMed

    Huovinen, Riikka; Auvinen, Päivi; Mattson, Johanna; Joensuu, Heikki

    2015-01-01

    Most breast cancers are hormone receptor positive and exhibit a slow growth pattern. Based on biological properties, breast cancers are divided into four different biological subtypes. Furthermore, these subtypes are indicative of the risk of recurrence, which is also influenced by the size of the tumor and extension to lymph nodes. Postoperative adjuvant drug therapy is chosen on the basis of the biological type. Chemotherapy can be used in all subtypes. Hormonal therapies are used exclusively for the treatment of hormone receptor positive breast cancer. Trastuzumab antibody belongs to the treatment of the HER2 positive subtype. PMID:26245052

  17. Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes

    PubMed Central

    2015-01-01

    Adjuvants improve the adaptive immune response to a vaccine antigen by modulating innate immunity or facilitating transport and presentation. The selection of an appropriate adjuvant has become vital as new vaccines trend toward narrower composition, expanded application, and improved safety. Functionally, adjuvants act directly or indirectly on antigen presenting cells (APCs) including dendritic cells (DCs) and are perceived as having molecular patterns associated either with pathogen invasion or endogenous cell damage (known as pathogen associated molecular patterns [PAMPs] and damage associated molecular patterns [DAMPs]), thereby initiating sensing and response pathways. PAMP-type adjuvants are ligands for toll-like receptors (TLRs) and can directly affect DCs to alter the strength, potency, speed, duration, bias, breadth, and scope of adaptive immunity. DAMP-type adjuvants signal via proinflammatory pathways and promote immune cell infiltration, antigen presentation, and effector cell maturation. This class of adjuvants includes mineral salts, oil emulsions, nanoparticles, and polyelectrolytes and comprises colloids and molecular assemblies exhibiting complex, heterogeneous structures. Today innovation in adjuvant technology is driven by rapidly expanding knowledge in immunology, cross-fertilization from other areas including systems biology and materials sciences, and regulatory requirements for quality, safety, efficacy and understanding as part of the vaccine product. Standardizations will aid efforts to better define and compare the structure, function and safety of adjuvants. This article briefly surveys the genesis of adjuvant technology and then re-examines polyionic macromolecules and polyelectrolyte materials, adjuvants currently not known to employ TLR. Specific updates are provided for aluminum-based formulations and polyelectrolytes as examples of improvements to the oldest and emerging classes of vaccine adjuvants in use. PMID:25648619

  18. The mode of action of immunological adjuvants.

    PubMed

    Allison, A C

    1998-01-01

    Adjuvants augment immune responses to antigens and influence the balance between cell-mediated and humoral responses, as well as the isotypes of antibodies formed. New adjuvant formulations include antigen-carrying vehicles and small molecules with immunomodulating activity. Widely used two-phase vehicles comprise liposomes and microfluidized squalene or squalane emulsions. These are believed to target antigens to antigen-presenting cells, including dendritic cells (DC), follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby stimulating the proliferation of the latter and the generation of B-memory. Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating agents induce the production of cytokine cascades. In a primary cascade at injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell-mediated immune responses and the formation of antibodies of protective isotypes, such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes activate complement and collaborate with antibody-dependent effector cells in protective immune responses.

  19. Assessing the safety of adjuvanted vaccines.

    PubMed

    Ahmed, S Sohail; Plotkin, Stanley A; Black, Steven; Coffman, Robert L

    2011-07-27

    Despite the very low risk-to-benefit ratio of vaccines, fear of negative side effects has discouraged many people from getting vaccinated, resulting in reemergence of previously controlled diseases such as measles, pertussis, and diphtheria. Part of this fear stems from the lack of public awareness of the many preclinical and clinical safety evaluations that vaccines must undergo before they are available to the general public, as well as from misperceptions of what adjuvants are or why they are used in vaccines. The resultant "black box" leads to a preoccupation with rare side effects (such as autoimmune diseases) that are speculated, but not proven, to be linked to some vaccinations. The focus of this review article is to open this black box and provide a conceptual framework for how vaccine safety is traditionally assessed. We discuss the strengths and shortcomings of tools that can be and are used preclinically (in animal studies), translationally (in biomarker studies with human sera or cells), statistically (for disease epidemiology), and clinically (in the design of human trials) to help ascertain the risk of the infrequent and delayed adverse events that arise in relation to adjuvanted vaccine administration.

  20. Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer.

    PubMed

    Mallmann, Peter; Mallmann, Christoph

    2016-01-01

    Neoadjuvant chemotherapy is indicated in patients who can tolerate the side effects of a chemotherapy and with preoperative presentation of one of the following clinical risk situations: bulky disease with a maximal tumor diameter of > 4 cm, suspicious lymph nodes in magnetic resonance imaging (MRI), computed tomography (CT) scan or endosonography, histopathologically confirmed lymph node metastasis, or histopathologically documented risk factors such as G3 and L1V1. A neoadjuvant chemotherapy followed by surgery should be performed with cisplatin at a dosage of > 25 mg/m2 per week and an application interval of < 14 days. The previously published data suggests an improved rate of complete resection and reduced incidences of positive lymph nodes and parametric infiltration. Accordingly, the percentage of patients in need for adjuvant radiochemotherapy after operation can be significantly reduced. Some studies demonstrated a prolongation of progression-free and overall survival. Following the previously published studies, adjuvant chemotherapy after operation or after radiochemotherapy has no significant effect on the overall survival and, following the current guidelines, should be avoided. PMID:27614740

  1. Safety assessment of adjuvanted vaccines: Methodological considerations.

    PubMed

    Tavares Da Silva, Fernanda; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines.

  2. The mode of action of immunological adjuvants.

    PubMed

    Allison, A C

    1998-01-01

    Adjuvants augment immune responses to antigens and influence the balance between cell-mediated and humoral responses, as well as the isotypes of antibodies formed. New adjuvant formulations include antigen-carrying vehicles and small molecules with immunomodulating activity. Widely used two-phase vehicles comprise liposomes and microfluidized squalene or squalane emulsions. These are believed to target antigens to antigen-presenting cells, including dendritic cells (DC), follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby stimulating the proliferation of the latter and the generation of B-memory. Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating agents induce the production of cytokine cascades. In a primary cascade at injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell-mediated immune responses and the formation of antibodies of protective isotypes, such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes activate complement and collaborate with antibody-dependent effector cells in protective immune responses. PMID:9554254

  3. Safety assessment of adjuvanted vaccines: Methodological considerations

    PubMed Central

    Da Silva, Fernanda Tavares; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID:26029975

  4. Adjuvant chemotherapy for soft tissue sarcoma.

    PubMed

    Casali, Paolo G

    2015-01-01

    Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS). However, when the risk of relapse is high, it is an option for shared decision making with the patient in conditions of uncertainty. This is because available evidence is conflicting, even if several randomized clinical trials have been performed for 4 decades and also have been pooled into meta-analyses. Indeed, available meta-analyses point to a benefit in the 5% to 10% range in terms of survival and distant relapse rate. Some local benefit also was suggested by some trials. Placing chemotherapy in the preoperative setting may help gain a local advantage in terms of the quality of surgical margins or decreased sequelae. This may be done within a personalized approach according to the clinical presentation. Attempts to personalize treatment on the basis of the variegated pathology and molecular biology of STS subgroups are ongoing as well, according to what is done in the medical treatment of advanced STS. Thus, decision making for adjuvant and neoadjuvant indications deserves personalization in clinical research and in clinical practice, taking profit from all multidisciplinary clinical skills available at a sarcoma reference center, though with a degree of subjectivity because of the limitations of available evidence. PMID:25993233

  5. CpG oligodeoxynucleotides as mucosal adjuvants

    PubMed Central

    Iho, Sumiko; Maeyama, Jun-ichi; Suzuki, Fumiko

    2015-01-01

    Bacterial DNA comprising palindromic sequences and containing unmethylated CpG is recognized by toll-like receptor 9 of plasmacytoid dendritic cells (pDCs) and induces the production of interferon-α and chemokines, leading to the activation of a Th1 immune response. Therefore, synthetic equivalents of bacterial DNA (CpG oligodeoxynucleotides) have been developed for clinical applications. They are usually phosphorothioated for in vivo use; this approach also leads to adverse effects as reported in mouse models.Mucosal vaccines that induce both mucosal and systemic immunity received substantial attention in recent years. For their development, phosphodiester-linked oligodeoxynucleotides, including the sequence of a palindromic CpG DNA may be advantageous as adjuvants because their target pDCs are present right there, in the mucosa of the vaccination site. In addition, the probability of adverse effects is believed to be low. Here, we review the discovery of such CpG oligodeoxynucleotides and their possible use as mucosal adjuvants. PMID:25751765

  6. A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients

    PubMed Central

    Lee, Eudocia Q.; Kaley, Thomas J.; Duda, Dan G.; Schiff, David; Lassman, Andrew B.; Wong, Eric T.; Mikkelsen, Tom; Purow, Benjamin W.; Muzikansky, Alona; Ancukiewicz, Marek; Huse, Jason T.; Ramkissoon, Shakti; Drappatz, Jan; Norden, Andrew D.; Beroukhim, Rameen; Weiss, Stephanie E.; Alexander, Brian M.; McCluskey, Christine S.; Gerard, Mary; Smith, Katrina H.; Jain, Rakesh K.; Batchelor, Tracy T.; Ligon, Keith L.; Wen, Patrick Y.

    2016-01-01

    Purpose Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). Experimental Design We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary end-point was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. Results The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0–22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9–20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). Conclusions The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study. PMID:25910950

  7. Evaluating spray adjuvants to extend residual activity of microbiol pesticides`

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Based on requests to improve the residual efficacy of baculovirus applications, a commercial adjuvant (Nu-Film 17(R) and an experimental lignin adjuvant were evaluated for resistance to environmental degradation. Nu-Film is a commercial product derived from pine resin; and lignin is a by-product of...

  8. Vaccine Adjuvants: from 1920 to 2015 and Beyond

    PubMed Central

    Di Pasquale, Alberta; Preiss, Scott; Tavares Da Silva, Fernanda; Garçon, Nathalie

    2015-01-01

    The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines. PMID:26343190

  9. Update on Adjuvant Chemotherapy for Early Breast Cancer

    PubMed Central

    Rampurwala, Murtuza M; Rocque, Gabrielle B; Burkard, Mark E

    2014-01-01

    Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come. PMID:25336961

  10. Adjuvants in micro- to nanoscale: current state and future direction.

    PubMed

    Gupta, Ankur; Das, Soumen; Schanen, Brian; Seal, Sudipta

    2016-01-01

    Adjuvants have been used in vaccines for over 70 years to promote long-lived and sterilizing immunity. Since then, various adjuvant systems were developed by combining nanotechnology with natural and/or synthetic immunomodulatory molecules. These systems are biocompatible, immunogenic, and possess higher antigen carrying capacity. This article showcases advancements made in the adjuvant systems formulations, their synthesis routes, and the improvement of these adjuvants have brought in response to combat against ongoing global health threats such as malaria, hepatitis C, universal influenza, and human immunodeficiency virus. This review also highlights the interaction of adjuvants with the delivery of antigens to cells and unfolds mechanism of actions. In addition, this review discusses the physicochemical factors responsible for the efficient interaction of nanoadjuvants with antigen receptors to develop more effective, less reactogenic, and multifunctional systems for the next generation vaccines.

  11. [Adjuvants--essential components of new generation vaccines].

    PubMed

    Dzierzbicka, Krystyna; Kołodziejczyk, Aleksander M

    2006-01-01

    Adjuvants are essential components of vaccines that augment an immunological reaction of organism. New vaccines based on recombinant proteins and DNA, are more save than traditional vaccines but they are less immunogenic. Therefore, there is an urgent need for the development of new, improved vaccine adjuvants. There are two classes of adjuvants: vaccine delivery systems (e.g. emulsions, microparticles, immune-stimulating complexes ISCOMs, liposomes) and immunostimulatory adjuvants (e.g. lipopolysaccharide, monophosphoryl lipid A, CpG DNA, or muramylpeptides). The discovery of more potent and safer adjuvants may allow to development better prophylactic and therapeutic vaccines against chronic infectious (e.g., HSV, HIV, HCV, HBV, HPV, or Helicobacter pylori) and noninfectious diseases as multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, allergy and tumors (e.g., melanoma, breast, or colon cancer). PMID:17078510

  12. Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

    PubMed Central

    Sayers, Samantha; Ulysse, Guerlain; Xiang, Zuoshuang; He, Yongqun

    2012-01-01

    Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format. PMID:22505817

  13. Formulation and optimization of temozolomide nanoparticles by 3 factor 2 level factorial design

    PubMed Central

    Jain, Aviral; Jain, Sanjay K.

    2013-01-01

    The aim of this study was to investigate the combined influence of 3 independent variables in the preparation of temozolomide bearing Non-PEGylated and PEGylated nanoparticles by emulsification solvent evaporation method. A 3 factor 2 level design was used to derive a polynomial quadratic model and construct contour plots to predict responses. The independent variables selected were concentration of drug (A), concentration of PLGA/PEG-PLGA (B), PVA concentration in aqueous phase (C) and sonication time (D) and evaluated for percentage drug entrapment (PDE) and particle size (PS). A 34 factorial design was used with 4 factors (A, B, C and D) at 3 levels and experimental trials were performed at all 82 possible combinations. In the present work, 28 runs are considered as the preliminary trials revealed that on increasing drug concentration from 2.5 to 5 mg the percent drug entrapment increases, but on further increasing the drug concentration (i.e., to 7.5 mg) no significant effect on the percent drug entrapment and particle size was observed. The 34 factorial design was used to derive a polynomial quadratic model and construct contour plots to predict responses. Contour plots were constructed to show the effects of A, B, C and D on the PDE and PS. PMID:23719178

  14. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes.

    PubMed

    Chen, Weiliang; Wang, Donghai; Du, Xinwen; He, Ying; Chen, Songyu; Shao, Qianqian; Ma, Chao; Huang, Bin; Chen, Anjing; Zhao, Peng; Qu, Xun; Li, Xingang

    2015-03-01

    Resistance to chemotherapeutic drugs remains a great obstacle to successful treatment of gliomas. Understanding the mechanism of glioma chemoresistance is conducive to develop effective strategies to overcome resistance. Astrocytes are the major stromal cells in the brain and have been demonstrated to play a key role in the malignant phenotype of gliomas. However, little is known regarding its role in glioma chemoresistance. In our study, we established a co-culture system of human astrocytes and glioma in vitro to simulate tumor microenvironment. Our results showed that astrocytes significantly reduced glioma cell apoptosis induced by the chemotherapeutic drugs temozolomide and vincristine. This protective effect was dependent on direct contact between astrocytes and glioma cells through Cx43-GJC. Moreover, in human glioma specimens, we found astrocytes infiltrating around the tumor, with a reactive appearance, suggesting that these astrocytes would play the same chemoprotective effect on gliomas in vivo. Our results expand the understanding of the interaction between astrocytes and glioma cells and provide a possible explanation for unsatisfactory clinical outcomes of chemotherapeutic drugs. Cx43-GJC between astrocytes and glioma cells may be a potential target for overcoming chemoresistance in gliomas clinically. PMID:25631631

  15. Temozolomide/PLGA microparticles plus vatalanib inhibits tumor growth and angiogenesis in an orthotopic glioma model.

    PubMed

    Zhang, Yu-Hui; Yue, Zhi-Jian; Zhang, He; Tang, Gu-Sheng; Wang, Yang; Liu, Jian-Min

    2010-11-01

    Temozolomide (TM) has anti-tumor activity in patients with malignant glioma. Implantable poly (D,L-lactide-co-glycolide) (PLGA) microparticles of TM (TM-MS) have been developed, enhancing the cytotoxicity of TM to Glioma C6 cells. Vatalanib, as anti-angiogenic agent, has also shown anti-tumor activity with malignant gliomas. We examined the combined effects of TM-MS and vatalanib in a rat orthotopic glioma model and found TM-MS offered a greater tumor inhibition than TM, and combination treatment with both of them improved the survival time versus single agent therapy. The combination treatment also demonstrated an inhibition to rat glioma tumors, a significant decrease in cell proliferation, an increase in apoptosis, and a lower microvessel density within the glioma tumors. The results suggest that TM-MS can more effectively inhibit tumor than TM, and combination treatment with TM-MS and vatalanib inhibits tumor growth and angiogenesis and may prove to be a promising therapy for malignant gliomas. PMID:20816959

  16. Chemical Screening Identifies EUrd as a Novel Inhibitor Against Temozolomide-Resistant Glioblastoma-Initiating Cells.

    PubMed

    Tsukamoto, Yoshihiro; Ohtsu, Naoki; Echizenya, Smile; Otsuguro, Satoko; Ogura, Ryosuke; Natsumeda, Manabu; Isogawa, Mizuho; Aoki, Hiroshi; Ichikawa, Satoshi; Sakaitani, Masahiro; Matsuda, Akira; Maenaka, Katsumi; Fujii, Yukihiko; Kondo, Toru

    2016-08-01

    Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multimodal treatment with surgery and chemo/radiotherapies. GBM-initiating cells (GICs) are the likely cell-of-origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)-resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1-(3-C-ethynyl-β-d-ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine-cytidine kinase-like 1 (UCKL1) and the decreased one of 5'-nucleotidase cytosolic III (NT5C3), which regulate uridine-monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3. Stem Cells 2016;34:2016-2025.

  17. Survival with concurrent temozolomide and radiotherapy in pediatric brainstem glioma with relation to the tumor volume

    PubMed Central

    Taran, Shachi Jain; Taran, Rakesh; Batra, Manika; Ladia, Deah Deepak; Bhandari, Virendra

    2015-01-01

    Background: Brainstem gliomas account for approximately 25% of all posterior fossa tumors. In pediatric age group, it constitutes about 10% of all brain tumors. Brainstem glioma is an aggressive and lethal type of malignancy with poor outcome despite all treatments. Aim: We studied the incidence and treatment outcome in pediatric patients with brainstem glioma depending on their tumor volume presenting in our institution in last 5 years. Brain tumors comprised 2.95% of all cancers and brainstem gliomas were 8% of all brain tumors. Materials and Methods: Nine pediatric patients were included in this analysis, who were treated with localized external radiotherapy 54–59.4 Gy along with temozolomide 75 mg/m2 during the whole course of radiotherapy. Results: The median survival in all these patients was 20 months and the overall 2 years survival is 44.4% (4/9). The median survival of patients with primary disease volume <40cc is 26 months whereas when the volume is more than 40cc the median survival is 13.5 months as calculated by Chi-square test. Conclusion: As this study includes a small number of patients with unknown histology and treated on the basis of magnetic resonance imaging findings, no definite opinion can be given as some patients may have a low-grade tumor. More studies are required to establish the relation of size of the tumor with survival. PMID:26962339

  18. Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

    PubMed Central

    HogenEsch, Harm

    2013-01-01

    Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines. PMID:23335921

  19. Advax-adjuvanted recombinant protective antigen provides protection against inhalational anthrax that is further enhanced by addition of murabutide adjuvant.

    PubMed

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita; Merkel, Tod J

    2014-04-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.

  20. Modern Vaccines/Adjuvants Formulation Session 6: Vaccine &Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland.

    PubMed

    Fox, Christopher B

    2013-09-01

    The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characterization of adjuvant-antigen interactions, the rational formulation design of a CD8+ T cell-inducing adjuvant based on immunological principles, and the development and production of a rabies vaccine by a developing country manufacturer. Throughout the session, the practical importance of sound formulation and manufacturing design accompanied by analytical characterization was highlighted.

  1. Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies

    SciTech Connect

    Kubicek, Gregory J.; Werner-Wasik, Maria; Machtay, Mitchell; Mallon, Gayle; Myers, Thomas; Ramirez, Michael; Andrews, David; Curran, Walter J.; Dicker, Adam P.

    2009-06-01

    Purpose: To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with central nervous system malignancies. Patients and Methods: This open-label, dose-escalation, Phase I clinical study evaluated the safety of three dose levels of intravenously administered bortezomib (0.7, 1.0, and 1.3 mg/m{sup 2}/dose) on Days 1, 4, 8, and 11 of a 21-day cycle, in addition to concurrent radiotherapy and temozolomide at a daily dose of 75 mg/m{sup 2} starting on Day 1. The primary endpoint was dose-limiting toxicity, defined as any Grade 4-5 toxicity or Grade 3 toxicity directly attributable to protocol treatment, requiring hospitalization and/or radiotherapy interruption. The secondary endpoints included feasibility, non-dose-limiting toxicity, and treatment response. Results: A total of 27 patients were enrolled, 23 of whom had high-grade glioma (10 recurrent and 13 newly diagnosed). No dose-limiting toxicities were noted in any dose group, including the highest (1.3 mg/m{sup 2}/dose). The most frequent toxicities were Grade 1 and 2 stomatitis, erythema, and alopecia. All 27 patients were evaluable for response. At a median follow-up of 15.0 months, 9 patients were still alive, with a median survival of 17.4 months for all patients and 15.0 months for patients with high-grade glioma. Conclusion: Bortezomib administered at its typical 'systemic' dose (1.3 mg/m{sup 2}) is well tolerated and safe combined with temozolomide and radiotherapy when used in the treatment of central nervous system malignancies. A Phase II study to characterize efficacy is warranted.

  2. Diffusion tensor imaging and chemical shift imaging assessment of heterogeneity in low grade glioma under temozolomide chemotherapy.

    PubMed

    Sijens, P E; Heesters, M A A M; Enting, R H; van der Graaf, W T A; Potze, J H; Irwan, R; Meiners, L C; Oudkerk, M

    2007-12-01

    Diffusion tensor imaging and multiple voxel magnetic resonance spectroscopy were performed in the MRI follow-up of a patient with a glioma treated with temozolomide chemotherapy. Tumor shrinkage was paralleled by reductions in choline level and by increases in apparent diffusion coefficient indicating decreased cellularity. Within the tumor, choline level and apparent diffusion coefficient showed a significant inverse correlation (P < 0.01). Fractional anisotropy distribution in the tumor correlated positively with N-acetyl aspartate level (P < 0.001), indicating that these parameters reflect (remaining) axonal structure. Tumor lactate level, also found to decrease under therapy, did not correlate with any other parameter.

  3. Herbal Medicines as Adjuvants for Cancer Therapeutics

    PubMed Central

    Wang, Chong-Zhi; Calway, Tyler; Yuan, Chun-Su

    2012-01-01

    In the United States, many patients, including cancer patients, concurrently take prescription drugs and herbal supplements. Co-administration of prescription medicines and herbal supplements may have negative outcomes via pharmacodynamic and pharmacokinetic herb-drug interactions. However, multiple constituents in botanicals may also yield beneficial pharmacological activities. Botanicals could possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity. Herbal medicines, such as ginseng, potentiated the effects of chemotherapeutic agents via synergistic activities, supported by cell cycle evaluations, apoptotic observations, and computer-based docking analysis. Since botanicals are nearly always administrated orally, the role of intestinal microbiota in metabolizing ginseng constituents is presented. Controlled clinical studies are warranted to verify the clinical utility of the botanicals in cancer chemoprevention. PMID:22809022

  4. The role of adjuvant in mediating antigen structure and stability.

    PubMed

    Braun, Latoya Jones; Eldridge, Aimee M; Cummiskey, Jessica; Arthur, Kelly K; Wuttke, Deborah S

    2012-04-01

    The purpose of this study was to probe the fate of a model antigen, a cysteine-free mutant of bacteriophage T4 lysozyme, to the level of fine structural detail, as a consequence of its interaction with an aluminum (Al)-containing adjuvant. Fluorescence spectroscopy and differential scanning calorimetry were used to compare the thermal stability of the protein in solution versus adsorbed onto an Al-containing adjuvant. Differences in accessible hydrophobic surface areas were investigated using an extrinsic fluorescence probe, 8-Anilino-1-naphthalenesulfonic acid (ANS). As has been observed with other model antigens, the apparent thermal stability of the protein decreased following adsorption onto the adjuvant. ANS spectra suggested that adsorption onto the adjuvant caused an increase in exposure of hydrophobic regions of the protein. Electrostatic interactions drove the adsorption, and disruption of these interactions with high ionic strength buffers facilitated the collection of two-dimensional (15) N heteronuclear single quantum coherence nuclear magnetic resonance data of protein released from the adjuvant. Although the altered stability of the adsorbed protein suggested changes to the protein's structure, the fine structure of the desorbed protein was nearly identical to the protein's structure in the adjuvant-free formulation. Thus, the adjuvant-induced changes to the protein that were responsible for the reduced thermal stability were not observed upon desorption.

  5. Glutamine synthetase predicts adjuvant TACE response in hepatocellular carcinoma

    PubMed Central

    Zhang, Bo; Liu, Kai; Zhang, Jian; Dong, Liwei; Jin, Zhichao; Zhang, Xinji; Xue, Feng; He, Jia

    2015-01-01

    Background: Adjuvant transcatheter arterial chemoembolization (TACE) is associated with better outcome and reduced tumor recurrence in hepatocellular carcinoma (HCC) patients. This study aimed to investigate the relationship between glutamine synthetase (GS) expression and survival of HCC patients after postoperative adjuvant TACE. Methods: We retrospectively analyzed 554 HCC patients in two independent cohorts who underwent curative resection. Immunohistochemistry assay was used to investigate the expression of GS protein and evaluate the association with survival and the response to adjuvant TACE. Results: In training cohort, patients with low GS expression who received postoperative adjuvant TACE showed a better overall survival (OS) (P<0.001) and less early phase recurrence (P=0.016). Adjuvant TACE was an independent prognostic factor for 5-year OS (HR=0.408, 95% CI 0.261-0.639, P<0.001) and early phase recurrence (HR=0.592, 95% CI 0.376-0.931, P=0.023). The same result was confirmed in validation cohort. Patients with high GS expression in both cohorts did not have a significant response to adjuvant TACE in OS and early phase recurrence. Conclusions: GS status in tumor might be a useful tool in the selection of HCC patients who would be likely to benefit from postoperative adjuvant TACE. PMID:26884995

  6. Adjuvants for veterinary vaccines--types and modes of action.

    PubMed

    Gerdts, Volker

    2015-01-01

    Adjuvants are used to improve the immune response to vaccines. Formulation with adjuvants can result in an earlier onset of immunity, an overall stronger immune response, a specific type of immunity, or a longer duration of immunity to the vaccine. Adjuvants were discovered empirically, and for decades, have been used in both humans and animals without understanding the mechanisms of action. With an improved understanding of the immune system, and in particular the interplay between innate and adaptive immunity, we are now getting better insight into the function of adjuvants. As a result, new adjuvants are being developed that are safe and highly effective for common use in humans and animals, as well as for use in high risk populations such as immunocompromised animals, neonates or very old animals. Furthermore, adjuvants can help to reduce the amount of antigen needed in the vaccine, increase the stability of the vaccine and enable alternatiye administration routes such as needle-free delivery of the vaccine. Here, I will provide an over view of the existing adjuvant technologies for veterinary vaccines and provide an outlook into some of the new technologies in preclinical and clinical development.

  7. Progress in adjuvant chemotherapy for breast cancer: an overview.

    PubMed

    Anampa, Jesus; Makower, Della; Sparano, Joseph A

    2015-01-01

    Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy.

  8. Adjuvants for Vaccines to Drugs of Abuse and Addiction

    PubMed Central

    Alving, Carl R.; Matyas, Gary R.; Torres, Oscar; Jalah, Rashmi; Beck, Zoltan

    2015-01-01

    Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA. PMID:25111169

  9. Adjuvants for vaccines to drugs of abuse and addiction.

    PubMed

    Alving, Carl R; Matyas, Gary R; Torres, Oscar; Jalah, Rashmi; Beck, Zoltan

    2014-09-22

    Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA.

  10. Tailored Nanoparticle Codelivery of antimiR-21 and antimiR-10b Augments Glioblastoma Cell Kill by Temozolomide: Toward a "Personalized" Anti-microRNA Therapy.

    PubMed

    Ananta, Jeyarama S; Paulmurugan, Ramasamy; Massoud, Tarik F

    2016-09-01

    Glioblastoma remains an aggressive brain malignancy with poor prognosis despite advances in multimodal therapy that include standard use of Temozolomide. MicroRNA-21 (miR-21) and microRNA-10b (miR-10b) are oncomiRs overexpressed in glioblastoma, promoting many aspects of cancer biology. We hypothesized that PLGA nanoparticles carrying antisense miR-21 (antimiR-21) and antisense miR-10b (antimiR-10b) might beneficially knockdown endogenous miR-21 and miR-10b function and reprogram cells prior to Temozolomide treatment. PLGA nanoparticles were effective in intracellular delivery of encapsulated oligonucleotides. Concentrations of delivered antimiR-21 and antimiR-10b were optimized and specifically tailored to copy numbers of intracellular endogenous microRNAs. Coinhibition of miR-21 and miR-10b significantly reduced the number of viable cells (by 24%; p < 0.01) and increased (2.9-fold) cell cycle arrest at G2/M phase upon Temozolomide treatment in U87 MG cells. Cell-tailored nanoparticle-assisted concurrent silencing of miR-21 and miR-10b prior to Temozolomide treatment is an effective molecular therapeutic strategy in cell culture, warranting the need for further studies prior to future in vivo "personalized" medicine applications.

  11. Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs.

    PubMed

    Petrovsky, Nikolai

    2015-11-01

    Use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminium salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable for better understanding of adjuvant action, but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer's disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects. PMID:26446142

  12. Comparative safety of vaccine adjuvants: a summary of current evidence and future needs

    PubMed Central

    Petrovsky, Nikolai

    2015-01-01

    Improved use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety or posing undue risk. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminum salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable in better understanding adjuvant action but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions such as narcolepsy, macrophagic myofasciitis or Alzheimer’s disease. While existing adjuvants based on aluminum salts have a strong safety record, there is an ongoing need for new adjuvants and for more intensive research into adjuvants and their effects. PMID:26446142

  13. SRPX2 Enhances the Epithelial-Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Cells.

    PubMed

    Tang, Haitao; Zhao, Jiaxin; Zhang, Liangyu; Zhao, Jiang; Zhuang, Yongzhi; Liang, Peng

    2016-10-01

    Glioblastoma (GBM) is the most common and most aggressive central nervous system tumor in adults. Due to GBM cell invasiveness and resistance to chemotherapy, current medical interventions are not satisfactory, and the prognosis for GBM is poor. It is necessary to investigate the underlying mechanism of GBM metastasis and drug resistance so that more effective treatments can be developed for GBM patients. sushi repeat-containing protein, X-linked 2 (SRPX2) is a prognostic biomarker in many different cancer cell lines and is associated with poor prognosis in cancer patients. SRPX2 overexpression promotes interactions between tumor and endothelial cells, leading to tumor progression and metastasis. We hypothesize that SRPX2 also contributes to GBM chemotherapy resistance and metastasis. Our results revealed that GBM tumor samples from 42 patients expressed higher levels of SRPX2 than the control normal brain tissue samples. High-SRPX2 expression levels are correlated with poor prognosis in those patients, as well as resistance to temozolomide in cultured GBM cells. Up-regulating SRPX2 expression in cultured GBM cell lines facilitated invasiveness and migration of GBM cells, while down-regulating SRPX2 through RNA interference was inhibitory. These results suggest that SRPX2 plays an important role in GBM metastasis. Epithelial to mesenchymal transition (EMT) is one of the processes that facilitate GBM metastasis and resistance to chemotherapy. EMT marker expression was decreased in SRPX2 down-regulated GBM cells, and MAPK signaling pathway marker expression was also decreased when SRPX2 is knocked down in GBM-cultured cells. Blocking the MAPK signaling pathway inhibited GBM metastasis but did not inhibit cell invasion and migration in SRPX2 down-regulated cells. Our results indicate that SRPX2 facilitates GBM metastasis by enhancing the EMT process via the MAPK signaling pathway. PMID:26643178

  14. SRPX2 Enhances the Epithelial-Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Cells.

    PubMed

    Tang, Haitao; Zhao, Jiaxin; Zhang, Liangyu; Zhao, Jiang; Zhuang, Yongzhi; Liang, Peng

    2016-10-01

    Glioblastoma (GBM) is the most common and most aggressive central nervous system tumor in adults. Due to GBM cell invasiveness and resistance to chemotherapy, current medical interventions are not satisfactory, and the prognosis for GBM is poor. It is necessary to investigate the underlying mechanism of GBM metastasis and drug resistance so that more effective treatments can be developed for GBM patients. sushi repeat-containing protein, X-linked 2 (SRPX2) is a prognostic biomarker in many different cancer cell lines and is associated with poor prognosis in cancer patients. SRPX2 overexpression promotes interactions between tumor and endothelial cells, leading to tumor progression and metastasis. We hypothesize that SRPX2 also contributes to GBM chemotherapy resistance and metastasis. Our results revealed that GBM tumor samples from 42 patients expressed higher levels of SRPX2 than the control normal brain tissue samples. High-SRPX2 expression levels are correlated with poor prognosis in those patients, as well as resistance to temozolomide in cultured GBM cells. Up-regulating SRPX2 expression in cultured GBM cell lines facilitated invasiveness and migration of GBM cells, while down-regulating SRPX2 through RNA interference was inhibitory. These results suggest that SRPX2 plays an important role in GBM metastasis. Epithelial to mesenchymal transition (EMT) is one of the processes that facilitate GBM metastasis and resistance to chemotherapy. EMT marker expression was decreased in SRPX2 down-regulated GBM cells, and MAPK signaling pathway marker expression was also decreased when SRPX2 is knocked down in GBM-cultured cells. Blocking the MAPK signaling pathway inhibited GBM metastasis but did not inhibit cell invasion and migration in SRPX2 down-regulated cells. Our results indicate that SRPX2 facilitates GBM metastasis by enhancing the EMT process via the MAPK signaling pathway.

  15. Amphiphilic chitosan-grafted-functionalized polylactic acid based nanoparticles as a delivery system for doxorubicin and temozolomide co-therapy.

    PubMed

    Di Martino, Antonio; Sedlarik, Vladimir

    2014-10-20

    The aim of this work was to investigate the potential of an amphiphilic system comprising chitosan-grafted polylactide and carboxyl-functionalized polylactide acid as a carrier for the controlled release and co-release of two DNA alkylating drugs: doxorubicin and temozolomide. Polylactide and carboxyl-functionalized polylactide acid were obtained through direct melt polycondensation reaction, using methanesulfonic acid as a non-toxic initiator, and subsequently these were grafted to the chitosan backbone through a coupling reaction, utilizing 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as a condensing agent. ATR-FTIR analysis and conductometric titration confirmed that a reaction between CS and PLA, PLACA2% and PLACA5% occurred. Chitosan-grafted-polylactide and polylactide-citric acid nanoparticles were prepared via the polyelectrolyte complex technique, applying dextran sulphate as a polyanion, and loaded with doxorubicin and temozolomide. The diameter of particles, ζ-potential and their relationship to temperature and pH were analysed in all formulations. Encapsulation, co-encapsulation efficiency and release studies were conducted in different physiological simulated environments and human serum. Results showed the continuous release of drugs without an initial burst in different physiological media.

  16. A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.

    PubMed

    Chen, Xishan; Tai, Lingyu; Gao, Jie; Qian, Jianchang; Zhang, Mingfei; Li, Beibei; Xie, Cao; Lu, Linwei; Lu, Wuyuan; Lu, Weiyue

    2015-11-28

    Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood-brain barrier and/or blood-brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide--a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM. PMID:26428461

  17. Amphiphilic chitosan-grafted-functionalized polylactic acid based nanoparticles as a delivery system for doxorubicin and temozolomide co-therapy.

    PubMed

    Di Martino, Antonio; Sedlarik, Vladimir

    2014-10-20

    The aim of this work was to investigate the potential of an amphiphilic system comprising chitosan-grafted polylactide and carboxyl-functionalized polylactide acid as a carrier for the controlled release and co-release of two DNA alkylating drugs: doxorubicin and temozolomide. Polylactide and carboxyl-functionalized polylactide acid were obtained through direct melt polycondensation reaction, using methanesulfonic acid as a non-toxic initiator, and subsequently these were grafted to the chitosan backbone through a coupling reaction, utilizing 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as a condensing agent. ATR-FTIR analysis and conductometric titration confirmed that a reaction between CS and PLA, PLACA2% and PLACA5% occurred. Chitosan-grafted-polylactide and polylactide-citric acid nanoparticles were prepared via the polyelectrolyte complex technique, applying dextran sulphate as a polyanion, and loaded with doxorubicin and temozolomide. The diameter of particles, ζ-potential and their relationship to temperature and pH were analysed in all formulations. Encapsulation, co-encapsulation efficiency and release studies were conducted in different physiological simulated environments and human serum. Results showed the continuous release of drugs without an initial burst in different physiological media. PMID:25124059

  18. mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance

    PubMed Central

    Garros-Regulez, Laura; Aldaz, Paula; Arrizabalaga, Olatz; Moncho-Amor, Veronica; Carrasco-Garcia, Estefania; Manterola, Lorea; Moreno-Cugnon, Leire; Barrena, Cristina; Villanua, Jorge; Ruiz, Irune; Pollard, Steven; Lovell-Badge, Robin; Sampron, Nicolas; Garcia, Idoia; Matheu, Ander

    2016-01-01

    ABSTRACT Background: SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear. Methods: SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance. Results: SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance. Conclusions: Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9. PMID:26878385

  19. Quantum chemical calculations and analysis of FTIR, FT-Raman and UV-Vis spectra of temozolomide molecule

    NASA Astrophysics Data System (ADS)

    Bhat, Sheeraz Ahmad; Ahmad, Shabbir

    2015-11-01

    A combined experimental and theoretical study of the structure, vibrational and electronic spectra of temozolomide molecule, which is largely used in the treatment of brain tumours, is presented. FTIR (4000-400 cm-1) and FT-Raman spectra (4000‒50 cm-1) have been recorded and analysed using anharmonic frequency calculations using VPT2, VSCF and CC-VSCF levels of theory within B3LYP/6-311++G(d,p) framework. Anharmonic methods give accurate frequencies of fundamental modes, overtones as well as Fermi resonances and account for coupling of different modes. The anharmonic frequencies calculated using VPT2 and CC-VSCF methods show better agreement with the experimental data. Harmonic frequencies including solvent effects are also computed using IEF-PCM model. The magnitudes of coupling between pair of modes have been calculated using coupling integral based on 2MR-QFF approximation. Intermolecular interactions are discussed for three possible dimers of temozolomide. UV-Vis spectrum, examined in ethanol solvent, is compared with the calculated spectrum at TD-DFT/6-311++G(d,p) level of theory. The electronic properties, such as excitation energy, frontier molecular orbital energies and the assignments of the absorption bands are also discussed.

  20. Sex hormone adjuvant therapy in rheumatoid arthritis.

    PubMed

    Cutolo, M

    2000-11-01

    RA is an autoimmune rheumatic disorder resulting from the combination of several predisposing factors, including the relation between epitopes of possible triggering agents and histocompatibility epitopes, the status of the stress response system, and the sex hormone status. Estrogens are implicated as enhancers of humoral immunity, and androgens and progesterone are natural immune suppressors. Sex hormone concentrations have been evaluated in RA patients before glucocorticoid therapy and have frequently been found to be altered, especially in premenopausal women and male patients. In particular, low levels of gonadal and adrenal androgens (testosterone and DHT, DHEA and DHEAS) and a reduced androgen:estrogen ratio have been detected in body fluids (i.e., blood, synovial fluid, smears, saliva) of male and female RA patients. These observations support a possible pathogenic role for the decreased levels of the immune-suppressive androgens. Exposure to environmental estrogens (estrogenic xenobiotics), genetic polymorphisms of genes coding for hormone metabolic enzymes or receptors, and gonadal disturbances related to stress system activation (hypothalamic-pituitary-adrenocortical axis) and physiologic hormonal perturbations such as during aging, the menstrual cycle, pregnancy, the postpartum period, and menopause may interfere with the androgen:estrogen ratio. Sex hormones might exert their immune-modulating effects, at least in RA synovitis, because synovial macrophages, monocytes, and lymphocytes possess functional androgen and estrogen receptors and may metabolize gonadal hormones. The molecular basis for sex hormone adjuvant therapy in RA is thus experimentally substantiated. By considering the well-demonstrated immune-suppressive activities exerted by androgens, male hormones and their derivatives seem to be the most promising therapeutic approach. Recent studies have shown positive effects of androgen replacement therapy at least in male RA patients

  1. 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants.

    PubMed

    Shoenfeld, Yehuda; Agmon-Levin, Nancy

    2011-02-01

    The role of various environmental factors in the pathogenesis of immune mediated diseases is well established. Of which, factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were associated with defined and non-defined immune mediated diseases both in animal models and in humans. In recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant. Furthermore, these four diseases share a similar complex of signs and symptoms which further support a common denominator.Thus, we review herein the current data regarding the role of adjuvants in the pathogenesis of immune mediated diseases as well as the amassed data regarding each of these four conditions. Relating to the current knowledge we would like to suggest to include these comparable conditions under a common syndrome entitled ASIA, "Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants". PMID:20708902

  2. The perfect mix: recent progress in adjuvant research.

    PubMed

    Guy, Bruno

    2007-07-01

    Developing efficient and safe adjuvants for use in human vaccines remains both a challenge and a necessity. Past approaches have been largely empirical and generally used a single type of adjuvant, such as aluminium salts or emulsions. However, new vaccine targets often require the induction of well-defined cell-mediated responses in addition to antibodies, and thus new immunostimulants are required. Recent advances in basic immunology have elucidated how early innate immune signals can shape subsequent adaptive responses and this, coupled with improvements in biochemical techniques, has led to the design and development of more specific and focused adjuvants. In this Review, I discuss the research that has made it possible for vaccinologists to now be able to choose between a large panel of adjuvants, which potentially can act synergistically, and combine them in formulations that are specifically adapted to each target and to the relevant correlate(s) of protection. PMID:17558426

  3. Adjuvants and inactivated polio vaccine: a systematic review.

    PubMed

    Hawken, Jennifer; Troy, Stephanie B

    2012-11-19

    Poliomyelitis is nearing universal eradication; in 2011, there were 650 cases reported globally. When wild polio is eradicated, global oral polio vaccine (OPV) cessation followed by use of universal inactivated polio vaccine (IPV) is believed to be the safest vaccination strategy as IPV does not mutate or run the risk of vaccine derived outbreaks that OPV does. However, IPV is significantly more expensive than OPV. One strategy to make IPV more affordable is to reduce the dose by adding adjuvants, compounds that augment the immune response to the vaccine. No adjuvants are currently utilized in stand-alone IPV; however, several have been explored over the past six decades. From aluminum, used in many licensed vaccines, to newer and more experimental adjuvants such as synthetic DNA, a diverse group of compounds has been assessed with varying strengths and weaknesses. This review summarizes the studies to date evaluating the efficacy and safety of adjuvants used with IPV.

  4. The Vaccine Formulation Laboratory: a platform for access to adjuvants.

    PubMed

    Collin, Nicolas; Dubois, Patrice M

    2011-07-01

    Adjuvants are increasingly used by the vaccine research and development community, particularly for their ability to enhance immune responses and for their dose-sparing properties. However, they are not readily available to the majority of public sector vaccine research groups, and even those with access to suitable adjuvants may still fail in the development of their vaccines because of lack of knowledge on how to correctly formulate the adjuvants. This shortcoming led the World Health Organization to advocate for the establishment of the Vaccine Formulation Laboratory at the University of Lausanne, Switzerland. The primary mission of the laboratory is to transfer adjuvants and formulation technology free of intellectual property rights to academic institutions, small biotechnology companies and developing countries vaccine manufacturers. In this context, the transfer of an oil-in-water emulsion to Bio Farma, an Indonesian vaccine manufacturer, was initiated to increase domestic pandemic influenza vaccine production capacity as part of the national pandemic influenza preparedness plan.

  5. Postoperative adjuvant radiotherapy for patients with gastric adenocarcinoma.

    PubMed

    Lim, Do Hoon

    2012-12-01

    In gastric adenocarcinoma, high rates of loco-regional recurrences have been reported even after complete resection, and various studies have been tried to find the role of postoperative adjuvant therapy. Among them, Intergroup 0116 trial was a landmark trial, and demonstrated the definite survival benefit in adjuvant chemoradiotherapy, compared with surgery alone. However, the INT 0116 trial had major limitation for global acceptance of the INT 0116 regimen as an adjuvant treatment modality because of the limited lymph node dissection. Lately, several randomized studies that were performed to patients with D2-dissected gastric cancer were published. This review summarizes the data about patterns of failure after surgical resection and the earlier prospective studies, including INT 0116 study. Author will introduce the latest studies, including ARTIST trial and discuss whether external beam radiotherapy should be applied to patients receiving extended lymph node dissection and adjuvant chemotherapy. PMID:23346491

  6. Endometrial adenocarcinoma, adjuvant radiotherapy tailored to prognostic factors.

    PubMed

    Meerwaldt, J H; Hoekstra, C J; van Putten, W L; Tjokrowardojo, A J; Koper, P C

    1990-02-01

    The optimal adjuvant radiotherapy for surgically treated endometrial cancer has not yet been defined. We report on 389 patients treated between 1970 and 1985 with adjuvant radiotherapy. The treatment was tailored to the known prognostic factors: myometrial invasion and grade of differentiation of the tumor. Ten-year overall survival was 67%, 10-year relapse-free survival 77%; 23% relapse, of which 21% distant and 6% locoregional relapse. In a multivariate analysis, stage (pT), grade, and myometrial invasion were prognostic factors. The number of locoregional failures was very small (n = 23). This small number, the fact that radiation treatment was tailored to prognostic factors, and the absence of a nontreated control group precluded an analysis of the effect of the adjuvant irradiation. Large randomized studies with a control (no treatment) arm should be performed to determine the value of adjuvant radiotherapy. PMID:2303362

  7. Activity of glycated chitosan and other adjuvants to PDT vaccines

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Banáth, Judit; Čiplys, Evaldas; Szulc, Zdzislaw; Bielawska, Alicja; Chen, Wei R.

    2015-03-01

    Glycated chitosan (GC), a water soluble galactose-conjugated natural polysaccharide, has proven to be an effective immunoadjuvant for treatment of tumors based on laser thermal therapy. It was also shown to act as adjuvant for tumor therapy with high-intensity ultrasound and in situ photodynamic therapy (PDT). In the present study, GC was examined as potential adjuvant to PDT-generated cancer vaccine. Two other agents, pure calreticulin protein and acid ceramidase inhibitor LCL521, were also tested as prospective adjuvants for use in conjunction with PDT vaccines. Single treatment with GC, included with PDT vaccine cells suspension, improved the therapeutic efficacy when compared to vaccine alone. This attractive prospect of GC application remains to be carefully optimized and mechanistically elucidated. Both calreticulin and LCL521 proved also effective adjuvants when combined with PDT vaccine tumor treatment.

  8. Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/β-catenin pathway

    PubMed Central

    Riganti, Chiara; Salaroglio, Iris Chiara; Caldera, Valentina; Campia, Ivana; Kopecka, Joanna; Mellai, Marta; Annovazzi, Laura; Bosia, Amalia; Ghigo, Dario; Schiffer, Davide

    2013-01-01

    Background Glioblastoma multiforme stem cells display a highly chemoresistant phenotype, whose molecular basis is poorly known. We aim to clarify this issue and to investigate the effects of temozolomide on chemoresistant stem cells. Methods A panel of human glioblastoma cultures, grown as stem cells (neurospheres) and adherent cells, was used. Results Neurospheres had a multidrug resistant phenotype compared with adherent cells. Such chemoresistance was overcome by apparently noncytotoxic doses of temozolomide, which chemosensitized glioblastoma cells to doxorubicin, vinblastine, and etoposide. This effect was selective for P-glycoprotein (Pgp) substrates and for stem cells, leading to an investigation of whether there was a correlation between the expression of Pgp and the activity of typical stemness pathways. We found that Wnt3a and ABCB1, which encodes for Pgp, were both highly expressed in glioblastoma stem cells and reduced by temozolomide. Temozolomide-treated cells had increased methylation of the cytosine–phosphate–guanine islands in the Wnt3a gene promoter, decreased expression of Wnt3a, disrupted glycogen synthase-3 kinase/β-catenin axis, reduced transcriptional activation of ABCB1, and a lower amount and activity of Pgp. Wnt3a overexpression was sufficient to transform adherent cells into neurospheres and to simultaneously increase proliferation and ABCB1 expression. On the contrary, glioblastoma stem cells silenced for Wnt3a lost the ability to form neurospheres and reduced at the same time the proliferation rate and ABCB1 levels. Conclusions Our work suggests that Wnt3a is an autocrine mediator of stemness, proliferation, and chemoresistance in human glioblastoma and that temozolomide may chemosensitize the stem cell population by downregulating Wnt3a signaling. PMID:23897632

  9. Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

    PubMed Central

    Reardon, David A.; Nabors, Louis B.; Mason, Warren P.; Perry, James R.; Shapiro, William; Kavan, Petr; Mathieu, David; Phuphanich, Surasak; Cseh, Agnieszka; Fu, Yali; Cong, Julie; Wind, Sven; Eisenstat, David D.

    2015-01-01

    Background This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Methods Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m2/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m2 for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Results Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Conclusions Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients. PMID:25140039

  10. Interferon-gamma as an adjuvant in immunocompromised mice.

    PubMed Central

    Heath, A W; Devey, M E; Brown, I N; Richards, C E; Playfair, J H

    1989-01-01

    We have compared interferon-gamma (IFN-gamma) with saponin and interleukin-1 (IL-1) as adjuvants for a blood-stage malaria vaccine in mice with various immunological abnormalities. IFN-gamma was particularly effective in Biozzi low antibody responder mice, mice selectively bred to produce antibody of low affinity, and mice depleted of CD4+ T cells. IFN-gamma and other cytokines may be safe adjuvants for use in human immunodeficiency states. PMID:2504662

  11. Effect of Freund's adjuvant on standard dark and pastel mink.

    PubMed

    Tabel, H; Ingram, D G

    1971-04-01

    Following a long series of injections of homologous immunoglobulin in complete and incomplete Freund's adjuvant into mink, a moderate elevation in the level of gammaglobulin in the serum was observed in a few animals. Relatively mild pathological changes also were seen in liver, spleen, lymph nodes, lungs and kidney. It is concluded that the injection of Freund's adjuvant, under the experimental conditions described, produced lesions which were readily distinguishable from the lesions characteristic of aleutian disease of mink.

  12. Learning Impairment in Honey Bees Caused by Agricultural Spray Adjuvants

    PubMed Central

    Ciarlo, Timothy J.; Mullin, Christopher A.; Frazier, James L.; Schmehl, Daniel R.

    2012-01-01

    Background Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s). The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. Methodology/Principal Findings An improved, automated version of the proboscis extension reflex (PER) assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants) were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. Conclusions/Significance A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many social interactions

  13. Adjuvant Therapy for Gallbladder Carcinoma: The Mayo Clinic Experience

    SciTech Connect

    Gold, Douglas G.; Miller, Robert C. Haddock, Michael G.; Gunderson, Leonard L.; Quevedo, Fernando; Donohue, John H.; Bhatia, Sumita; Nagorney, David M.

    2009-09-01

    Purpose: To analyze the effect of adjuvant chemoradiotherapy on gallbladder carcinoma. Methods and Materials: We retrospectively reviewed the records from consecutive patients who underwent R0 resection of gallbladder carcinoma between January 1, 1985, and December 31, 2004. Patients had either Stage I (T1-T2N0M0) or Stage II (T3N0M0 or T1-T3N1M0) disease. Patients undergoing adjuvant therapy received 5-fluorouracil chemotherapy concurrently with radiotherapy (median dosage, 50.4 Gy in 28 fractions). Adverse prognostic factors and the effect of adjuvant treatment on overall survival (OS) were evaluated. Results: A total of 73 patients were included in the analysis; of these, 25 received adjuvant chemoradiotherapy. On univariate analysis, no adverse prognostic factors for OS reached statistical significance, but trends were noted for Stage N1 vs. N0 (p = .06), Nx vs. N0 (p = .09), Stage T3 vs. T1-T2 (p = .06), and histologic findings other than adenocarcinoma (p = .13). The median OS for patients receiving adjuvant chemoradiotherapy vs. surgery alone was 4.8 years and 4.2 years, respectively (log-rank test, p = .56). However, a significantly greater percentage of patients receiving adjuvant chemoradiotherapy had Stage II disease (p <.001). In the multivariate Cox model, increasing T and N category and histologic findings other than adenocarcinoma were significant predictors of decreased OS. Additionally, adjuvant chemoradiotherapy was a significant predictor of improved OS after adjusting for these prognostic factors (hazard ratio for death, 0.3; 95% confidence interval, 0.13-0.69; p = .004). Conclusion: After adjusting for the stage parameters and histologic findings, our data suggest that adjuvant chemoradiotherapy might improve OS for patients with gallbladder cancer.

  14. Chitosan-based mucosal adjuvants: Sunrise on the ocean.

    PubMed

    Xia, Yufei; Fan, Qingze; Hao, Dongxia; Wu, Jie; Ma, Guanghui; Su, Zhiguo

    2015-11-01

    Mucosal vaccination, which is shown to elicit systemic and mucosal immune responses, serves as a non-invasive and convenient alternative to parenteral administration, with stronger capability in combatting diseases at the site of entry. The exploration of potent mucosal adjuvants is emerging as a significant area, based on the continued necessity to amplify the immune responses to a wide array of antigens that are poorly immunogenic at the mucosal sites. As one of the inspirations from the ocean, chitosan-based mucosal adjuvants have been developed with unique advantages, such as, ability of mucosal adhesion, distinct trait of opening the junctions to allow the paracellular transport of antigen, good tolerability and biocompatibility, which guaranteed the great potential in capitalizing on their application in human clinical trials. In this review, the state of art of chitosan and its derivatives as mucosal adjuvants, including thermo-sensitive chitosan system as mucosal adjuvant that were newly developed by author's group, was described, as well as the clinical application perspective. After a brief introduction of mucosal adjuvants, chitosan and its derivatives as robust immune potentiator were discussed in detail and depth, in regard to the metabolism, safety profile, mode of actions and preclinical and clinical applications, which may shed light on the massive clinical application of chitosan as mucosal adjuvant.

  15. Natural products and the search for novel vaccine adjuvants.

    PubMed

    Rey-Ladino, Jose; Ross, Allen G; Cripps, Allan W; McManus, Donald P; Quinn, Ronald

    2011-09-01

    Vaccines that protect against intracellular infections such as malaria, Leishmania and Chlamydia require strong cellular responses based on CD4(+) T cells and CD8(+) T cells in addition to antibodies. Such cell-mediated responses can be potentiated with adjuvants. However, very few adjuvants have been licensed for use in humans; thus there is an urgent need for the discovery of new non-toxic adjuvants in order to produce more efficacious vaccines. Until recently, the mechanisms of how adjuvants worked remained largely unknown, but, it is becoming clearer that many function via host germline-encoded pattern recognition receptors (PRRs) expressed by most immune and non-immune cells. Most PRRs sense infection and transmit a series of signals that ultimately lead to the development of immunity. PRR mediated signalling can be harnessed to search for new vaccine adjuvants. Dendritic cells (DCs) express many PRRs and are remarkably effective at directing T cell immunity. Natural products (NPs) have been the basis of many drugs and are a rich source of immune activators and/or regulators of the immune response. Here we review PRRs in the context of NPs and propose the use of DCs as biological probes to help identify novel immune type molecules and adjuvants within collections of NPs.

  16. Squalene and squalane emulsions as adjuvants.

    PubMed

    Allison, A C

    1999-09-01

    Microfluidized squalene or squalane emulsions are efficient adjuvants, eliciting both humoral and cellular immune responses. Microfluidization stabilizes the emulsions and allows sterilization by terminal filtration. The emulsions are stable for years at ambient temperature and can be frozen. Antigens are added after emulsification so that conformational epitopes are not lost by denaturation and to facilitate manufacture. A Pluronic block copolymer can be added to the squalane or squalene emulsion. Soluble antigens administered in such emulsions generate cytotoxic T lymphocytes able to lyse target cells expressing the antigen in a genetically restricted fashion. Optionally a relatively nontoxic analog of muramyl dipeptide (MDP) or another immunomodulator can be added; however, the dose of MDP must be restricted to avoid systemic side effects in humans. Squalene or squalane emulsions without copolymers or MDP have very little toxicity and elicit potent antibody responses to several antigens in nonhuman primates. They could be used to improve a wide range of vaccines. Squalene or squalane emulsions have been administered in human cancer vaccines, with mild side effects and evidence of efficacy, in terms of both immune responses and antitumor activity.

  17. Adjuvant chemotherapy in head and neck cancer.

    PubMed Central

    Stell, P. M.; Rawson, N. S.

    1990-01-01

    An overview is presented of 23 trials of adjuvant chemotherapy in squamous cell carcinoma of the head and neck. These were reviewed from the point of view of design of the trial, analysis of survival, response rates, meta-analysis, site of failure, toxicity and cost. The minimal increase in survival that could be detected ranged from 11 to 51%, with a median of 25%. No trial was big enough to detect the likely increase of survival, which is 5%. Many trials excluded some eligible patients before randomisation, the proportion being 21% in those series with details. A further 9% of treated patients were excluded from analysis. A response rate in four induction studies of 47% equated with a 6% increase in cancer mortality. Meta-analysis showed an insignificant overall improvement in cancer mortality of 0.5%. Induction chemotherapy, synchronous chemotherapy and induction/maintenance chemotherapy did not affect cancer mortality whereas synchronous/maintenance therapy did. Cisplatinum, methotrexate, bleomycin, 5-FU and a variety of other regimens did not affect the death rate from cancer, but the combination of VBM significantly increased it. Neither single agent nor combination chemotherapy produced a significant reduction of cancer deaths. The rate of locoregional failure was significantly lower in the treated arms, whereas the metastatic rate was similar in both arms. Only three papers gave full details of toxicity with grading: these showed a high toxicity rate. The mortality rate from chemotherapy in nine series averaged 6.5%. PMID:2140045

  18. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

    PubMed

    Savelkoul, Huub F J; Ferro, Valerie A; Strioga, Marius M; Schijns, Virgil E J C

    2015-03-05

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines.

  19. Regulation of cytokine gene expression by adjuvants in vivo.

    PubMed

    Victoratos, P; Yiangou, M; Avramidis, N; Hadjipetrou, L

    1997-09-01

    Antibody isotype affects biological activity of the antibodies and therefore should be considered in prevention of disease by vaccination. In previous reports, we demonstrated that adjuvants affect the antibody isotype switching process and favour the production of certain isotypes. The present study extends these findings and shows fundamental differences in the cytokine induction pattern according to the adjuvant used. Cytokine mRNA levels were determined by in situ RNA-RNA hybridization performed on splenocytes isolated from mice injected with different adjuvants. The results revealed that Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), Al(OH)3 and QuilA administration results in a type-2 (humoral) response, increasing IL-4, IL-5 and IL-13 gene expression, while poly I:C exhibits a type-1 (cell-mediated) response, increasing the production of interferon-gamma (IFN-gamma), IL-2 and IL-6 mRNA. Finally, BeSO4 and poly A:U augment IL-5 and IL-6 mRNA production, while lipopolysaccharide (LPS) and LiCl augment IL-6 and tumour necrosis factor-alpha (TNF-alpha) mRNA production. Also, the adjuvants appear capable of overcoming the inherent IL-2/IFN-gamma and IL-4 dichotomy of C57B1/6 and BALB/c mice, respectively, in response to cellular antigens such as Leishmania and herpes simplex virus (HSV). The overall data suggest that adjuvants direct the isotype switching process via induction of certain cytokines, a finding that can be useful in selection of the most efficient isotype of protective antibodies for disease prevention by vaccination.

  20. DNA minigene vaccination for adjuvant neuroblastoma therapy.

    PubMed

    Lode, Holger N; Huebener, Nicole; Zeng, Yan; Fest, Stefan; Weixler, S; Gaedicke, Gerhard

    2004-12-01

    The disruption of self-tolerance against neuroblastoma is the ultimate goal of an effective DNA-vaccine. We demonstrate the induction of protective immunity against syngeneic murine NXS2 neuroblastoma in A/J mice following vaccination with tyrosine hydroxylase (TH)-derived antigens. Oral gene delivery was accomplished using an attenuated strain of Salmonella typhimurium as a carrier harboring vectors encoding for mouse tyrosine hydroxylase (mTH) antigens. Vaccination was effective in protecting animals from a lethal challenge with wild-type NXS2 tumor cells. These findings were extended by comparing efficacy of mTH minigene vaccines with a minigene vaccine comprising three novel epitopes isolated fom NXS2 neuroblastoma cells. For this purpose, MHC class I was immunoprecipitated from NXS2 cell lysates, and peptides were eluted and examined in tandem-mass spectrometry analysis. This led to the identification of three novel natural MHC class I peptide ligands: TEALPVKLI, from ribonucleotide reductase M2; NEYIMSLI, from Ser/Thr protein phosphatase 2A; and FEMVSTLI, of unknown origin. Two minigenes were constructed, one encoding for the three novel epitopes and the second for three known mTH-derived epitopes with high predicted binding affinity to MHC class I, by cloning them into the mammalian expression vector pCMV-3FUB. Immunized mice showed a reduction in primary tumor growth and the absence of spontaneous liver metastasis in the majority of animals. Importantly, there was no significant difference between the two minigenes, suggesting that, compared with tumor peptide isolation, mTH epitope prediction is similarly effective for designing efficient DNA-minigene vaccines. In summary, these findings establish proof of the concept that disruption of self-tolerance against neuroblastoma-associated epitopes may be an effective adjuvant therapeutic strategy.

  1. Novel adjuvants & delivery vehicles for vaccines development: a road ahead.

    PubMed

    Mohan, Teena; Verma, Priyanka; Rao, D Nageswara

    2013-11-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines.

  2. Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy

    PubMed Central

    De Souza Rebouças, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, María Luisa; Irache, Juan Manuel; Gamazo, Carlos

    2012-01-01

    In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines. PMID:22496608

  3. Nanoparticulate adjuvants and delivery systems for allergen immunotherapy.

    PubMed

    De Souza Rebouças, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, María Luisa; Irache, Juan Manuel; Gamazo, Carlos

    2012-01-01

    In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines.

  4. Regulatory considerations on new adjuvants and delivery systems.

    PubMed

    Sesardic, D

    2006-04-12

    New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.

  5. Environmental adjuvants, apoptosis and the censorship over autoimmunity.

    PubMed

    Rovere-Querini, Patrizia; Manfredi, Angelo A; Sabbadini, Maria Grazia

    2005-11-01

    Alterations during apoptosis lead to the activation of autoreactive T cells and the production of autoantibodies. This article discusses the pathogenic potential of cells dying in vivo, dissecting the role of signals that favor immune responses (adjuvants) and the influence of genetic backgrounds. Diverse factors determine whether apoptosis leads or not to a self-sustaining, clinically apparent autoimmune disease. The in vivo accumulation of uncleared dying cells per se is not sufficient to cause disease. However, dying cells are antigenic and their complementation with immune adjuvants causes lethal diseases in predisposed lupus-prone animals. At least some adjuvant signals directly target the function and the activation state of antigen presenting cells. Several laboratories are aggressively pursuing the molecular identification of endogenous adjuvants. Sodium monourate and the high mobility group B1 protein (HMGB1) are, among those identified so far, well known to rheumatologists. However, even the complementation of apoptotic cells with potent adjuvant signals fail to cause clinical autoimmunity in most strains: autoantibodies generated are transient, do not undergo to epitope/spreading and do not cause disease. Novel tools for drug development will derive from the molecular identification of the constraints that prevent autoimmunity in normal subjects. PMID:16214095

  6. Novel adjuvants & delivery vehicles for vaccines development: a road ahead.

    PubMed

    Mohan, Teena; Verma, Priyanka; Rao, D Nageswara

    2013-11-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines. PMID:24434331

  7. Role of Adjuvant Chemoradiotherapy for Resected Extrahepatic Biliary Tract Cancer

    SciTech Connect

    Kim, Tae Hyun; Han, Sung-Sik; Park, Sang-Jae Lee, Woo Jin; Woo, Sang Myung; Moon, Sung Ho; Yoo, Tae; Kim, Sang Soo; Kim, Seong Hoon; Hong, Eun Kyung; Kim, Dae Yong; Park, Joong-Won

    2011-12-01

    Purpose: To evaluate the effect of adjuvant chemoradiotherapy (CRT) on locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) for patients with extrahepatic biliary tract cancer treated with curative resection. Methods and Materials: The study involved 168 patients with extrahepatic biliary tract cancer undergoing curative resection between August 2001 and April 2009. Of the 168 patients, 115 received adjuvant CRT (CRT group) and 53 did not (no-CRT group). Gender, age, tumor size, histologic differentiation, pre- and postoperative carbohydrate antigen 19-9 level, resection margin, vascular invasion, perineural invasion, T stage, N stage, overall stage, and the use of adjuvant CRT were analyzed to identify the prognostic factors associated with LRC, DFS, and OS. Results: For all patients, the 5-year LRC, DFS, and OS rate was 54.8%, 30.6%, and 33.9%, respectively. On univariate analysis, the 5-year LRC, DFS, and OS rates in the CRT group were significantly better than those in the no-CRT group (58.5% vs. 44.4%, p = .007; 32.1% vs. 26.1%, p = .041; 36.5% vs. 28.2%, p = .049, respectively). Multivariate analysis revealed that adjuvant CRT was a significant independent prognostic factor for LRC, DFS, and OS (p < .05). Conclusion: Our results have suggested that adjuvant CRT helps achieve LRC and, consequently, improves DFS and OS in patients with extrahepatic biliary tract cancer.

  8. Novel adjuvants & delivery vehicles for vaccines development: A road ahead

    PubMed Central

    Mohan, Teena; Verma, Priyanka; Rao, D. Nageswara

    2013-01-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines. PMID:24434331

  9. Specific Inhibition of DNMT3A/ISGF3γ Interaction Increases the Temozolomide Efficiency to Reduce Tumor Growth

    PubMed Central

    Cheray, Mathilde; Pacaud, Romain; Nadaradjane, Arulraj; Oliver, Lisa; Vallette, François M; Cartron, Pierre-François

    2016-01-01

    DNA methylation is a fundamental feature of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantage. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention. By focusing on interactions existing between DNMT3A and DNMT3A-binding protein (D3A-BP), our work identifies the DNMT3A/ISGF3γ interaction such as a biomarker whose the presence level is associated with a poor survival prognosis and with a poor prognosis of response to the conventional chemotherapeutic treatment of glioblastoma multiforme (radiation plus temozolomide). Our data also demonstrates that the disruption of DNMT3A/ISGF3γ interactions increases the efficiency of chemotherapeutic treatment on established tumors in mice. Thus, our data opens a promising and innovative alternative to the development of specific DNMT inhibitors. PMID:27698935

  10. Specific Inhibition of DNMT3A/ISGF3γ Interaction Increases the Temozolomide Efficiency to Reduce Tumor Growth

    PubMed Central

    Cheray, Mathilde; Pacaud, Romain; Nadaradjane, Arulraj; Oliver, Lisa; Vallette, François M; Cartron, Pierre-François

    2016-01-01

    DNA methylation is a fundamental feature of genomes and is a candidate for pharmacological manipulation that might have important therapeutic advantage. Thus, DNA methyltransferases (DNMTs) appear to be ideal targets for drug intervention. By focusing on interactions existing between DNMT3A and DNMT3A-binding protein (D3A-BP), our work identifies the DNMT3A/ISGF3γ interaction such as a biomarker whose the presence level is associated with a poor survival prognosis and with a poor prognosis of response to the conventional chemotherapeutic treatment of glioblastoma multiforme (radiation plus temozolomide). Our data also demonstrates that the disruption of DNMT3A/ISGF3γ interactions increases the efficiency of chemotherapeutic treatment on established tumors in mice. Thus, our data opens a promising and innovative alternative to the development of specific DNMT inhibitors.

  11. Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model.

    PubMed

    Ouyang, Mao; White, Ethan E; Ren, Hui; Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R; Zhang, Leying; Vonderfecht, Steven L; Alizadeh, Darya; Berlin, Jacob M; Badie, Behnam

    2016-01-01

    Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG. PMID:26829221

  12. Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model

    PubMed Central

    Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R.; Zhang, Leying; Vonderfecht, Steven L.; Alizadeh, Darya; Berlin, Jacob M.; Badie, Behnam

    2016-01-01

    Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG. PMID:26829221

  13. Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma

    PubMed Central

    Diallo, Alhassane; Etienne-Grimaldi, Marie-Christine; Bidard, François-Clément; Rodrigues, Manuel; Plancher, Corine; Mariani, Pascale; Cassoux, Nathalie; Decaudin, Didier; Asselain, Bernard; Servois, Vincent

    2016-01-01

    Lessons Learned Trials dedicated to metastatic uveal melanoma are needed because of the poor prognosis of this rare cancer and because its biology is distinct from that of cutaneous melanoma. Agents targeting the MEK/ERK/MAP kinase pathways are being tested. Background. In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells. Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine. Methods. This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m2 on days 1–7 and 15–21) in 36 patients with metastatic uveal melanoma (MUM). The primary endpoint was the progression-free rate (PFR) at 6 months. Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%. Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Results. First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively. Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10–39), with long-lasting stable disease in 5 patients (14%). Median PFS and OS were 12 weeks and 10 months, respectively. No unexpected toxicity occurred. Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival. Conclusion. In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%. PMID:26911405

  14. Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing’s Sarcoma

    PubMed Central

    Pshenichnaya, Irina; Kogera, Fiona A.; Barthorpe, Syd; Mironenko, Tatiana; Richardson, Laura; Benes, Cyril H.; Stratton, Michael R.; McDermott, Ultan; Jackson, Stephen P.; Garnett, Mathew J.

    2015-01-01

    Ewing’s sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing’s sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing’s sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing’s sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing’s sarcoma patients with PARP inhibitors. PMID:26505995

  15. Use of adjuvants in the treatment of Acinetobacter baumannii.

    PubMed

    Pachón-Ibáñez, María Eugenia; Smani, Younes; Pachón, Jerónimo

    2016-01-01

    The current antibiotic crisis to treat infections by Acinetobacter baumannii is linked with the increase of antimicrobial resistance and the lack of development of new antimicrobial drugs. For this reason, new alternatives for the treatment and control of infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents. Herein, we analyzed the main results on the development of adjuvant drugs, as monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising results in vitro and in vivo. However, caution is needed and further extensive in vivo studies have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives. PMID:26620637

  16. Development of CpG ODN Based Vaccine Adjuvant Formulations.

    PubMed

    Gursel, Mayda; Gursel, Ihsan

    2016-01-01

    Development of effective vaccine mediated immune responses relies on the use of vaccine adjuvants capable of enhancing and directing the adaptive immune response to the antigen. When used as vaccine adjuvants, type I interferon inducing agents can elicit potent effector/memory T cell responses and humoral immunity. Distinct sequences of single stranded synthetic oligodeoxynucleotides containing unmethylated cytosine-phosphate-guanine oligodeoxynucleotide motifs (CpG ODN) can generate type I interferon production via a TLR9-MyD88-IRF7-mediated signaling pathway. Here, we describe two different methods of preparing CpG ODN-based vaccine adjuvant formulations that can induce a robust IFNα response from human peripheral blood mononuclear cells. PMID:27076306

  17. Adjuvant Endocrine Therapy in Premenopausal Women with Breast Cancer

    PubMed Central

    Kadakia, Kunal C.; Henry, N. Lynn

    2016-01-01

    Breast cancer remains the leading cause of cancer related mortality in premenopausal women. Multiple advances in local and systemic therapies have dramatically improved outcomes in women with HR+ early stage breast cancer. Despite these advances, early and late relapses occur. Therefore multiple adjuvant endocrine therapy trials have been conducted with the goal of decreasing breast cancer recurrence and mortality. Recently, large international trials evaluating extended endocrine therapy as well as ovarian suppression with and without tamoxifen or exemestane have been reported. These studies add to the large body of existing data related to adjuvant endocrine therapy in premenopausal women with breast cancer and provide additional therapeutic options in those at high risk of disease recurrence. This review will synthesize the most recent data and provide an evidenced based approach, highlighting quality-of-life concerns, when considering adjuvant endocrine therapies in premenopausal women. PMID:27058571

  18. The Safety of Adjuvanted Vaccines Revisited: Vaccine-Induced Narcolepsy.

    PubMed

    Ahmed, S Sohail; Montomoli, Emanuele; Pasini, Franco Laghi; Steinman, Lawrence

    2016-01-01

    Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine. PMID:27228647

  19. The Safety of Adjuvanted Vaccines Revisited: Vaccine-Induced Narcolepsy.

    PubMed

    Ahmed, S Sohail; Montomoli, Emanuele; Pasini, Franco Laghi; Steinman, Lawrence

    2016-01-01

    Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine.

  20. Management of Pediatric Myxopapillary Ependymoma: The Role of Adjuvant Radiation

    SciTech Connect

    Agbahiwe, Harold C.; Wharam, Moody; Batra, Sachin; Cohen, Kenneth; Terezakis, Stephanie A.

    2013-02-01

    Introduction: Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE. Methods: Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis. Results: All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT. Conclusions: Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE.

  1. Ginseng and aluminium hydroxide act synergistically as vaccine adjuvants.

    PubMed

    Rivera, E; Hu, S; Concha, C

    2003-03-01

    The dry extract prepared from the Panax ginseng C.A. Meyer-root (total ginseng (T-ginseng)) contain ginsenosides (G-des) which were shown to have adjuvant properties as demonstrated by: (a) injecting guinea pigs with a mixture of T-ginseng and inactivated porcine parvovirus (PPV) as a conventional vaccine; (b)injecting PPV-antigen and T-ginseng simultaneously but separately at different sites on the animal and (c)injecting only the T-ginseng 1 or 2 weeks prior to immunisation with the PPV-antigen. Using a haemagglutination inhibition (HI) test in the antibody titration, it was found that the mean HI-titre for the animals injected with PPV-antigen only was 320 +/- 0. By comparison, the mean titre value was 2026 +/- 1206 for the sera from the animals injected with the same vaccine but adjuvanted with 4 mg of T-ginseng, while the antibody titre induced by a vaccine containing Al(OH)(3)-gel was 2986 +/- 1596. Interestingly, the T-ginseng and Al(OH)(3) acted synergistically and further improved the antibody response to the PPV-antigen to 6826 +/- 2413, i.e. more than 20 times the HI titre of the non-adjuvanted PPV-vaccine. Immunisations using PPV-vaccines adjuvanted with single purified G-des demonstrated that the ginseng fractions Rb1 and Rg1 are potent adjuvants inducing higher or similar antibody titres than the vaccine adjuvanted with Al(OH)(3), e.g. Rb1 tested at a concentration of 830 microg per dose induced a significantly (P = 0.009) higher antibody titre than the one adjuvanted with Al(OH)(3). Nevertheless, different than the mixture Al(OH)(3)-T-ginseng; Rb1 and Rg1 act antagonistically and partially inhibit each other. The G-des adjuvanted vaccines induced significantly (P = 0.0011) higher titres of IgG2 antibodies compared with IgG1.

  2. [Human adjuvant disease which developed after silicone augumentation mammoplasty].

    PubMed

    Muramatsu, Yoko; Sugino, Keishi; Kikuchi, Naoshi; Sano, Go; Isobe, Kazutoshi; Takai, Yujiro; Takagi, Keigo; Shibuya, Kazutoshi; Homma, Sakae

    2009-03-01

    A 73-year-old woman was admitted to our hospital to evaluate mediastinal lymphadenopathy found on a chest CT scan. She had undergone mammoplasty with silicone augmentation 50 years previously and had the implants removed 5 years previously. Biopsied specimens of a mediastinal lymph node under video-assisted thoracic surgery (VATS) revealed multiple hyalinized non-caseating epithelioid cell granulomas and multinucleated giant cells and foamy macrophages containing some vacuoles. According to these clinicopathological findings, we diagnosed human adjuvant disease which developed after mammoplasty with silicone augmentation. In cases of mammoplasty, we should pay attention to the complication of chronic thoracic disorder as a human adjuvant disease.

  3. Knowns and Known Unknowns of Gastrointestinal Stromal Tumor Adjuvant Therapy.

    PubMed

    Martínez-Marín, Virginia; Maki, Robert G

    2016-09-01

    The first 15 years of management of gastrointestinal stromal tumor (GIST) have led to 3 lines of therapy for metastatic disease: imatinib, sunitinib, and regorafenib. In the adjuvant setting, imatinib is usually given for 3 years postoperatively to patients with higher-risk primary tumors that are completely resected. In this review, issues regarding GIST adjuvant therapy are discussed. It is hoped this review will help the reader understand the present standard of care to improve upon it in years to come. PMID:27546844

  4. Chemotherapy: Does Neoadjuvant or Adjuvant Therapy Improve Outcomes?

    PubMed

    Canter, Robert J

    2016-10-01

    Since preoperative chemotherapy has been clearly shown to improve outcomes for patients with Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, practitioners have attempted to extend the use of adjuvant/neoadjuvant chemotherapy to other types of adult soft tissue sarcoma. Given the high risk of distant recurrence and disease-specific death for patients with soft tissue sarcoma tumors larger than 10 cm, these patients should be considered candidates for neoadjuvant chemotherapy as well as investigational therapies. Yet, potential toxicity from cytotoxic chemotherapy is substantial, and there remains little consensus and wide variation regarding the indications for use of chemotherapy in the adjuvant/neoadjuvant setting. PMID:27591503

  5. Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment

    SciTech Connect

    Jakubowicz-Gil, Joanna; Langner, Ewa; Bądziul, Dorota; Wertel, Iwona; Rzeski, Wojciech

    2013-12-15

    The aim of the present study was to investigate whether silencing of Hsp27 or Hsp72 expression in glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cells increases their sensitivity to programmed cell death induction upon temozolomide and/or quercetin treatment. Transfection with specific siRNA was performed for the Hsp gene silencing. As revealed by microscopic observation and flow cytometry, the inhibition of Hsp expression was correlated with severe apoptosis induction upon the drug treatment studied. No signs of autophagy were detected. This was correlated with a decreased mitochondrial membrane potential, increased level of cytochrome c in the cytoplasm, and activation of caspase 3 and caspase 9. All these results suggest that the apoptotic signal was mediated by an internal pathway. Additionally, in a large percentage of cells treated with temozolomide, with or without quercetin, granules within the ER system were found, which was accompanied by an increased level of caspase 12 expression. This might be correlated with ER stress. Quercetin and temozolomide also changed the shape of nuclei from circular to “croissant like” in both transfected cell lines. Our results indicate that blocking of Hsp27 and Hsp72 expression makes T98G cells and MOGGCCM cells extremely vulnerable to apoptosis induction upon temozolomide and quercetin treatment and that programmed cell death is initiated by an internal signal. - Highlights: • Hsps gene silencing induced severe apoptosis upon temozolomide–quercetin treatment • Apoptosis in transfected glioma cells was initiated by internal signal • Programmed cell death was preceded by ER stress • Temozolomide–quercetin treatment changed nuclei shape in transfected glioma cells.

  6. Craniospinal irradiation with concurrent temozolomide and nimotuzumab in a child with primary metastatic diffuse intrinsic pontine glioma. A compassionate use treatment.

    PubMed

    Müller, K; Schlamann, A; Seidel, C; Warmuth-Metz, M; Christiansen, H; Vordermark, D; Kortmann, R-D; Kramm, C M; von Bueren, A O

    2013-08-01

    Primary metastatic diffuse intrinsic pontine glioma (DIPG) is relatively rare and associated with a dismal prognosis. Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab therapy may slightly improve tumor control and overall survival. However, little is known about the feasibility and toxicity of this treatment approach. Here, we describe the case of an 8-year-old girl with primary metastatic DIPG who received craniospinal radiotherapy, a local boost, and concurrent temozolomide and nimotuzumab treatment based on an individual therapy recommendation. Radiotherapy could be completed without any interruption. However, concurrent temozolomide had to be disrupted several times due to considerable acute myelotoxicity (grade III-IV).Maintenance immunochemotherapy could be started with a delay of 5 days and was performed according to treatment schedule. The disease could be stabilized for a few months. A routine MRI scan finally depicted disease progression 5.7 months after the start of irradiation. The patient died 1.9 months later.

  7. The adherens junction-associated protein 1 is a negative transcriptional regulator of MAGEA2, which potentiates temozolomide-induced apoptosis in GBM.

    PubMed

    Zeng, Liang; Kang, Chunsheng; Di, Chunhui; Fee, Brian E; Rivas, Miriam; Lin, James; Adamson, David Cory

    2014-04-01

    Previous studies identified the frequent loss of adherens junction-associated protein 1 (AJAP1) expression in glioblastoma (GBM) and its correlation with worse survival. AJAP1 may suppress glioma cell migration, which plays an important role in tumor progression in malignant gliomas such as GBM. However, the role of AJAP1 in cell cycle arrest or apoptosis and resistance to chemotherapy remains unclear. Based on microarray screening results, quantitative PCR and luciferase plasmid reporter constructs were used to evaluate the possible regulatory role of AJAP1 on MAGEA2 expression and function. Cell death assays, TUNEL and other markers of apoptosis were utilized to detect cell apoptosis. Restoration of AJAP1 expression in glioma cells was analyzed after temozolomide exposure. AJAP1 suppressed the expression of MAGEA2 and inhibited the transcriptional activity of MAGEA2 in glioma cells. As AJAP1 expression decreased MAGEA2 protein expression apoptosis increased moderately. Consistent with increased cell death, the induced loss of MAGEA2 expression correlated with increased caspase 3/7 activity, BCL2/BAX ratio and TUNEL signal. AJAP1 expression enhanced cell death in the presence of temozolomide. This study suggests AJAP1 may also function as a pro-apoptotic factor and potentiate cell death by temozolomide in glioma cells. This effect may be partially explained by AJAP1-mediated gene regulation of MAGEA2. PMID:24481586

  8. Time Relationships Between Injection of Antigen and Adjuvant III. Adjuvancy of Bordetella pertussis Given at Various Times After the Primary Antigenic Stimulus

    PubMed Central

    Finger, H.; Emmerling, P.; Plager, L.

    1972-01-01

    The adjuvant activity of Bordetella pertussis was investigated, both at the cellular and humoral levels, when the bacterial adjuvant was given at various times after the primary antigenic stimulus of both 2 × 107 (suboptimal dose) and 4 × 108 (optimal dose) of sheep erythrocytes. In all experiments, both adjuvant and sheep erythrocytes were administered by the intraperitoneal route. Adjuvant activity was measured on the basis of the early and late phases of the primary response and on the degree of priming for the secondary immune reaction. A maximal adjuvant activity was found in mice which had received B. pertussis vaccine simultaneously with the antigen. Adjuvant effectiveness became less as the time interval between the injection of antigen and adjuvant increased. Adjuvancy also depended on the amount of antigen used as the primary antigenic stimulus. With 4 × 108 sheep erythrocytes, significantly increased priming for the secondary response was produced only when B. pertussis cells were administered within a period of 24 hr. When the bacterial adjuvant was administered either 48 or 72 hr after the primary antigenic stimulus, adjuvancy was found to be limited to the late phase of the primary response and to the prolonged development of antibody-forming cells during the secondary immune reaction. In contrast, significantly enhanced priming for the secondary response was detectable when the adjuvant was administered as late as 48 hr after primary immunization with 2 × 107 sheep erythrocytes. When the bacterial adjuvant was administered either 6, 24, 48, or 72 hr after the primary immunization with 2 × 107 sheep erythrocytes, the early phase of the primary 19S and 7S hemolysin response was found to be suppressed, and adjuvancy became detectable only thereafter. PMID:4344394

  9. 21 CFR 178.3010 - Adjuvant substances used in the manufacture of foamed plastics.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... foamed plastics. 178.3010 Section 178.3010 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND SANITIZERS Certain Adjuvants and Production Aids § 178.3010 Adjuvant substances used in the manufacture of...

  10. Prospects for the development of new vaccine adjuvants.

    PubMed

    Cox, J; Coulter, A

    1999-12-01

    This review focuses on the impact of various new adjuvant formulations on the efficacy of existing and new human vaccines. Despite major advances in our understanding of immunology and vaccine adjuvants, existing and even new prophylactic vaccines seem likely to maintain their dependence upon aluminium salts for the foreseeable future. Additional immunomodulators may be included in these formulations to improve efficacy. A number of immunotherapeutic cancer vaccines appear likely to be registered soon and these will be dependent for efficacy upon new adjuvant formulations. The most useful to date have been the saponins e.g. QS-21, detox-B and Mycobacterial cells (either live as BCG, or killed). Vaccines to treat chronic infections will doubtless benefit from these developments. Adjuvant formulations and technologies exist to permit development of mucosal delivery, needle-free parenteral delivery and single dose vaccines. However, each of these will require intensive development, which will doubtless arrive when demanded by a specific application. Possibilities exist to improve responses in the elderly and to overcome the inhibitory effects of maternal antibodies in neonates. However, considerable work is required to establish the practicality and general utility of new approaches. PMID:18031193

  11. [Expression and adjuvant effects of the fusion peptide TBP5].

    PubMed

    Wang, Chen; Guo, Xiangling; Li, Xiaokang; Wu, Tingcai; Li, Deyuan; Chen, Puyan

    2015-05-01

    Thymopentin (TP5) and bursopentin (BP5) are both immunopotentiators. To explore whether the TP5-BP5 fusion peptide (TBP5) has adjuvant activity or not, we cloned the TBP5 gene and confirmed that the TBP5 gene in a recombinant prokaryotic expression plasmid was successfully expressed in Escherichia coli BL21. TBP5 significantly promoted the proliferation of thymic and splenic lymphocytes of mice. The potential adjuvant activity of the TBP5 was examined in mice by coinjecting TBP5 and H9N2 avian influenza virus (AIV) inactivated vaccine. HI antibody titers, HA antibodies and cytokines levels (IL-4 and IFN-γ) were determined. We found that TBP5 markedly elevated serum HI titers and HA antibody levels, induced the secretion of both IL-4 and IFN-γ cytokines. Furthermore, virus challenge experiments confirmed that TBP5 contributed to inhibition replication of the virus [H9N2 AIV (A/chicken/Jiangsu/NJ07/05)] from mouse lungs. Altogether, these findings suggest that TBP5 may be an effective adjuvant for avian vaccine and that this study provides a reference for further research on new vaccine adjuvants. PMID:26571686

  12. Adjuvant disease induced by mycobacteria, determinants of arthritogenicity.

    PubMed

    Audibert, F; Chedid, L

    1976-02-01

    Genetic, endocrine and immunological factors are probably involved in adjuvant polyarthritis. The nature of the vehicle and of the mycobacterial components administered also has a major influence. It was originally assumed that arthritogenicity and adjuvanticity of mycobacterial fractions such as wax D were intimately related. Our previous findings showed that the water soluble adjuvant (WSA) of M.smegmatis which could substitute for mycobacterial cells in Freund's complete adjuvant and induce delayed hypersensitivity was not arthritogenic in the Wistar rat. We have since observed that auto-immune diseases could be elicited by WSA. Therefore experiments were repeated using the very susceptible Lewis strain. The activity of cord factor and of various mycobacterial preparations suspended in mineral or in peanut oil was also evaluated in mice and in normal or hypophysectomized rats. Our present findings confirm the absence of arthritogenicity of WSA in the Lewis strain. They also indicate that cord factor with WSA does not suffice to induce a generalized adjuvant disease, but that a mycobacterial component which could be susceptible to lysozyme treatment is required also. However, the local inflammation of the injected limb was produced by a preparation of cord factor administered in mineral or even in peanut oil. This was observed in normal or hypophysectomized rats and in Swiss mice which were not susceptible to the generalized disease.

  13. Oily adjuvants and autoimmunity: now time for reconsideration?

    PubMed

    Whitehouse, M

    2012-02-01

    Immunologists have relied heavily on oil-based adjuvants to generate antibodies or induce auto-allergic responses in experimental animals. These are rarely used today for human vaccination because of their persistent irritancies and propensity to cause ulcers at sites of injection. However oily materials with adjuvant properties abound in our modern environment, both personal and extraneous. Their inadvertent impact as cryptotoxins may contribute to the rising incidence of auto-allergic diseases in recent times. Experimentally, the potential adjuvanticity of various oils, fats and other lipids can be evaluated by their ability (or otherwise) to induce auto-allergic disease(s) in rats and mice with, or even without, the addition of a mycobacterial immunostimulant. Genetic factors have been recognized that determine an animal's susceptibility or resistance to these oil-induced immunopathies. So it may be profitable to further characterize these factors, first in animals and then perhaps in human populations, to help find ways to enhance natural resistance to those adjuvant-active oils that may be widely distributed in the personal environment, notably mineral oil(s). (The six tables in this article summarize some relevant facts and a few conjectures.) A caveat: This review is restricted to the adjuvant properties of some oils in the personal environment. It does not cover the mechanisms of adjuvanticity.

  14. Ready-to-use colloidal adjuvant systems for intranasal immunization.

    PubMed

    Lee, Jeong-Jun; Shim, Aeri; Lee, Song Yi; Kwon, Bo-Eun; Kim, Seong Ryeol; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2016-04-01

    Adjuvant systems based on oil-in-water (o/w) microemulsions (MEs) for vaccination via intranasal administration were prepared and evaluated. A ready-to-use blank ME system composed of mineral oil (oil), Labrasol (surfactant), Tween 80 (cosurfactant), and water was prepared and blended with antigen (Ag) solution prior to use. The o/w ME system developed exhibited nano-size droplets within the tested range of Ag concentrations and dilution factors. The maintenance of primary, secondary, and tertiary structural stability of ovalbumin (OVA) in ME, compared with OVA in solution, was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence intensity measurements, respectively. The uptake efficiency in RAW 264.7 cells, evaluated by flow cytometry, of OVA in the ME group was significantly higher than that of the OVA solution group (p<0.05). In an intranasal immunization study with OVA ME in mice, elevated adjuvant effects in terms of mucosal immunization and Th1-dominant cell-mediated immune responses were identified. Given the convenience of use (simply mixing with Ag solution prior to use) and the adjuvant effects after intranasal immunization, the new o/w ME may be a practical and efficient adjuvant system for intranasal vaccination. PMID:26775242

  15. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy.

    PubMed

    Kim, Su-Yeon; Joo, Hong-Gu

    2015-01-01

    Fucoidan is a sulfated polysaccharide derived from brown seaweed, including Fucus vesiculosus. This compound is known to have immunostimulatory effects on various types of immune cells including macrophages and dendritic cells. A recent study described the application of fucoidan as a vaccine adjuvant. Vaccination is regarded as the most efficient prophylactic method for preventing harmful or epidemic diseases. To increase vaccine efficacy, effective adjuvants are needed. In the present study, we determined whether fucoidan can function as an adjuvant using vaccine antigens. Flow cytometric analysis revealed that fucoidan increases the expression of the activation markers major histocompatibility complex class II, cluster of differentiation (CD)25, and CD69 in spleen cells. In combination with Bordetella bronchiseptica antigen, fucoidan increased the viability and tumor necrosis factor-α production of spleen cells. Furthermore, fucoidan increased the in vivo production of antigen-specific antibodies in mice inoculated with Mycoplasma hyopneumoniae antigen. Overall, this study has provided valuable information about the use of fucoidan as a vaccine adjuvant. PMID:25549218

  16. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy.

    PubMed

    Kim, Su-Yeon; Joo, Hong-Gu

    2015-01-01

    Fucoidan is a sulfated polysaccharide derived from brown seaweed, including Fucus vesiculosus. This compound is known to have immunostimulatory effects on various types of immune cells including macrophages and dendritic cells. A recent study described the application of fucoidan as a vaccine adjuvant. Vaccination is regarded as the most efficient prophylactic method for preventing harmful or epidemic diseases. To increase vaccine efficacy, effective adjuvants are needed. In the present study, we determined whether fucoidan can function as an adjuvant using vaccine antigens. Flow cytometric analysis revealed that fucoidan increases the expression of the activation markers major histocompatibility complex class II, cluster of differentiation (CD)25, and CD69 in spleen cells. In combination with Bordetella bronchiseptica antigen, fucoidan increased the viability and tumor necrosis factor-α production of spleen cells. Furthermore, fucoidan increased the in vivo production of antigen-specific antibodies in mice inoculated with Mycoplasma hyopneumoniae antigen. Overall, this study has provided valuable information about the use of fucoidan as a vaccine adjuvant.

  17. Have adjuvant tyrosine kinase inhibitors lost their shine?

    PubMed

    Sabari, Joshua K; Chaft, Jamie E

    2016-08-01

    Despite broad advances in molecularly targeted therapies, lung cancer remains the leading cause of cancer related mortality in the United States. Epidermal growth factor receptor (EGFR) mutations occur in approximately 17% of advanced non-small cell lung cancer (NSCLC) in the US population. The remarkable efficacy of small-molecule EGFR tyrosine kinase inhibitors (TKIs) in this unique subset of patients has revolutionized the therapeutic approach to lung cancer. The success of these agents in the metastatic setting leads to the logical question of what role these drugs may have in the adjuvant setting for patients with earlier stage disease. RADIANT, an international randomized, double-blind, placebo controlled phase III study in patients with completely resected stage IB to IIIA NSLC whose tumors expressed EGFR by IHC and EGFR amplification by FISH, attempted to answer the question of whether erlotinib would improve disease free survival and overall survival in the adjuvant setting. While RADIANT does not conclude for or against adjuvant use of EGFR-TKIs, all data points towards benefit in a selected population. As clinicians, we must continue to enroll to potentially practice changing therapeutic neoadjuvant and adjuvant chemotherapy studies internationally. PMID:27568486

  18. Have adjuvant tyrosine kinase inhibitors lost their shine?

    PubMed Central

    Sabari, Joshua K.

    2016-01-01

    Despite broad advances in molecularly targeted therapies, lung cancer remains the leading cause of cancer related mortality in the United States. Epidermal growth factor receptor (EGFR) mutations occur in approximately 17% of advanced non-small cell lung cancer (NSCLC) in the US population. The remarkable efficacy of small-molecule EGFR tyrosine kinase inhibitors (TKIs) in this unique subset of patients has revolutionized the therapeutic approach to lung cancer. The success of these agents in the metastatic setting leads to the logical question of what role these drugs may have in the adjuvant setting for patients with earlier stage disease. RADIANT, an international randomized, double-blind, placebo controlled phase III study in patients with completely resected stage IB to IIIA NSLC whose tumors expressed EGFR by IHC and EGFR amplification by FISH, attempted to answer the question of whether erlotinib would improve disease free survival and overall survival in the adjuvant setting. While RADIANT does not conclude for or against adjuvant use of EGFR-TKIs, all data points towards benefit in a selected population. As clinicians, we must continue to enroll to potentially practice changing therapeutic neoadjuvant and adjuvant chemotherapy studies internationally. PMID:27568486

  19. Effect of adjuvant physical properties on spray characteristics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of adjuvant physical properties on spray characteristics were studied. Dynamic surface tension was measured with a Sensa Dyne surface tensiometer 6000 using the maximum bubble pressure method. Viscosity was measured with a Brookfield synchro-lectric viscometer model LVT using a UL adap...

  20. Bacillus subtilis spores as adjuvants for DNA vaccines.

    PubMed

    Aps, Luana R M M; Diniz, Mariana O; Porchia, Bruna F M M; Sales, Natiely S; Moreno, Ana Carolina R; Ferreira, Luís C S

    2015-05-11

    Recently, Bacillus subtilis spores were shown to be endowed with strong adjuvant capacity when co-administered with purified antigenic proteins. In the present study we assessed whether spores possess adjuvant properties when combined with DNA vaccines. We showed that B. subtilis spores promoted the activation of dendritic cells in vitro and induced migration of pro-inflammatory cells after parenteral administration to mice. Likewise, co-administration of spores with a DNA vaccine encoding the human papillomavirus type 16 (HPV-16) E7 protein enhanced the activation of antigen-specific CD8(+) T cell responses in vivo. Mice immunized with the DNA vaccine admixed with spores presented a protective immunity increase to previously implanted tumor cells, capable of expressing HPV-16 oncoproteins. Finally, we observed that the adjuvant effect can vary accordingly to the number of co-administered spores which may be ascribed with the ability to induce. Collectively, the present results demonstrate for the first time that B. subtilis spores can also confer adjuvant effects to DNA vaccines.

  1. Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens.

    PubMed

    Wegmann, Frank; Gartlan, Kate H; Harandi, Ali M; Brinckmann, Sarah A; Coccia, Margherita; Hillson, William R; Kok, Wai Ling; Cole, Suzanne; Ho, Ling-Pei; Lambe, Teresa; Puthia, Manoj; Svanborg, Catharina; Scherer, Erin M; Krashias, George; Williams, Adam; Blattman, Joseph N; Greenberg, Philip D; Flavell, Richard A; Moghaddam, Amin E; Sheppard, Neil C; Sattentau, Quentin J

    2012-09-01

    Protection against mucosally transmitted infections probably requires immunity at the site of pathogen entry, yet there are no mucosal adjuvant formulations licensed for human use. Polyethyleneimine (PEI) represents a family of organic polycations used as nucleic acid transfection reagents in vitro and DNA vaccine delivery vehicles in vivo. Here we show that diverse PEI forms have potent mucosal adjuvant activity for viral subunit glycoprotein antigens. A single intranasal administration of influenza hemagglutinin or herpes simplex virus type-2 (HSV-2) glycoprotein D with PEI elicited robust antibody-mediated protection from an otherwise lethal infection, and was superior to existing experimental mucosal adjuvants. PEI formed nanoscale complexes with antigen, which were taken up by antigen-presenting cells in vitro and in vivo, promoted dendritic cell trafficking to draining lymph nodes and induced non-proinflammatory cytokine responses. PEI adjuvanticity required release of host double-stranded DNA that triggered Irf3-dependent signaling. PEI therefore merits further investigation as a mucosal adjuvant for human use. PMID:22922673

  2. Schistosome Vaccine Adjuvants in Preclinical and Clinical Research

    PubMed Central

    Stephenson, Rachel; You, Hong; McManus, Donald; Toth, Istvan

    2014-01-01

    There is currently no vaccine available for human use for any parasitic infections, including the helminth disease, schistosomiasis. Despite many researchers working towards this goal, one of the focuses has been on identifying new antigenic targets. The bar to achieve protective efficacy in humans was set at a consistent induction of 40% protection or better by the World Health Organisation (WHO), and although this is a modest goal, it is yet to be reached with the six most promising schistosomiasis vaccine candidates (Sm28GST, IrV5, Sm14, paramyosin, TPI, and Sm23). Adjuvant selection has a large impact on the effectiveness of the vaccine, and the use of adjuvants to aid in the stimulation of the immune system is a critical step and a major variable affecting vaccine development. In addition to a comprehensive understanding of the immune system, level of protection and the desired immune response required, there is also a need for a standardised and effective adjuvant formulation. This review summarises the status of adjuvants that have been or are being employed in schistosomiasis vaccine development focusing on immunisation outcomes at preclinical and clinical stages. PMID:26344751

  3. Modulation of Primary Immune Response by Different Vaccine Adjuvants

    PubMed Central

    Ciabattini, Annalisa; Pettini, Elena; Fiorino, Fabio; Pastore, Gabiria; Andersen, Peter; Pozzi, Gianni; Medaglini, Donata

    2016-01-01

    Adjuvants contribute to enhancing and shaping the vaccine immune response through different modes of action. Here early biomarkers of adjuvanticity after primary immunization were investigated using four different adjuvants combined with the chimeric tuberculosis vaccine antigen H56. C57BL/6 mice were immunized by the subcutaneous route with different vaccine formulations, and the modulation of primary CD4+ T cell and B cell responses was assessed within draining lymph nodes, blood, and spleen, 7 and 12 days after priming. Vaccine formulations containing the liposome system CAF01 or a squalene-based oil-in-water emulsion (o/w squalene), but not aluminum hydroxide (alum) or CpG ODN 1826, elicited a significant primary antigen-specific CD4+ T cell response compared to antigen alone, 7 days after immunization. The effector function of activated CD4+ T cells was skewed toward a Th1/Th17 response by CAF01, while a Th1/Th2 response was elicited by o/w squalene. Differentiation of B cells in short-lived plasma cells, and subsequent early H56-specific IgG secretion, was observed in mice immunized with o/w squalene or CpG adjuvants. Tested adjuvants promoted the germinal center reaction with different magnitude. These results show that the immunological activity of different adjuvants can be characterized by profiling early immunization biomarkers after primary immunization. These data and this approach could give an important contribution to the rational development of heterologous prime–boost vaccine immunization protocols. PMID:27781036

  4. Adverse events following immunization with vaccines containing adjuvants.

    PubMed

    Cerpa-Cruz, S; Paredes-Casillas, P; Landeros Navarro, E; Bernard-Medina, A G; Martínez-Bonilla, G; Gutiérrez-Ureña, S

    2013-07-01

    A traditional infectious disease vaccine is a preparation of live attenuated, inactivated or killed pathogen that stimulates immunity. Vaccine immunologic adjuvants are compounds incorporated into vaccines to enhance immunogenicity. Adjuvants have recently been implicated in the new syndrome named ASIA autoimmune/inflammatory syndrome induced by adjuvants. The objective describes the frequencies of post-vaccination clinical syndrome induced by adjuvants. We performed a cross-sectional study; adverse event following immunization was defined as any untoward medical occurrence that follows immunization 54 days prior to the event. Data on vaccinations and other risk factors were obtained from daily epidemiologic surveillance. Descriptive statistics were done using means and standard deviation, and odds ratio adjusted for potential confounding variables was calculated with SPSS 17 software. Forty-three out of 120 patients with moderate or severe manifestations following immunization were hospitalized from 2008 to 2011. All patients fulfilled at least 2 major and 1 minor criteria suggested by Shoenfeld and Agmon-Levin for ASIA diagnosis. The most frequent clinical findings were pyrexia 68%, arthralgias 47%, cutaneous disorders 33%, muscle weakness 16% and myalgias 14%. Three patients had diagnosis of Guillain-Barre syndrome, one patient had Adult-Still's disease 3 days after vaccination. A total of 76% of the events occurred in the first 3 days post-vaccination. Two patients with previous autoimmune disease showed severe adverse reactions with the reactivation of their illness. Minor local reactions were present in 49% of patients. Vaccines containing adjuvants may be associated with an increased risk of autoimmune/inflammatory adverse events following immunization.

  5. Role of Adjuvant Chemoradiotherapy for Ampulla of Vater Cancer

    SciTech Connect

    Kim, Kyubo; Chie, Eui Kyu Jang, Jin-Young; Kim, Sun Whe; Oh, Do-Youn; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Ha, Sung W.

    2009-10-01

    Purpose: To evaluate the role of adjuvant chemoradiotherapy for ampulla of Vater cancer. Methods and Materials: Between January 1991 and December 2002, 118 patients with ampulla of Vater cancer underwent en bloc resection. Forty-one patients received adjuvant chemoradiotherapy [RT(+) group], and 77 did not [RT(-) group]. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes, for a total dose of up to 40 Gy delivered in 2-Gy fractions, with a planned 2-week rest period halfway through the treatment period. Intravenous 5-fluorouracil (500 mg/m{sup 2}/day) was given on Days 1 to 3 of each split course. The median follow-up was 65 months. Results: The 5-year overall survival rate in the RT(-) and RT(+) groups was 66.9% and 52.8%, respectively (p = 0.2225). The 5-year locoregional relapse-free survival rate in the RT(-) and RT(+) groups was 79.9% and 80.2%, respectively (p = 0.9582). When age, type of operation, T stage, N stage, histologic differentiation, and the use of adjuvant chemoradiotherapy were incorporated into the Cox proportional hazard model, there was an improvement in the locoregional relapse-free survival rate (p = 0.0050) and a trend toward a longer overall survival (p = 0.0762) associated with the use of adjuvant chemoradiotherapy. Improved overall survival (p = 0.0235) and locoregional relapse-free survival (p = 0.0095) were also evident in patients with nodal metastasis. In contrast, enhanced locoregional control (p = 0.0319) did not result in longer survival in patients with locally advanced disease (p = 0.4544). Conclusions: Adjuvant chemoradiotherapy may enhance locoregional control and overall survival in patients with ampulla of Vater cancer after curative resection, especially in those with nodal involvement.

  6. Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma.

    PubMed

    Luthra, Pratibha Mehta; Lal, Neetika

    2016-02-15

    GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM.

  7. Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma.

    PubMed

    Luthra, Pratibha Mehta; Lal, Neetika

    2016-02-15

    GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM. PMID:26748069

  8. Antigen sparing with adjuvanted inactivated polio vaccine based on Sabin strains

    PubMed Central

    Westdijk, Janny; Koedam, Patrick; Barro, Mario; Steil, Benjamin P.; Collin, Nicolas; Vedvick, Thomas S.; Bakker, Wilfried A.M.; van der Ley, Peter; Kersten, Gideon

    2013-01-01

    Six different adjuvants, each in combination with inactivated polio vaccine (IPV) produced with attenuated Sabin strains (sIPV), were evaluated for their ability to enhance virus neutralizing antibody titers (VNTs) in the rat potency model. The increase of VNTs was on average 3-, 15-, 24-fold with adjuvants after one immunization (serotype 1, 2, and 3, respectively). Also after a boost immunization the VNTs of a