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1

Paclitaxel Injection  

MedlinePLUS

... organs where eggs are formed), breast cancer, and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also ... of your medications or monitor you carefully for side effects. Many other medications may also interact with paclitaxel, ...

2

[Pharmacological action of paclitaxel].  

PubMed

Paclitaxel (taxol, Tax) is a novel plant product isolated from the Pacific yew (Taxus brevifolia). It has a unique mechanism of action, because it induces very stable and dysfunctional microtubules. Paclitaxel has a broad spectrum of antineoplastic activity. It has been successfully used in the treatment of ovarian cancer, metastatic breast cancer, lung cancer, carcinoma of the head and neck, malignant melanoma and other human neoplasms. Tax has response rates of 20-36% in patients with refractory ovarian cancer. Toxic effects include myelosuppresion, hypersensitivity reactions, peripheral neuropathy, cardiac disturbances, alopecia. However, studies evaluating the drug still are ongoing paclitaxel seems to be one of the most promising antineoplastic agents. PMID:10344150

Potemski, P; P?uza?ska, A

1999-01-01

3

Overview of paclitaxel (TAXOL).  

PubMed

The history of development of paclitaxel (TAXOL [Bristol-Myers Squibb Co., Princeton, NJ]) is a long story and serves as a model of perseverance for those involved in drug development. Notations of the use of products of the yew tree date back to the Celts, but it was in the 1950s to the 1960s that the National Cancer Institute (NCI) selected the product for trials and the current process began. The active agent was identified in the 1970s, and when its unique mechanism of action was isolated in 1979, interest reemerged. Paclitaxel is an antimicrotubule agent that, unlike other antimicrotubule agents, promotes microtubule assembly. This unique mechanism of action has generated considerable interest in oncology. The clinical trials in the 1980s documented the drug's safety, identified its side effects, and demonstrated its activity in patients with ovarian cancer who had received prior treatment. The many clinical trials currently under way will provide information on the drug's range of activity. Paclitaxel's development has been an arduous process. Its development and supply initially were complicated, but these hurdles have been overcome, and the drug's unique mechanism of action and initial clinical trial results hold promise in the 1990s. PMID:7904376

Martin, V

1993-11-01

4

Paclitaxel (Taxol) in breast cancer.  

PubMed

Paclitaxel (Taxol) is a diterpine plant compound that was isolated initially from the bark of the western yew tree, Taxus brevifolia, but can now be produced by semisynthesis from a renewable source. Paclitaxel is the first new agent in the past decade to have confirmed single agent activity in breast cancer in excess of 50%. A 28% response rate has been reported in doxorubicin-refractory patients. Ongoing studies include attempts to combine paclitaxel with other drugs used for breast cancer treatment and with radiation. PMID:7908664

Arbuck, S G; Dorr, A; Friedman, M A

1994-02-01

5

Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer  

Microsoft Academic Search

background Standard chemotherapy for newly diagnosed ovarian cancer is a platinum-taxane combination. The Gynecologic Oncology Group conducted a randomized, phase 3 trial that compared intravenous paclitaxel plus cisplatin with intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel in patients with stage III ovarian cancer. methods We randomly assigned patients with stage III ovarian carcinoma or primary perito- neal carcinoma with no

Deborah K. Armstrong; Brian Bundy; Lari Wenzel; Helen Q. Huang; Rebecca Baergen; Shashikant Lele; Larry J. Copeland; Joan L. Walker; Robert A. Burger

2010-01-01

6

Possible Side Effects of Carboplatin and Paclitaxel  

Cancer.gov

Page of 1Possible Side Effects of Carboplatin and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Carboplatin and Paclitaxel, more than 20 and up to 100 may have: Hair loss Infection, especially when

7

Paclitaxel: new uses for an old drug  

PubMed Central

Paclitaxel (Taxol), one of the most important anticancer drugs, has been used for therapy of different types of cancers. Mechanistically, paclitaxel arrests cell cycle and induces cell death by stabilizing microtubules and interfering with microtubule disassembly in cell division. Recently, it has been found that low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. Future studies need to understand the mechanisms underlying these effects in order to design therapies with specificity. PMID:24591817

Zhang, Dongshan; Yang, Ruhao; Wang, Shixuan; Dong, Zheng

2014-01-01

8

Paclitaxel Versus Docetaxel for Early Breast Cancer  

Cancer.gov

Weekly treatment with the drug paclitaxel (Taxol®) in addition to standard chemotherapy proved most effective in extending overall survival among women with early-stage breast cancer, according to the April 17, 2008, New England Journal of Medicine.

9

Paclitaxel Arrests Growth of Intracellular Toxoplasma gondii  

Microsoft Academic Search

Addition of paclitaxel (Taxol) at a concentration of 1 m Mt oToxoplasma gondii-infected human foreskin fi- broblasts arrested parasite multiplication. Division of the T. gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this

RANDEE ESTES; NICOLAS VOGEL; DOUGLAS MACK; RIMA MCLEOD

1998-01-01

10

Src family kinases and paclitaxel sensitivity  

PubMed Central

Src-family Kinases (SFKs) participate in the regulation of proliferation, differentiation, apoptosis, autophagy, adhesion, migration, invasion and angiogenesis in normal and cancer cells. Abnormal expression of SFKs has been documented in cancers that arise in breast, colon, ovary, melanocyte, gastric mucosa, head and neck, pancreas, lung and brain. Targeting SFKs in cancer cells has been shown to be a promising therapeutic strategy in solid tumors, particularly in ovarian, colon and breast cancers. Paclitaxel is one of most widely used chemotherapeutic agents for the management of ovarian, breast, lung and head and neck cancers. As a microtubule-stabilizing agent, paclitaxel possesses both mitosis-dependent and mitosis-independent activities against cancer cells. A variety of mechanisms such as deregulation of P-glycoprotein, alteration of tubulin isotypes, alteration of microtubule-regulatory proteins, deregulation of apoptotic signaling pathways, mutation of tubulins and overexpression of copper transporters have been implicated in the development of primary or secondary resistance to paclitaxel. By affecting cancer cell survival, proliferation, autophagy, microtubule stability, motility, and/or angiogenesis, SFKs interact with mechanisms that regulate paclitaxel sensitivity. Inhibition of SFKs can potentiate the anti-tumor activity of paclitaxel by enhancing apoptosis, autophagy and microtubule stability. Based on pre-clinical observations, administration of SFK inhibitors in combination with paclitaxel could improve treatment for ovarian, breast, lung and head and neck cancers. Identification and validation of predictive biomarkers could also permit personalization of the therapy. PMID:21646863

2011-01-01

11

Possible Side Effects of Cyclophosphamide, Doxorubicin, and Paclitaxel  

Cancer.gov

Page of 1Possible Side Effects of Cyclophosphamide, Doxorubicin, and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Cyclophosphamide, Doxorubicin, and Paclitaxel, more than 20 and up to 100 may have: Hair

12

Tumor targeting by conjugation of DHA to paclitaxel.  

PubMed

Targeting an anti-cancer drug to tumors should increase the Area Under the drug concentration-time Curve (AUC) in tumors while decreasing the AUC in normal cells and should therefore increase the therapeutic index of that drug. Anti-tumor drugs typically have half-lives far shorter than the cell cycle transit times of most tumor cells. Tumor targeting, with concomitant long tumor exposure times, will increase the proportion of cells that move into cycle when the drug concentration is high, which should result in more tumor cell killing. In an effort to test that hypothesis, we conjugated a natural fatty acid, docosahexaenoic acid (DHA), through an ester bond to the paclitaxel 2'-oxygen. The resulting paclitaxel fatty acid conjugate (DHA-paclitaxel) does not assemble microtubules and is non-toxic. In the M109 mouse tumor model, DHA-paclitaxel is less toxic than paclitaxel and cures 10/10 tumored animals, whereas paclitaxel cures 0/10. One explanation for the conjugate's greater therapeutic index is that the fatty acid alters the pharmacokinetics of the drug to increase its AUC in tumors and decrease its AUC in normal cells. To test that possibility, we compared the pharmacokinetics of DHA-paclitaxel with paclitaxel in CD2F1 mice bearing approximately 125 mg sc M109 tumors. The mice were injected at zero time with a bolus of either DHA-paclitaxel or paclitaxel formulated in 10% cremophor/10% ethanol/80% saline. Animals were sacrificed as a function of time out to 14 days. Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DHA-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets paclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i.v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v. paclitaxel. The tumor concentration of paclitaxel derived from i.v. paclitaxel drops rapidly, so that by 16 h it has fallen to the same concentration (2.8 microM) as after an equi-toxic concentration of DHA-paclitaxel. In plasma, paclitaxel AUC after an MTD dose of DHA-paclitaxel is approximately 0.5% of DHA-paclitaxel AUC. Thus, the increase in tumor AUC and the limited plasma AUC of paclitaxel following DHA-paclitaxel administration are consistent with the increase in therapeutic index of DHA-paclitaxel relative to paclitaxel in the M109 mouse tumor model. A phase I clinical study has been completed at The Johns Hopkins Hospital to evaluate the safety of DHA-paclitaxel in patients with a variety of solid tumors. Twenty-one patients have been treated to date. The recommended phase II dose is 1100 mg/m(2), which is equivalent to 4.6 times the maximum approved paclitaxel dose on a molar basis. No alopecia or significant peripheral neuropathy, nausea, or vomiting have been observed. Asymptomatic, transient neutropenia has been the primary side effect. Eleven of 22 evaluable phase I patients transitioned from progressive to stable disease, as assessed by follow-up CT. Significant quality of life improvements have been observed. Thus, DHA-paclitaxel is well tolerated in patients and cures tumors in mice by targeting drug to tumors. PMID:11489499

Bradley, M O; Swindell, C S; Anthony, F H; Witman, P A; Devanesan, P; Webb, N L; Baker, S D; Wolff, A C; Donehower, R C

2001-07-01

13

Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel  

PubMed Central

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20?mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1?g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel. PMID:24198846

Bahar, Muh. Akbar; Andoh, Tsugunobu; Ogura, Keisuke; Hayakawa, Yoshihiro; Saiki, Ikuo; Kuraishi, Yasushi

2013-01-01

14

K252a, KT5720, KT5926, and U98017 support paclitaxel (taxol)-dependent cells and synergize with paclitaxel.  

PubMed

We have used paclitaxel-dependent Tax 2-4 cells to screen for compounds that have paclitaxel-like functional activity. The indolocarbazole serine/threonine kinase inhibitor K252a and analogues such as KT5926, KT5720, and K252b partially support the growth of the paclitaxel-dependent cells in the absence of paclitaxel. A novel kinase inhibitor of similar structure, U98017, supports the growth of the dependent cells to 48% of that seen with paclitaxel. Used in combination with paclitaxel, these compounds reduce the amount of paclitaxel required for maximum growth of the dependent cells. Isobologram analysis demonstrates that these compounds also act synergistically with paclitaxel to promote toxicity in wild-type Chinese hamster ovary cells. These selected indolocarbazoles may act at sites distinct from that of paclitaxel and may specifically inhibit kinases that contribute to the destabilization of microtubules. Other indolocarbazoles such as staurosporine and rebeccamycin do not support paclitaxel-dependent cell growth. Structurally unrelated serine/threonine kinase inhibitors such as H-9 and H-7 or tyrosine kinase inhibitors such as lavendustin do not support the growth of these cells. These results define a screen for functional paclitaxel analogues and suggest that it may be useful to investigate the possible synergy of selected indolocarbazoles and paclitaxel in vivo. PMID:7954419

Abraham, I; Wolf, C L; Sampson, K E; Laborde, A L; Shelly, J A; Aristoff, P A; Skulnick, H I

1994-11-15

15

Advancements in the understanding of Paclitaxel metabolism in tissue culture.  

PubMed

Paclitaxel is a potent chemotherapeutic agent approved in the treatment of a variety of cancers, and under evaluation for the treatment of Alzheimer's and heart disease. Originally isolated from Taxus brevifolia, this highly substituted ring diterpenoid belongs to a family of plant secondary metabolites known as taxoids. Paclitaxel is currently supplied through both a semi-synthetic process and plant cell culture. Taxus spp. cell culture offers the potential to produce large amounts of paclitaxel and related taxoids, although variability in accumulation and low yields represent key limitations. Thus, intense efforts have been put forth towards understanding Taxus spp. metabolism to increase paclitaxel accumulation in cell culture. While elicitation and environmental optimization have provided some success in increasing paclitaxel accumulation in vitro, understanding metabolism of paclitaxel on the molecular level is essential for process optimization. Utilizing direct and indirect molecular techniques, a further understanding of paclitaxel biosynthesis has been gained, though knowledge into other aspects of paclitaxel global metabolism, such as regulation, transport, and degradation is lacking. Taxus spp. cell cultures are highly heterogeneous, displaying significant cell-cell variability in growth and paclitaxel accumulation. Information gathered on culture subpopulations as well as putative transcriptional bottlenecks in paclitaxel biosynthesis, coupled with successful transformation of Taxus spp. will allow for the targeted metabolic engineering of Taxus spp. or other model organisms for paclitaxel accumulation to ensure future supply of this important pharmaceutical. PMID:17691991

Vongpaseuth, Kham; Roberts, Susan C

2007-08-01

16

An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) versus conventional paclitaxel for metastatic breast cancer patients: the COSTANza study  

PubMed Central

Purpose Paclitaxel albumin (nab-paclitaxel) is a nanoparticle albumin-bound paclitaxel formulation aimed at increasing therapeutic index in metastatic breast cancer. When compared to conventional paclitaxel, nab-paclitaxel has a reported longer time to progression, higher response, lower incidence of neutropenia, no need for premedication, shorter time of administration, and in pretreated metastatic breast cancer patients, extended overall survival. This study investigates the cost-effectiveness of nab-paclitaxel versus conventional paclitaxel for pretreated metastatic breast cancer patients in Italy. Materials and methods A Markov model with progression-free, progressed, and dead states was developed to estimate costs, outcomes, and quality adjusted life years over 5 years from the Italian National Health Service viewpoint. Patients were assumed to receive nab-paclitaxel 260 mg/m2 three times weekly or conventional paclitaxel 175 mg/m2 three times weekly. Data on health care resource consumption was collected from a convenience sample of five Italian centers. Resources were valued at Euro (€) 2011. Published utility weights were applied to health states to estimate the impact of response, disease progression, and adverse events on quality adjusted life years. Three sensitivity analyses tested the robustness of the base case incremental cost-effectiveness ratio (ICER). Results and conclusion Compared to conventional paclitaxel, nab-paclitaxel gains an extra 0.165 quality adjusted life years (0.265 life years saved) and incurs additional costs of €2506 per patient treated. This translates to an ICER of €15,189 (95% confidence interval: €11,891–€28,415). One-way sensitivity analysis underscores that ICER for nab-paclitaxel remains stable despite varying taxanes cost. Threshold analysis shows that ICER for nab-paclitaxel exceeds €40,000 only if cost per mg of conventional paclitaxel is set to zero. Probabilistic sensitivity analysis highlights that nab-paclitaxel has a 0.99 probability to be cost-effective for a threshold value of €40,000 and is the optimal alternative from a threshold value of €16,316 onwards. Based on these findings, nab-paclitaxel can be considered highly cost-effective when compared to the acceptability range for ICER proposed by the Italian Health Economics Association (€25,000–€40,000). PMID:23610525

Lazzaro, Carlo; Bordonaro, Roberto; Cognetti, Francesco; Fabi, Alessandra; De Placido, Sabino; Arpino, Grazia; Marchetti, Paolo; Botticelli, Andrea; Pronzato, Paolo; Martelli, Elisa

2013-01-01

17

Estrogen receptor expression and sensitivity to paclitaxel in breast cancer.  

PubMed

A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERalpha and the effectiveness of adjuvant paclitaxel reflects the observation that ERalpha positive (ERalpha+) breast cancers proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell line. For the T47D and ZR-75 cell lines, loss of ERalpha was associated with a decrease in doubling time and an increase in paclitaxel sensitivity. However, when cell culture conditions were altered to achieve equivalent cell proliferation rates, no difference in paclitaxel sensitivity was observed. Similarly, an ERalpha- clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERalpha+ counterpart also did not show increased paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these in vitro models, the effectiveness of paclitaxel correlated more closely with growth rate than ERalpha expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERalpha analysis. PMID:15020841

Dougherty, Michele K; Schumaker, Lisa M; Jordan, V Craig; Welshons, Wade V; Curran, Edward M; Ellis, Matthew J; El-Ashry, Dorraya

2004-05-01

18

Peripheral neuropathy induced by paclitaxel: recent insights and future perspectives.  

PubMed

Paclitaxel is an antineoplastic agent derived from the bark of the western yew, Taxus brevifolia, with a broad spectrum of activity. Because paclitaxel promotes microtubule assembly, neurotoxicity is one of its side effects. Clinical use of paclitaxel has led to peripheral neuropathy and this has been demonstrated to be dependent upon the dose administered, the duration of the infusion, and the schedule of administration. Vehicles in the drug formulation, for example Cremophor in Taxol, have been investigated for their potential to induce peripheral neuropathy. A variety of neuroprotective agents have been tested in animal and clinical studies to prevent paclitaxel neurotoxicity. Recently, novel paclitaxel formulations have been developed to minimize toxicities. This review focuses on recent advances in the etiology of paclitaxel-mediated peripheral neurotoxicity, and discusses current and ongoing strategies for amelioration of this side effect. PMID:18615126

Scripture, Charity D; Figg, William D; Sparreboom, Alex

2006-04-01

19

Current status of paclitaxel in the treatment of breast cancer  

Microsoft Academic Search

Paclitaxel is a highly active single agent as therapy for previously untreated as well as doxorubicin-refractory metastatic breast cancer, with associated response rates of 62% and 20–48%, respectively. Complete responses with paclitaxel occur chiefly in breast cancer patients whose metastatic disease has not been previously treated with chemotherapy. Early data suggest a possible dose-response relationship for paclitaxel in metastatic breast

Joyce A. O'Shaughnessy; Kenneth H. Cowan

1995-01-01

20

Possible Side Effects of Cisplatin, 5-Fluorouracil, and Paclitaxel  

Cancer.gov

Page of 1Possible Side Effects of Cisplatin, 5-Fluorouracil, and Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving Cisplatin, 5-Fluorouracil, and Paclitaxel, more than 20 and up to 100 may have: Diarrhea,

21

Possible Side Effects of 5-Fluorouracil, Oxaliplatin, Paclitaxel  

Cancer.gov

Page of 2Possible Side Effects of 5-Fluorouracil, Oxaliplatin, Paclitaxel (Table Version Date: October 8, 2013) COMMON, SOME MAY BE SERIOUS In 100 people receiving 5-Fluorouracil, Oxaliplatin, Paclitaxel, more than 20 and up to 100 may have: Hair loss Redness,

22

Paclitaxel and concurrent radiation in upper gastrointestinal cancers.  

PubMed

Effective locoregional treatments are needed for adenocarcinomas of the esophagus, stomach, and pancreas. Paclitaxel has been investigated as a radiation sensitizer for upper gastrointestinal malignancies. In esophageal cancer, the combination of low-dose weekly paclitaxel, platinum, and concurrent radiation therapy (RT) has substantial activity and is well tolerated. Regimens that add fluorouracil (5-FU) to paclitaxel and platinum or incorporate hyperfractionation radiation have a higher incidence of severe esophagitis. In gastric cancer, adjuvant concurrent paclitaxel, 5-FU, and radiation is being investigated in the cooperative group setting. In pancreatic cancer, paclitaxel may be a radiation sensitizer even to tumor cells that are resistant to paclitaxel as a single agent. The Radiation Therapy Oncology Group (RTOG) demonstrated a 43% 1-year survival with paclitaxel/RT for patients with locally advanced pancreatic cancer. This represented a 40% improvement in survival compared to the previous RTOG 92-09 study of 5-FU-based chemoradiation. Ongoing trials in pancreatic cancer are investigating the addition of gemcitabine to paclitaxel and radiation and incorporating molecular targeting agents. PMID:14735693

Constantinou, Maria; Tsai, James Y; Safran, Howard

2003-01-01

23

A Randomized Clinical Trial of Cisplatin\\/Paclitaxel Versus Carboplatin\\/Paclitaxel as First-Line Treatment of Ovarian Cancer  

Microsoft Academic Search

Background: Despite considerable improvement in the treat- ment of advanced ovarian cancer, the optimization of effi- cacy and tolerability remains an important issue. Therefore, we performed a randomized, phase III non-inferiority trial comparing paclitaxel plus cisplatin (PT) with paclitaxel plus carboplatin (TC) in patients with advanced ovarian cancer. Methods: A total of 798 patients with International Federa- tion of Gynecology

Hans-Joachim Luck; Werner Meier; Hans-Peter Adams; Volker Mobus; Serban Costa; Thomas Bauknecht; Barbara Richter; Matthias Warm; Willibald Schroder; Sigrid Olbricht; Ulrike Nitz; Christian Jackisch; Gunther Emons; Uwe Wagner; Walther Kuhn; Jacobus Pfisterer

2003-01-01

24

Development of paclitaxel-TyroSpheres for topical skin treatment  

PubMed Central

A potential topical psoriasis therapy has been developed consisting of tyrosine-derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4,000 times greater than PBS) by effective encapsulation and enable sustained, dose-controlled release over 72 hours under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations >100 ng/cm2 of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC50 of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape. PMID:22732474

Kilfoyle, Brian E.; Sheihet, Larisa; Zhang, Zheng; Laohoo, Marissa; Kohn, Joachim; Michniak-Kohn, Bozena B.

2012-01-01

25

Combination paclitaxel (Taxol) and doxorubicin therapy for metastatic breast cancer.  

PubMed

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a very active agent for the treatment of breast cancer, with associated complete response rates of 12% in patients with minimally pretreated metastatic disease. Simultaneous paclitaxel and doxorubicin administration by 72-hour continuous infusion in patients with previously untreated metastatic breast cancer has yielded an overall response rate of 72% with 8% complete responses. No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination. Two phase I studies from the M.D. Anderson Cancer Center (Houston, TX) and the University of Indiana (Indianapolis, IN) have shown that administration of a 24-hour paclitaxel infusion prior to doxorubicin results in a significantly higher incidence of mucositis than the reverse sequence. Preliminary pharmacokinetic studies from M.D. Anderson suggest that peak plasma concentration and clearance of doxorubicin are altered by pretreatment with 24-hour paclitaxel. In contrast, in an ongoing phase I study at the Istituto Nazionale Tumori in Milan, Italy, no differences in toxicities have been observed with the combination of intravenous bolus doxorubicin and 3-hour infusional paclitaxel administered by either sequence. Preclinical in vitro and in vivo studies suggest that the combination of paclitaxel and doxorubicin is associated with no or minimal additive antitumor effects. The modest complete response rates that have been observed in patients with metastatic breast cancer to date are in agreement with these observations. A randomized study of paclitaxel versus doxorubicin versus intravenous bolus doxorubicin followed by 24-hour paclitaxel is now being conducted by the Eastern Cooperative Oncology Group. PMID:7939757

O'Shaughnessy, J A; Fisherman, J S; Cowan, K H

1994-10-01

26

Clinical trials and progress with paclitaxel in ovarian cancer.  

PubMed

Paclitaxel is a front-line agent for ovarian cancer chemotherapy, along with the platinum agents. Derived from the Pacific yew tree, Taxus brevifolia, paclitaxel has covered significant ground from the initial discovery of its antineoplastic properties to clinical applications in many forms of human cancers, including ovarian cancer. Although much has been published about the unique mechanism of action of this agent, several issues remain to be resolved. Finding the appropriate dosage schedule for paclitaxel in chemo-naïve and recurrent ovarian cancer, defining the role of paclitaxel in maintenance chemotherapy, and elucidating the mechanisms of taxane resistance are areas of intense research. Newer forms of taxanes are being manufactured to avoid troublesome adverse effects and to improve clinical efficacy. These issues are reviewed in detail in this paper with an emphasis on clinically relevant evidence-based information. PMID:21270965

Kumar, Sanjeev; Mahdi, Haider; Bryant, Christopher; Shah, Jay P; Garg, Gunjal; Munkarah, Adnan

2010-01-01

27

Weekly paclitaxel infusion as salvage therapy in ovarian cancer.  

PubMed

The majority of women diagnosed with epithelial ovarian cancer will have persistent or recurrent disease after initial treatment. We evaluated response and toxicity in women with advanced stage disease given salvage paclitaxel as a low-dose, weekly infusion. We performed a retrospective review of 22 women with advanced stage epithelial ovarian (19 women) or primary peritoneal carcinoma (3 women) who had received low-dose, weekly paclitaxel salvage therapy. All women had refractory, persistent, or recurrent disease following first-line treatment with paclitaxel and platin chemotherapy. Response and toxicity were assessed. Measurable disease present on physical or radiologic exam and serum carbohydrate antigen-125 levels were used to assess disease response. Overall response rate to low-dose, weekly paclitaxel salvage therapy was 50% (27% complete, 23% partial). Median progression-free interval (PFI) in responders was 27 weeks (range, 14-68 weeks). Stabilization of disease occurred in an additional 27% of patients with a median PFI of 22 weeks (range, 15-89 weeks). No difference in response was detected between the 7 women with platin-sensitive disease and the 15 women with platin-resistant disease (P = 0.19). The median dose of paclitaxel was 80 mg/m2 (range, 60-80 mg/m2). During a total of 325 weeks of paclitaxel treatment (median per patient, 12 weeks; range, 6-49 weeks), 13 treatment delays occurred (hematologic indication, 9; nonhematologic indication, 4). No cases of grade 4 hematologic toxicity, sepsis, or worsening neuropathy were documented. Weekly paclitaxel infusion given as salvage therapy results in significant clinical response, even in women previously treated with paclitaxel. The regimen is well tolerated with no cases of grade 4 neutropenia or worsening neuropathy in our population. PMID:14628424

Boruta, David M; Fowler, Wesley C; Gehrig, Paola A; Boggess, John F; Walton, Leslie A; Van Le, Linda

2003-01-01

28

Paclitaxel Induces Apoptosis in AIDS-Related Kaposi's Sarcoma Cells  

PubMed Central

Paclitaxel is a microtubule stabilizing drug that causes dividing cells to arrest and then undergo apoptosis. It also has antiangiogenic activity because it alters cytoskeletal structure, affecting migration and invasion. Paclitaxel is an effective treatment for AIDS-related Kaposi’s sarcoma (KS). KS is a tumor in which there is marked proliferation of endothelial cells in addition to the tumor cells, which themselves share many markers with activated (proliferating) endothelial cells.We sought to determine the mechanism by which paclitaxel exerts its anti-KS tumor effects. In vitro, KS cells are very sensitive to paclitaxel, with half-maximal growth inhibition observed at 0.8 nM. Inhibition of migration of KS cells was also observed at nanomolar concentrations of the drug. Paclitaxel induced cell cycle arrest with an accumulation of cells in sub-G1.This was accompanied in vitro by various events typical of apoptosis: phosphorylation of two anti-apoptotic proteins Bcl-2 and Bcl-xL , release of cytochrome c into the cytoplasm, cleavage and activation of caspase-3. In vitro results were borne out by studies of KS tumor xenografts in nude mice. Paclitaxel (10 mg/kg) inhibited tumor growth by 75% over 21 days. Histological examination of the tumors revealed a decrease in proliferative index, a decrease in the number of mitotic figures and an increase in apoptotic cells compared to tumors from untreated mice. PMID:18521433

Cai, Jie; Zheng, Tong; Masood, Rizwan; Smith, D. Lynne; Hinton, David R.; Kim, Caryn Nae; Fang, Guofu; Bhalla, Kapil

2000-01-01

29

Modulation of human mammary cell sensitivity to paclitaxel by new quinoline sulfonamides.  

PubMed

Sulfonamide derivatives of chloroquine and primaquine were synthesised and evaluated against both paclitaxel-sensitive and paclitaxel-resistant mammarian cancer cell lines. All derivatives exhibited at least 96% MDR reversal activity when co-administered with paclitaxel at 5 microM. The best compound, a chloroquine derivative, exhibited 99% MDR reversal activity when co-administered with paclitaxel at 1 microM. Molecular modelling studies reveal that these derivatives share a common pharmacophore with taxane MDR reversal agents. PMID:11549446

Chibale, K; Ojima, I; Haupt, H; Geng, X; Pera, P; Bernacki, R J

2001-09-17

30

Paclitaxel nanoparticle inhibits growth of ovarian cancer xenografts and enhances lymphatic targeting  

Microsoft Academic Search

Objectives: Ovarian cancer has the highest mortality of all the gynecologic cancers. The antitumor agent paclitaxel has been proved to be efficient in the treatment of ovarian cancer. Our study is to develop a polymeric drug delivery system for paclitaxel and determine whether paclitaxel nanoparticle can inhibit growth of ovarian carcinoma xenografts in Fisher344 (F344) rats by intraperitoneal administration. The

Hongxia Lu; Bin Li; Yu Kang; Wei Jiang; Qian Huang; Qinghua Chen; Limin Li; Congjian Xu

2007-01-01

31

RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells  

Microsoft Academic Search

ABSTRACT: INTRODUCTION: Paclitaxel is a widely used drug in the treatment of patients with locally advanced and metastatic breast cancer. However, only a small portion of patients have a complete response to paclitaxel-based chemotherapy, and many patients are resistant. Strategies that increase sensitivity and limit resistance to paclitaxel would be of clinical use, especially for patients with triple-negative breast cancer

Joshua A Bauer; Fei Ye; Clayton B Marshall; Brian D Lehmann; Christopher S Pendleton; Yu Shyr; Carlos L Arteaga; Jennifer A Pietenpol

2010-01-01

32

Genome sequencing and analysis of the paclitaxel-producing endophytic fungus Penicillium aurantiogriseum NRRL 62431  

PubMed Central

Background Paclitaxel (Taxol™) is an important anticancer drug with a unique mode of action. The biosynthesis of paclitaxel had been considered restricted to the Taxus species until it was discovered in Taxomyces andreanae, an endophytic fungus of T. brevifolia. Subsequently, paclitaxel was found in hazel (Corylus avellana L.) and in several other endophytic fungi. The distribution of paclitaxel in plants and endophytic fungi and the reported sequence homology of key genes in paclitaxel biosynthesis between plant and fungi species raises the question about whether the origin of this pathway in these two physically associated groups could have been facilitated by horizontal gene transfer. Results The ability of the endophytic fungus of hazel Penicillium aurantiogriseum NRRL 62431 to independently synthesize paclitaxel was established by liquid chromatography-mass spectrometry and proton nuclear magnetic resonance. The genome of Penicillium aurantiogriseum NRRL 62431 was sequenced and gene candidates that may be involved in paclitaxel biosynthesis were identified by comparison with the 13 known paclitaxel biosynthetic genes in Taxus. We found that paclitaxel biosynthetic gene candidates in P. aurantiogriseum NRRL 62431 have evolved independently and that horizontal gene transfer between this endophytic fungus and its plant host is unlikely. Conclusions Our findings shed new light on how paclitaxel-producing endophytic fungi synthesize paclitaxel, and will facilitate metabolic engineering for the industrial production of paclitaxel from fungi. PMID:24460898

2014-01-01

33

Enabling Anticancer Therapeutics by Nanoparticle Carriers: The Delivery of Paclitaxel  

PubMed Central

Anticancer drugs, such as paclitaxel (PTX), are indispensable for the treatment of a variety of malignancies. However, the application of most drugs is greatly limited by the low water solubility, poor permeability, or high efflux from cells. Nanoparticles have been widely investigated to enable drug delivery due to their low toxicity, sustained drug release, molecular targeting, and additional therapeutic and imaging functions. This review takes paclitaxel as an example and compares different nanoparticle-based delivery systems for their effectiveness in cancer chemotherapy. PMID:21845085

Liu, Yongjin; Zhang, Bin; Yan, Bing

2011-01-01

34

Preclinical evaluation of nanoparticle albumin-bound paclitaxel for treatment of pediatric bone sarcoma.  

PubMed

The combination of docetaxel and gemcitabine is frequently used to treat recurrent bone sarcoma. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is less toxic and more active than docetaxel or paclitaxel for breast cancer patients. The combination of nab-paclitaxel and gemcitabine has preclinical synergy and is approved to treat pancreatic cancer. We observed growth inhibition and improved survival with nab-paclitaxel in a Ewing sarcoma xenograft, and activity was additive with gemcitabine in an osteosarcoma model. Primary Ewing sarcoma tumors expressed the transport protein SPARC, previously associated with nab-paclitaxel activity. These findings provide rationale for further evaluation of nab-paclitaxel with gemcitabine for bone sarcoma. Pediatr Blood Cancer 2014;61:2096-2098. © 2014 Wiley Periodicals, Inc. PMID:24753077

Wagner, Lars M; Yin, Hong; Eaves, David; Currier, Mark; Cripe, Timothy P

2014-11-01

35

Improving the antitumor activity of squalenoyl-paclitaxel conjugate nanoassemblies by manipulating the linker between paclitaxel and squalene.  

PubMed

A series of new lipid prodrugs of paclitaxel, which can be formulated as nanoassemblies, are described. These prodrugs which are designed to overcome the limitations due to the systemic toxicity and low water solubility of paclitaxel consist of a squalene chain bound to the 2'-OH of paclitaxel through a 1,4-cis,cis-dienic linker. This design allows the squalene-conjugates to self-assemble as nanoparticular systems while preserving an efficient release of the free drug, thanks to the dienic spacer. The size, steric hindrance, and functional groups of the spacer have been modulated. All these prodrugs self-assemble into nanosized aggregates in aqueous solution as characterized by dynamic light scattering and transmission electron microscopy and appear stable in water for several days as determined by particle size measurement. In vitro biological assessment shows that these squalenoyl-paclitaxel nanoparticles display notable cytotoxicity on several tumor cell lines including A549 lung cell line, colon cell line HT-29, or KB 3.1 nasopharyngeal epidermoid cell line. The cis,cis-squalenyl-deca-5,8-dienoate prodrug show improved activity over simple 2'-squalenoyl-paclitaxel prodrug highlighting the favourable effect of the dienic linker. The antitumor efficacy of the nanoassemblies constructed with the more active prodrugs has been investigated on human lung (A549) carcinoma xenograft model in mice. The prodrug bearing the cis,cis-deca-5,8-dienoyl linker shows comparable antitumor efficacy to the parent drug, but reveals a much lower subacute toxicity as seen in body weight loss. Thus, nanoparticles with the incorporated squalenoyl paclitaxel prodrug may prove useful for replacement of the toxic Cremophor EL. PMID:23213041

Caron, Joachim; Maksimenko, Andrei; Wack, Séverine; Lepeltier, Elise; Bourgaux, Claudie; Morvan, Estelle; Leblanc, Karine; Couvreur, Patrick; Desmaële, Didier

2013-01-01

36

A MATHEMATICAL MODEL FOR THE TRANSPORT OF PACLITAXEL (TAXOL)  

E-print Network

the central nervous system by the blood-brain barrier is a major obstacle for paclitaxel-based treat- ment from entering the central nervous system (CNS) from blood via the wall of brain capillaries. The wall, however, the human brain became a volitional target of xenobiotics. Today, drugs against brain diseases

37

Testing Dose-Dense Paclitaxel for Ovarian and Related Cancers  

Cancer.gov

In this trial, women with stage III or IV ovarian epithelial, fallopian tube, or primary peritoneal cancer will be randomly assigned to receive either standard or dose-dense paclitaxel in addition to standard carboplatin (given once every 3 weeks) and optional bevacizumab.

38

BAD partly reverses paclitaxel resistance in human ovarian cancer cells  

Microsoft Academic Search

Although paclitaxel is an important chemotherapy agent for the treatment of patients with epithelial ovarian cancer, its utility is significantly limited by the frequent development of drug resistance. Recent evidence suggests that resistance to chemotherapy may be partly related to defects in the apoptotic pathway. In this study we have investigated whether enhancement of apoptotic pathway function through stable expression

Thomas Strobel; Yu-Tzu Tai; Stanley Korsmeyer; Stephen A Cannistra

1998-01-01

39

Kinetics of P-glycoprotein-mediated efflux of paclitaxel.  

PubMed

Paclitaxel is a substrate of the mdr1 P-glycoprotein (Pgp). The objective of the present study was to determine the kinetics of the Pgp-mediated efflux and its contribution to the overall efflux of paclitaxel at the clinically achievable concentration range of 1 to 1500 nM. Human breast carcinoma BC19 cells that were derived from MCF7 cells by mdr1 transfection and show a >10-fold higher level of the Pgp protein were used to measure the uptake and efflux of [(3)H]paclitaxel. A computational model of intracellular paclitaxel pharmacokinetics was developed to analyze for the Pgp efflux parameters. The results show a saturable Pgp-mediated efflux in BC19 cells; the dissociation constant was 14 nM, and the maximal efflux rate was 2.8 x 10(-4) pmol/h/cell. The contribution of Pgp-mediated efflux to the total efflux decreased with increasing extracellular drug concentrations; the Pgp efflux accounted for 86 and 34% of total efflux at 1 and 1500 nM, respectively. The validity of the model was confirmed by the close agreement between the model-predicted data and the experimentally obtained data (approximately 6% deviation) describing the effect of cell density and intracellular-to-extracellular concentration gradient on the kinetics of drug accumulation and efflux. In conclusion, our results indicate that the Pgp-mediated efflux represents a major efflux mechanism of paclitaxel at the low end of the clinically observed drug concentration range, but accounts for only a minor part of the efflux at higher concentrations in BC19 cells. PMID:11504826

Jang, S H; Wientjes, M G; Au, J L

2001-09-01

40

Human cancer cell line microRNAs associated with in vitro sensitivity to paclitaxel  

PubMed Central

Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI50) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson’s correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC50, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (?0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC50, 17.8 nM, low miR-367 (?0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics. PMID:24220856

CHEN, NING; CHON, HYE SOOK; XIONG, YIN; MARCHION, DOUGLAS C.; JUDSON, PATRICIA L.; HAKAM, ARDESHIR; GONZALEZ-BOSQUET, JESUS; PERMUTH-WEY, JENNIFER; WENHAM, ROBERT M.; APTE, SACHIN M.; CHENG, JIN Q.; SELLERS, THOMAS A.; LANCASTER, JOHNATHAN M.

2014-01-01

41

Amphiphilic dextran-graft-poly(epsilon-caprolactone) films for the controlled release of paclitaxel.  

PubMed

Amphiphilic graft copolymers with dextrans as the main chains and poly(epsilon-caprolactone) as the side chains were synthesized by solution polymerization in dimethyl sulfoxide using stannous 2-ethylhexanoate as a catalyst. The copolymers were characterized with nuclear magnetic resonance spectroscopy and gel permeation chromatography. Paclitaxel loaded copolymer films were prepared using a solution cast method. In vitro release rates were influenced by both the initial paclitaxel loading and the morphology of the films. The films with paclitaxel loadings up to 10% (w/w) showed a single-phase morphology when dry. However, paclitaxel crystallization occurred in the films with high loadings (5 and 10%) upon incubation in phosphate buffered saline at 37 degrees C. The crystals had a spherulitic structure and were found to be paclitaxel dihydrate based on X-ray diffraction analysis. The formation of paclitaxel dihydrate in the films produced a marked effect on the in vitro release rates. PMID:15129983

Shi, Ruiwen; Burt, Helen M

2004-03-01

42

Paclitaxel loaded nanosponges: in-vitro characterization and cytotoxicity study on MCF-7 cell line culture.  

PubMed

Beta cyclodextrin (?-CD) based nanosponges were synthesized and paclitaxel inclusion complex with nanosponges were prepared using techniques of inclusion complex formation. The paclitaxel nanosponge's complexes were evaluated for their release. The nanosponges complexes were also evaluated using DSC, FTIR, and NMR techniques for confirmation of inclusion complex formation between paclitaxel and nanosponges. Particle size and morphology of paclitaxel nanosponge's complex were estimated using SEM, TEM and dynamic light scattering techniques. The particle sizes were found out to be in range of 400 to 600 nm. Cytotoxic efficacy of paclitaxel nanosponge complex was determined against MCF-7 cells and paclitaxel nanosponge's complex was found to be cytotoxic and more effective against this cell line. PMID:21235471

Ansari, Khalid A; Torne, Satyen J; Vavia, Pradeep R; Trotta, Francesco; Cavalli, Roberta

2011-03-01

43

Increased elimination of paclitaxel by magnesium isoglycyrrhizinate in epithelial ovarian cancer patients treated with paclitaxel plus cisplatin: a pilot clinical study.  

PubMed

Magnesium isoglycyrrhizinate (MI) has been complementarily used for restoring the hepatic impairments caused by taxol plus platinum based chemotherapies in China. Due to the hepatic dependence of paclitaxel elimination, this pilot clinical study aimed to investigate the influence of MI on the pharmacokinetics of paclitaxel in epithelial ovarian cancer patients. During the standard chemotherapy of intravenous paclitaxel (125 mg/m(2) infused over a 3-h period) and intraperitoneal cisplatin (60 mg/m(2)) for patients with FIGO stage II epithelial ovarian cancer, 9 each of total 18 patients were respectively treated with intravenous MI (100 mg) or vehicle control for 4 days. Plasma paclitaxel was analyzed by HPLC and the pharmacokinetic parameters were calculated with non-compartmental analysis. The hematological, hepatic and renal status was monitored before and 3 days after paclitaxel administration. It was observed the terminal t 1/2 and MRT of paclitaxel were significantly (p = 0.002 and 0.001) reduced by MI, respectively, from 11.0 ± 2.2 and 5.6 ± 1.0 h to 7.7 ± 1.7 and 4.0 ± 0.3 h. Hematological toxicity indicated by platelet count and hepatic events marked with ALT, AST and ?-GT were significant in both groups. In spite of the insignificance of decreased system exposure of paclitaxel and recovered hepatic function by MI, they did correlate with each other. It was therefore deduced that the liver toxicities of paclitaxel plus cisplatin chemotherapy potentially decrease hepatic elimination and increase system exposure of paclitaxel, and the recovery of liver function by MI helps to restore hepatic clearance of paclitaxel. The clinical significance of this pharmacokinetic interaction requires further studies with larger population size. PMID:23681836

Chen, Kai Jie; Chen, Wan Yi; Chen, Xia; Jia, Yi Ming; Peng, Gui Qin; Chen, Li

2014-03-01

44

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery  

PubMed Central

Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)0–? (20.343 ± 9.119 ?g · h · mL?1 vs 5.196 ± 1.426 ?g · h · mL?1), greater clearance (2.050 ± 0.616 L · kg?1 · h?1 vs 0.556 ± 0.190 L · kg?1 · h?1), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC0–? in liver, lung, and spleen (all P < 0.01), but not in heart or kidney. PMID:21796250

Wang, Yonglu; Li, Xueming; Wang, Liyao; Xu, Yuanlong; Cheng, Xiaodan; Wei, Ping

2011-01-01

45

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery.  

PubMed

Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)(0-?) (20.343 ± 9.119 ?g · h · mL(-1) vs 5.196 ± 1.426 ?g · h · mL(-1)), greater clearance (2.050 ± 0.616 L · kg(-1) · h(-1) vs 0.556 ± 0.190 L · kg(-1) · h(-1)), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC(0-?) in liver, lung, and spleen (all P < 0.01), but not in heart or kidney. PMID:21796250

Wang, Yonglu; Li, Xueming; Wang, Liyao; Xu, Yuanlong; Cheng, Xiaodan; Wei, Ping

2011-01-01

46

Combined Delivery of Paclitaxel and Tanespimycin via Micellar Nanocarriers: Pharmacokinetics, Efficacy and Metabolomic Analysis  

PubMed Central

Background Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo. Methodology/Principal Findings Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles. Conclusions/Significance We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy. PMID:23505544

Wang, Yingzhe; Teng, Quincy; Tan, Chalet

2013-01-01

47

Paclitaxel stimulates chromosomal fusion and instability in cells with dysfunctional telomeres: Implication in multinucleation and chemosensitization  

SciTech Connect

Research highlights: {yields} Paclitaxel serves as a stimulator of chromosomal fusion in cells in which telomeres are dysfunctional. {yields} Typical fusions involve p-arms, but paclitaxel-induced fusions occur between both q- and p-arms. {yields} Paclitaxel-stimulated fusions in cells in which telomeres are dysfunctional evoke prolonged G2/M cell cycle arrest and delay multinucleation. {yields} Upon telomere erosion, paclitaxel promotes chromosomal instability and subsequent apoptosis. {yields} Chromosomal fusion enhances paclitaxel chemosensitivity under telomere dysfunction. -- Abstract: The anticancer effect of paclitaxel is attributable principally to irreversible promotion of microtubule stabilization and is hampered upon development of chemoresistance by tumor cells. Telomere shortening, and eventual telomere erosion, evoke chromosomal instability, resulting in particular cellular responses. Using telomerase-deficient cells derived from mTREC-/-p53-/- mice, here we show that, upon telomere erosion, paclitaxel propagates chromosomal instability by stimulating chromosomal end-to-end fusions and delaying the development of multinucleation. The end-to-end fusions involve both the p- and q-arms in cells in which telomeres are dysfunctional. Paclitaxel-induced chromosomal fusions were accompanied by prolonged G2/M cell cycle arrest, delayed multinucleation, and apoptosis. Telomere dysfunctional cells with mutlinucleation eventually underwent apoptosis. Thus, as telomere erosion proceeds, paclitaxel stimulates chromosomal fusion and instability, and both apoptosis and chemosensitization eventually develop.

Park, Jeong-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Woo, Seon Rang [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of) [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kang, Chang-Mo [Laboratory of Cytogenetics and Tissue Regeneration, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Laboratory of Cytogenetics and Tissue Regeneration, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Juhn, Kyoung-Mi; Ju, Yeun-Jin; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun Ran; Park, In-chul; Hong, Sung Hee; Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Lee, Jung-Kee [Department of Life Science and Genetic Engineering, Paichai University, Daejeon 302-735 (Korea, Republic of)] [Department of Life Science and Genetic Engineering, Paichai University, Daejeon 302-735 (Korea, Republic of); Kim, Hae Kwon [Department of Biotechnology, Seoul Woman's University, Seoul 139-774 (Korea, Republic of)] [Department of Biotechnology, Seoul Woman's University, Seoul 139-774 (Korea, Republic of); Cho, Myung-Haing [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-74-2 (Korea, Republic of)] [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-74-2 (Korea, Republic of); Park, Gil Hong [Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of)] [Department of Biochemistry, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Lee, Kee-Ho, E-mail: khlee@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

2011-01-14

48

Human liver microsomal metabolism of paclitaxel and drug interactions  

Microsoft Academic Search

Summary  The aim of this study was to investigate the influence of several anticancer drugs and investigational multidrug resistance\\u000a (MDR) reversing agents on the hepatic metabolism of paclitaxel (Taxol) to its primary metabolites, 6 ?-hydroxypaclitaxel (metabolite,\\u000a MA) and 3?-p-hydroxypaclitaxel (metabolite, MB). There is significant inter-individual variability associated with the levels of these two metabolites. In many cases, 6?-hydroxypaclitaxel\\u000a has been observed

P. B. Desai; J. Z. Duan; Y. W. Zhu; S. Kouzi

1998-01-01

49

Supporting information for: Paclitaxel-Conjugated PAMAM Dendrimers Adversely  

E-print Network

OH:CH2Cl2) to yield the N-Boc protected cystamine-5 succinic acid (2) as a white solid (1.64 g, 21 %). Rf of paclitaxel (200 mg, 0.234 mmol) and the N-Boc protected cystamine-9 succinic acid (2; 87 mg, 0.246 mmol H (2) (Boc)2O, 12 h RT 1 2 34 PX, EDC/ DMF, 48 h RT TFA, CH2Cl2 20 min RT (1) Succinic anhydride Na

Walter, Nils G.

50

Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer  

PubMed Central

Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel, a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. For pancreatic ductal adenocarcinoma cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, gemcitabine IC50 ranged from 494nM to 23.9 ?M; docetaxel IC50 range was from 5 to 34nM; nab-paclitaxel IC50 range was from 243nM to 4.9 ?M. Addition of IC25 dose of docetaxel or nab-paclitaxel decreased gemcitabine IC50. Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67, 31 and 72%, which corresponded with intratumoral proliferative and apoptotic indices. Tumor stromal density was decreased by nab-paclitaxel and to a lesser extent by docetaxel as measured through reduction in ?-smooth muscle actin, S100A4 and collagen 1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, P < 0.002) compared with gemcitabine (32 days, P = 0.005), docetaxel (32 days, P = 0.005) and controls (20 days). Survival in nab-paclitaxel/gemcitabine and docetaxel/gemcitabine sequential treatment groups was not superior to nab-paclitaxel alone. Low-dose combination of gemcitabine with nab-paclitaxel or docetaxel was more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of gemcitabine+nab-paclitaxel or gemcitabine+docetaxel increased gemcitabine concentration in plasma and tumor. The superior antitumor activity of nab-paclitaxel provides a strong rationale for considering nab-paclitaxel as first-line monotherapy in pancreatic ductal adenocarcinoma. PMID:23803690

Schwarz, Roderich E.

2013-01-01

51

Chemical inhibitors suggest endophytic fungal paclitaxel is derived from both mevalonate and non-mevalonate-like pathways.  

PubMed

Taxus trees possess fungal endophytes reported to produce paclitaxel. Inhibitors that block early steps in plant paclitaxel biosynthesis were applied to a paclitaxel-producing fungus to determine whether these steps are shared. The plant paclitaxel backbone is reportedly derived from the non-mevalonate terpenoid pathway, while the side chain is phenylalanine-derived. Evidence that the shikimate pathway contributes to fungal paclitaxel was shown by decreased paclitaxel accumulation following inhibition of phenylalanine ammonia lyase. Expression of another shikimate pathway enzyme, 3-dehydroquinate synthase, coincided with paclitaxel production. The importance of the mevalonate pathway in fungal paclitaxel biosynthesis was shown by inhibition of fungal paclitaxel accumulation using compactin, a specific inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase. Expression of another mevalonate pathway enzyme, 3-hydroxy-3-methyl-glutaryl-CoA synthase, coincided with fungal paclitaxel accumulation. Unexpectedly, results from using fosmidomycin suggested that fungal paclitaxel requires 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an enzyme in the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway normally found in bacteria/plants. Additional lines of evidence support this finding; first, a plant DXR antibody recognized a fungal peptide of the correct size; second, expression of an apparent fungal DXR ortholog correlated to changes in paclitaxel production; finally, BLAST searching identified a gene putatively encoding 1-deoxy-D-xylulose-5-phosphate synthase, the first enzyme in the MEP pathway in Aspergillus. PMID:22103292

Soliman, Sameh S M; Tsao, Rong; Raizada, Manish N

2011-12-27

52

Paclitaxel Induces Apoptosis in Breast Cancer Cells through Different Calcium—Regulating Mechanisms Depending on External Calcium Conditions  

PubMed Central

Previously, we reported that endoplasmic reticulum calcium stores were a direct target for paclitaxel initiation of apoptosis. Furthermore, the actions of paclitaxel attenuated Bcl-2 resistance to apoptosis through endoplasmic reticulum-mediated calcium release. To better understand the calcium-regulated mechanisms of paclitaxel-induced apoptosis in breast cancer cells, we investigated the role of extracellular calcium, specifically; whether influx of extracellular calcium contributed to and/or was necessary for paclitaxel-induced apoptosis. Our results demonstrated that paclitaxel induced extracellular calcium influx. This mobilization of extracellular calcium contributed to subsequent cytosolic calcium elevation differently, depending on dosage. Under normal extracellular calcium conditions, high dose paclitaxel induced apoptosis-promoting calcium influx, which did not occur in calcium-free conditions. In the absence of extracellular calcium an “Enhanced Calcium Efflux” mechanism in which high dose paclitaxel stimulated calcium efflux immediately, leading to dramatic cytosolic calcium decrease, was observed. In the absence of extracellular calcium, high dose paclitaxel’s stimulatory effects on capacitative calcium entry and apoptosis could not be completely restored. Thus, normal extracellular calcium concentrations are critical for high dose paclitaxel-induced apoptosis. In contrast, low dose paclitaxel mirrored controls, indicating that it occurs independent of extracellular calcium. Thus, extracellular calcium conditions only affect efficacy of high dose paclitaxel-induced apoptosis. PMID:24549172

Pan, Zhi; Avila, Andrew; Gollahon, Lauren

2014-01-01

53

EFFICIENT EXTRACTION OF PACLITAXEL AND RELATED TAXOIDS FROM LEAF TISSUE OF TAXUS USING A POTABLE SOLVENT SYSTEM  

Microsoft Academic Search

Leaves of Taxus x media and Taxus brevifolia were examined for their potential use as a source of paclitaxel and related taxoids. Various solvent systems were compared for their efficacy in the extraction of paclitaxel, as well as the extraction of contaminating residue. A method of extraction has been developed that enriches paclitaxel by over 500-fold using only potable solvents

Raymond E. B. Ketchum; Judy V. Luong; Donna M. Gibson

1999-01-01

54

Determinants of paclitaxel uptake, accumulation and retention in solid tumors.  

PubMed

This report addresses the determinants of the rate and extent of paclitaxel accumulation in tumors. In a 2-dimensional system such as monolayers where the drug is directly in contact with tumor cells, drug accumulation is determined by the extracellular-to-intracellular concentration gradient, the drug binding to extracellular and intracellular macromolecules, the presence of the mdrl p-glycoprotein (Pgp). and the time-dependent and drug concentration-dependent changes in tubulins and cell density. Intracellular pharmacokinetic models were developed to depict the effects of these parameters. Computer simulation results indicate that at the clinically relevant concentration range of 1 to 1,000 nM, (a) the binding affinity and the number of intracellular saturable drug binding sites are important for drug accumulation at low and high extracellular concentrations, respectively, (b) saturation in the drug binding to the high affinity intracellular binding sites (e.g., tubulin/microtubule) occurs at extracellular drug concentration above 100 nM, (c) treatment with 1,000 nM paclitaxel for >4 hr results in increased levels of tubulin/microtubule and consequently increased intracellular drug accumulation, whereas the continued cell proliferation after treatment with low drug concentrations results in reduced intracellular accumulation, and (d) saturation of Pgp in mdr1-transfected cells occurs at the high end of the clinically relevant concentration range. In a 3-dimensional system such as the solid tumor histocultures, which contain tumor cells as well as stromal cells, the drug accumulation into the inner cell layers is determined by the unique properties of solid tumors, including tumor cell density and spatial arrangement of tumor and stromal tissues. Most interestingly, drug penetration is modulated by the drug-induced apoptosis; the reduced cell density due to apoptosis results in an enhancement of the rate of drug penetration into the inner cell layers of solid tumors. In conclusion, the uptake, accumulation, and retention of paclitaxel in solid tumors are determined by (a) factors that are independent of biological changes in tumor cells induced by paclitaxel, i.e., ratio of extracellular and intracellular concentrations, and drug binding to extracellular and intracellular macromolecules, and (b) factors that are dependent on the time- and drug concentration-dependent biological changes induced by paclitaxel, i.e., induction of apoptosis, enhancement of tubulin/microtubule production, and induction of Pgp expression. PMID:11392446

Jang, S H; Wientjes, M G; Au, J L

2001-05-01

55

Preparation and biological activity of a paclitaxel-single-walled carbon nanotube complex.  

PubMed

Single-walled carbon nanotubes (SWCNTs) have unique transmembrane abilities. The huge superficial area and abundance of ? electrons confer SWCNTs perfect absorptive capability toward proteins, nucleates, and many drugs. These characteristics make SWCNTs a new and efficient drug carrier. The purpose of this study was to disperse SWCNTs in water and have paclitaxel absorbed onto them in order to construct an asparagine-glycine-arginine (NGR)-SWCNT-Paclitaxel complex as a targeting nanoparticle system. The NGR-SWCNT-Paclitaxel complex was systematically studied, and analytical methods, including spectrophotometry for SWCNTs and high-performance liquid chromatography for paclitaxel, were employed. The preparation and the prescription of the NGR-SWCNT-Paclitaxel complex lyophilized powder were investigated. MCF-7 cancer cells, Sprague-Dawley rats, and S180 tumor-bearing mice were used as experimental subjects to evaluate the in vitro and in vivo activity of NGR-SWCNT-Paclitaxel complex dispersion. The complex dispersion showed obvious inhibition activity against MCF-7 cancer cells. Within 1 h, the NGR-SWCNT-Paclitaxel complex could be transferred to cells, and sustained the release of drugs. In addition, the tumor and liver targeting and improved therapeutic effects of the NGR-SWCNT-Paclitaxel complex were confirmed. PMID:24668633

Fu, X D; Zhang, Y Y; Wang, X J; Shou, J X; Zhang, Z Z; Song, L J

2014-01-01

56

Paclitaxel: A Pharmacoeconomic Review of its Use in the Treatment of Ovarian Cancer  

Microsoft Academic Search

Paclitaxel belongs to the group of antitumour agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomised phase III clinical trials. When used in combination with cisplatin for first-line treatment of advanced ovarian cancer, it is superior to cyclophosphamide\\/cisplatin, with gains in median survival of around 1 year. Paclitaxel plus carboplatin has similar efficacy

Melissa Young; Greg L. Plosker

2001-01-01

57

Pharmaceutical Nanotechnology Enhanced solubility and stability of PEGylated liposomal paclitaxel: In vitro and in vivo evaluation  

Microsoft Academic Search

An improved PEGylated liposomal formulation of paclitaxel has been developed with the purpose of improving the solubility of paclitaxel as well as the physicochemical stability of liposome in comparison to the current Taxol® formulation. The use of 3% (v\\/v) Tween 80 in the hydration media was able to increase the solubility of drug. The addition of sucrose as a lyoprotectant

Tao Yang; Fu-De Cui; Min-Koo Choi; Jei-Won Cho; Suk-Jae Chung; Chang-Koo Shim; Dae-Duk Kim

58

Combination of Nab-Paclitaxel and Gemcitabine Improves Survival in Patients with Metastatic Pancreatic Cancer  

Cancer.gov

In an international randomized phase III trial, patients with metastatic pancreatic cancer who were treated with a combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) lived longer than patients who were treated with gemcitabine alone. Patients who received both drugs also lived longer without their disease getting worse (progression-free survival).

59

Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes  

Microsoft Academic Search

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by the FDA for the treatment of ovarian and breast cancers. Due to its low solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side effects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to

Paola Crosasso; Maurizio Ceruti; Paola Brusa; Silvia Arpicco; Franco Dosio; Luigi Cattel

2000-01-01

60

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel  

Microsoft Academic Search

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used clinically for the treatment of ovarian and breast cancer. Due to its aqueous insolubility it is administered dissolved in ethanol and Cremophor EL (polyethoxylated castor oil), which has serious side effects. In order to eliminate this vehicle, in previous work we entrapped paclitaxel in conventional and in polyethylene glycol coated

Maurizio Ceruti; Paola Crosasso; Paola Brusa; Silvia Arpicco; Franco Dosio; Luigi Cattel

2000-01-01

61

The Extracellular Matrix Protein TGFBI Induces Microtubule Stabilization and Sensitizes Ovarian Cancers to Paclitaxel  

PubMed Central

Summary The extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability. PMID:18068629

Ahmed, Ahmed Ashour; Mills, Anthony D.; Ibrahim, Ashraf E.K.; Temple, Jillian; Blenkiron, Cherie; Vias, Maria; Massie, Charlie E.; Iyer, N. Gopalakrishna; McGeoch, Adam; Crawford, Robin; Nicke, Barbara; Downward, Julian; Swanton, Charles; Bell, Stephen D.; Earl, Helena M.; Laskey, Ronald A.; Caldas, Carlos; Brenton, James D.

2007-01-01

62

Hydrotropic Polymeric Micelles for Enhanced Paclitaxel Solubility: In Vitro and In Vivo Characterization  

PubMed Central

The purpose of this investigation was to characterize the in vitro stability and in vivo disposition of paclitaxel in rats after solubilization of paclitaxel into hydrotropic polymeric micelles. The amphiphilic block copolymers consisted of micellar a shell-forming poly(ethylene glycol) (PEG) block and a core-forming poly(2-(4-vinylbenzyloxy)-N,N-diethylnicotinamide) (P(VBODENA)) block. N,N-Diethylnicotinamide (DENA) in the micellar inner core resulted in effective paclitaxel solubilization and stabilization. Solubilization of paclitaxel using polymeric micelles of poly(ethylene glycol)-b-P(D,L-lactide) (PEG-b-PLA) served as a control for the stability study. Up to 37.4 wt% paclitaxel could be loaded in PEG-b-P(VBODENA) micelles, whereas the maximum loading amount for PEG-b-PLA micelles was 27.6 wt%. Thermal analysis showed that paclitaxel in the polymeric micelles existed in the molecularly dispersed amorphous state even at loadings over 30 wt%. Paclitaxel-loaded hydrotropic polymeric micelles retained their stability in water for weeks, whereas paclitaxel-loaded PEG-b-PLA micelles precipitated in a few days. Hydrotropic polymer micelles were more effective than PEG-PLA micelle formulations in inhibiting the proliferation of human cancer cells. Paclitaxel in hydrotropic polymer micelles was administered orally (3.8 mg/kg), intravenously (2.5 mg/kg) or via the portal vein (2.5 mg/kg) to rats. The oral bioavailability was 12.4% of the intravenous administration. Our data suggest that polymeric micelles with a hydrotropic structure are superior as a carrier of paclitaxel due to a high solubilizing capacity combined with long-term stability which has not been accomplished by other existing polymeric micelle systems. PMID:17206808

Lee, Sang Cheon; Huh, Kang Moo; Lee, Jaehwi; Cho, Yong Woo; Galinsky, Raymond E.; Park, Kinam

2008-01-01

63

KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells  

PubMed Central

Background We previously described a sub-population of epithelial ovarian cancer (EOC) cells with a functional TLR-4/MyD88/NF-?B pathway (Type I EOC cells), which confers the capacity to respond to Paclitaxel, a known TLR-4 ligand, by enhancing NF-?B activity and upregulating cytokine secretion – events that are known to promote tumor progression. It is therefore important to distinguish those patients that should not receive Paclitaxel; it is also important to identify alternative chemotherapy options that would benefit this sub-group of patients. The objective of this study is to determine if the KSP inhibitor, ARRY-520, can be a substitute for Paclitaxel in patients with Type I EOC. Methods EOC cells isolated from either ascites or tumor tissue were treated with increasing concentrations of ARRY-520 or Paclitaxel and cell viability determined. Activation of the apoptotic pathway was determined using Western blot analysis. Mitochondrial integrity was quantified using JC1 dye. Cytokine profiling was performed from supernatants using xMAP technology. NF-?B activity was measured using a Luciferase reporter system. In vivo activity was determined using a subcutaneous xenograft mouse model. Results ARRY-520 and Paclitaxel exhibited the same cytotoxic effect on Type I and II cells. The GI50 at 48 h for Type II EOC cells was 0.0015 ?M and 0.2 ?M for ARRY-520 and Paclitaxel, respectively. For Type I EOC cells, the GI50 at 48 h was > 3 ?M and >20 ?M for ARRY-520 and Paclitaxel, respectively. Decrease in the number of viable cells was accompanied by mitochondrial depolarization and caspase activation. Unlike Paclitaxel, ARRY-520 did not induce NF-?B activation, did not enhance cytokine secretion, nor induce ERK phosphorylation in Type I EOC cells. Conclusion Administration of Paclitaxel to patients with high percentage Type I cancer cells could have detrimental effects due to Paclitaxel-induced enhancement of NF-?B and ERK activities, and cytokine production (e.g. IL-6), which promote chemoresistance and tumor progression. ARRY-520 has similar anti-tumor activity in EOC cells as that of Paclitaxel. However, unlike Paclitaxel, it does not induce these pro-tumor effects in Type I cells. Therefore, the KSP inhibitor ARRY-520 may represent an alternative to Paclitaxel in this subgroup of EOC patients. PMID:19619321

Kim, Ki Hyung; Xie, Yanhua; Tytler, Ewan M; Woessner, Richard; Mor, Gil; Alvero, Ayesha B

2009-01-01

64

Effects of Goshajinkigan, Hachimijiogan, and Rokumigan on Mechanical Allodynia Induced by Paclitaxel in Mice  

PubMed Central

Peripheral neuropathy is a major dose-limiting side effect of the chemotherapeutic agent paclitaxel. This study examined whether the three related traditional herbal formulations, goshajinkigan (GJG; ????? Niú Ch? Shèn Qì Wán), hachimijiogan (HJG; ????? B? Wèi Dì Huáng Wán), and rokumigan (RMG; ??? Liù Wèi Wán), would relieve paclitaxel-induced mechanical allodynia in mice. A single intraperitoneal injection of paclitaxel (5 mg/kg) induced mechanical allodynia, which peaked on day 14 after injection. On day 14 after paclitaxel injection, oral administration of GJG (0.1-1.0 g/kg) produced a significant inhibition of established allodynia, but HJG and RMG did not affect the allodynia. Repeated oral administration of GJG (0.1-1.0 g/kg) starting from the day after paclitaxel injection did not affect allodynia development, but significantly inhibited allodynia exacerbation. Repeated oral administration of HJG produced a slight inhibition of allodynia exacerbation, but that of RMG did not. These results suggest that prophylactic administration of GJG is effective in preventing the exacerbation of paclitaxel-induced allodynia. The herbal medicines Plantaginis Semen (??? Ch? Qián Z?) and Achyranthis Radix (?? Niú X?), which are present in GJG but not in HJG, may contribute to the inhibitory action of GJG on the exacerbation of paclitaxel-induced allodynia. PMID:25379475

Andoh, Tsugunobu; Kitamura, Ryo; Fushimi, Hirotoshi; Komatsu, Katsuko; Shibahara, Naotoshi; Kuraishi, Yasushi

2014-01-01

65

Development of New Lipid-Based Paclitaxel Nanoparticles Using Sequential Simplex Optimization  

PubMed Central

The objective of these studies was to develop Cremophor-free lipid-based paclitaxel (PX) nanoparticle formulations prepared from warm microemulsion precursors. To identify and optimize new nanoparticles, experimental design was performed combining Taguchi array and sequential simplex optimization. The combination of Taguchi array and sequential simplex optimization efficiently directed the design of paclitaxel nanoparticles. Two optimized paclitaxel nanoparticles (NPs) were obtained: G78 NPs composed of glyceryl tridodecanoate (GT) and polyoxyethylene 20-stearyl ether (Brij 78), and BTM NPs composed of Miglyol 812, Brij 78 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both nanoparticles successfully entrapped paclitaxel at a final concentration of 150 ?g/ml (over 6% drug loading) with particle sizes less than 200 nm and over 85% of entrapment efficiency. These novel paclitaxel nanoparticles were stable at 4°C over three months and in PBS at 37°C over 102 hours as measured by physical stability. Release of paclitaxel was slow and sustained without initial burst release. Cytotoxicity studies in MDA-MB-231 cancer cells showed that both nanoparticles have similar anticancer activities compared to Taxol®. Interestingly, PX BTM nanocapsules could be lyophilized without cryoprotectants. The lyophilized powder comprised only of PX BTM NPs in water could be rapidly rehydrated with complete retention of original physicochemical properties, in-vitro release properties, and cytotoxicity profile. Sequential Simplex Optimization has been utilized to identify promising new lipid-based paclitaxel nanoparticles having useful attributes. PMID:19111929

Dong, Xiaowei; Mattingly, Cynthia A.; Tseng, Michael; Cho, Moo; Adams, Val R.; Mumper, Russell J.

2008-01-01

66

Efficient purification of paclitaxel from yews using high-performance displacement chromatography technique.  

PubMed

Paclitaxel was purified using high-performance displacement chromatography (HPDC) technique, but not by the mechanism of HPDC. On small scale, paclitaxel was extracted with methanol from dry needles of Taxus canadensis and was enriched by extracting with chloroform after removing water-soluble hydrophilic components and hexane-soluble hydrophobic components. Then, 93-99% purity of paclitaxel was obtained using the HPDC technique. On large scale, taxanes were enriched by solvent partitioning between acetic acid/MeOH/H(2)O and hexane and extracted with CH(2)Cl(2). Taxanes except paclitaxel were further removed by extracting with methanol-water-trifluoroacetic acid (1.0:98.9:0.1, v/v/v). Applying HPDC technique to water-insoluble substances is problematic as this method requires a highly aqueous solvent system. In order to overcome this incompatibility, a system was set up where paclitaxel, although in low concentration, was extracted by methanol-water-trifluoroacetic acid (10.0:89.9:0.1, v/v/v). Recycling the extracting solvent to ensure minimal volume, the extracted paclitaxel was adsorbed on a C(18) trap column. A C(18) column of 4.6mm internal diameter was then connected to the trap column. The HPDC technique was thus carried out using an isocratic acetonitrile-water-trifluoroacetic acid (30.0:69.9:0.1, v/v/v) mobile phase consisting of a displacer cetylpyridinium trifluoroacetate (3mg/mL). Paclitaxel was co-eluted with the displacer and spontaneously crystallized. The crystal (114mg) showed 99.4% purity and only 10% of paclitaxel in the starting crude extract was lost during the enrichment/purification processes. This large scale purification method was successfully applied to purify paclitaxel from Chinese yew in small scale, suggesting general applicability of the method. This is the first report of purifying a water-insoluble natural product using HPDC technique. PMID:21457989

Watchueng, Jean; Kamnaing, Pierre; Gao, Jin-Ming; Kiyota, Taira; Yeboah, Faustinus; Konishi, Yasuo

2011-05-20

67

Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy.  

PubMed

A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2 ± 2.5% in 24 h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3 ± 10.2 to 4.4 ± 1.3%) and control the release of PTX (43.6 ± 3.2% released in 24 h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using (99m)Tc-(Technetium radionuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24 h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel. PMID:22809646

Jain, Vikas; Swarnakar, Nitin K; Mishra, Prabhat R; Verma, Ashwni; Kaul, Ankur; Mishra, Anil K; Jain, Narendra K

2012-10-01

68

Hydrotropic polymer micelle system for delivery of paclitaxel.  

PubMed

Hydrotropic polymer micelle system has been developed for delivery of poorly water-soluble drugs such as paclitaxel. Hydrotropic polymers based on N,N-diethylnicotinamide were synthesized and used as a hydrophobic block for constructing amphiphilic block copolymers. The hydrotropic block copolymers self-assembled to form micelles in aqueous media. The size of the prepared polymer micelles was in the range of 30-50 nm, and increased to 100-120 nm after paclitaxel loading. The critical micelle concentrations (CMCs) of the block copolymers were higher by an order of magnitude than those of other typical polymer micelles, due to less hydrophobicity of the hydrotropic blocks. The drug loading capacity and physical stability of the polymer micelles were characterized and compared with those of other polymer micelles. The hydrotropic polymer micelles containing hydrotrope-rich cores showed not only higher loading capacity but also enhanced physical stability in aqueous media. They could be redissolved in aqueous media by simple vortexing and/or a mild heating. The hydrotropic polymer micelles provide an alternative approach for formulation of poorly soluble drugs. PMID:15588894

Huh, Kang Moo; Lee, Sang Cheon; Cho, Yong Woo; Lee, Jaehwi; Jeong, Jae Hyun; Park, Kinam

2005-01-01

69

Cytotoxicity of Paclitaxel Incorporated in PLGA Nanoparticles on Hypoxic Human Tumor Cells  

Microsoft Academic Search

Purpose  The aim of this work was to prepare paclitaxel-loaded PLGA nanoparticles and determine cytotoxicity of released paclitaxel\\u000a for two hypoxic human tumor cell lines: breast carcinoma (MCF-7) and carcinoma cervicis (HeLa).\\u000a \\u000a \\u000a \\u000a Methods  Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing paclitaxel were prepared by o\\/w emulsification-solvent evaporation\\u000a method. Physicochemical characteristics of nanoparticles were studied. Cellular uptake of nanoparticles was evaluated by transmission\\u000a electronic microscopy and

Cheng Jin; Ling Bai; Hong Wu; Wenjie Song; Guozhen Guo; Kefeng Dou

2009-01-01

70

Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel  

PubMed Central

Novel paclitaxel-mimicking alkaloids were designed and synthesized based on a bioactive conformation of paclitaxel, i.e., REDOR-Taxol. The alkaloid 2 bearing a 5-7-6 tricyclic scaffold mimics REDOR-Taxol best among the compounds designed and was found to be the most potent compound against several drug-sensitive and drug-resistant human cancer cell lines. MD simulation study on the paclitaxel mimics 1 and 2 as well as REDOR-Taxol bound to the 1JFF tubulin structure was quite informative to evaluate the level of mimicking. The MD simulation study clearly distinguishes the 5-6-6 and 5-7-6 tricyclic scaffolds, and also shows substantial difference in the conformational stability of the tubulin-bound structures between 2 and REDOR-Taxol. The latter may account for the large difference in potency, and provides critical information for possible improvement in the future design of paclitaxel mimics. PMID:20800500

Sun, Liang; Veith, Jean M.; Pera, Paula; Bernacki, Ralph J.; Ojima, Iwao

2010-01-01

71

Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel.  

PubMed

Novel paclitaxel-mimicking alkaloids were designed and synthesized based on a bioactive conformation of paclitaxel, that is, REDOR-Taxol. The alkaloid 2 bearing a 5-7-6 tricyclic scaffold mimics REDOR-Taxol best among the compounds designed and was found to be the most potent compound against several drug-sensitive and drug-resistant human cancer cell lines. MD simulation study on the paclitaxel mimics 1 and 2 as well as REDOR-Taxol bound to the 1JFF tubulin structure was quite informative to evaluate the level of mimicking. The MD simulation study clearly distinguishes the 5-6-6 and 5-7-6 tricyclic scaffolds, and also shows substantial difference in the conformational stability of the tubulin-bound structures between 2 and REDOR-Taxol. The latter may account for the large difference in potency, and provides critical information for possible improvement in the future design of paclitaxel mimics. PMID:20800500

Sun, Liang; Veith, Jean M; Pera, Paula; Bernacki, Ralph J; Ojima, Iwao

2010-10-01

72

Short Communication Coating with paclitaxel improves graft survival in a porcine model of  

E-print Network

patency at 5, 6, 6 and 8 weeks, respectively. In Kaplan­Meier analysis, paclitaxel- coated grafts showed and subsequent thrombosis. Several pharmacologic agents, such as warfarin, aspirin and clopidogrel, have been

Park, Jong-Sang

73

Cost-effectiveness of paclitaxel plus cisplatin in advanced non-small-cell lung cancer  

PubMed Central

The aim of this study was to assess the cost-effectiveness of combination chemotherapy with paclitaxel/cisplatin, compared with standard etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). We obtained the primary survival and resource utilization data from a large three-arm randomized trial comparing: paclitaxel 135 mg m?2 by 24-h intravenous (i.v.) infusion + cisplatin; paclitaxel 250 mg m?2 by 24-h i.v. infusion + cisplatin + granulocyte colony-stimulating factor (G-CSF); and standard etoposide/cisplatin in patients with stage IIIb or IV NSCLC. We also modelled the regimens with paclitaxel 135 mg m?2 + cisplatin administered as an outpatient by 3-h infusion, as clinical data suggest that this is equivalent to 24-h infusion. We collected costing data from the Ottawa Regional Cancer Centre and applied it to the resources consumed in the randomized trial. We integrated these data into the Statistics Canada POpulation HEalth Model (POHEM), which generated hypothetical cohorts of patients treated with each regimen. The POHEM model assigned diagnostic work-up, treatment, disease progression and survival characteristics to each individual in these cohorts and tabulated the costs associated with each. We did sensitivity analyses around the costs of chemotherapy and its administration, and the survival differences between the two regimens. All costs are in 1997 Canadian dollars ($1.00 Canadian ˜ £0.39 sterling). The perspective is that of the Canadian health care system. In the trial, the two paclitaxel-containing arms had almost identical survival curves with a median survival of 9.7 months compared with 7.4 months for etoposide/cisplatin. As administered in the trial, paclitaxel/cisplatin cost $76 370 per life-year gained (LYG) and paclitaxel/cisplatin/G-CSF $138 578 per LYG relative to etoposide/cisplatin. However, when modelled as an outpatient 3-h infusion, paclitaxel/cisplatin was moderately cost-effective at $30 619 per LYG. When compared with historical controls treated with best supportive care, this regimen of paclitaxel/cisplatin cost $4539 per LYG. Assuming a 3-h paclitaxel infusion yields the same survival advantage as the 24-h infusion did in the randomized trial, paclitaxel/cisplatin is a cost-effective improvement over standard etoposide/cisplatin for patients with advanced non-small cell lung cancer. © 1999 Cancer Research Campaign PMID:10360660

Earle, C C; Evans, W K

1999-01-01

74

Targeting carrier-mediated transport to improve the blood-brain barrier permeation of paclitaxel  

E-print Network

TARGETING CARRIER-MEDIATED TRANSPORT TO IMPROVE THE BLOOD-BRAIN BARRIER PERMEATION OF PACLITAXEL Kelly E. Desino1, Kenneth L. Audus1, Haibo Ge2, Gunda I. Georg2, Jariat Oyetunji2, Jared T. Spletstoser2, and Brandon J. Turunen2 University of Kansas..., Department of Pharmaceutical Chemistry1 and Department of Medicinal Chemistry2, Lawrence, KS 66047 ABSTRACT Purpose: Paclitaxel is a chemotherapeutic used for a variety of cancers; however, it cannot be used for cancers of the CNS. The permeation...

Desino, Kelly Elizabeth; Audus, Kenneth L.; Ge, Haibo; Georg, Gunda I.; Oyetunji, Jariat; Spletstoser, J. T.; Turunen, B. J.

2006-10-27

75

Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia at 4 Weeks in a Porcine Model of Coronary Restenosis  

Microsoft Academic Search

Background—Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. Methods

Alan W. Heldman; Linda Cheng; G. Mark Jenkins; Phillip F. Heller; Dong-Woon Kim; Melvin Ware; Cynthia Nater; Ralph H. Hruban; Banafsheh Rezai; Benjamin S. Abella; Katherine E. Bunge; James L. Kinsella; Steven J. Sollott; Edward G. Lakatta; Jeffrey A. Brinker; William L. Hunter; Jeffrey P. Froehlich

2010-01-01

76

Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer  

Microsoft Academic Search

Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P) yielded superior disease-free\\u000a survival than FEC in the adjuvant breast cancer trial GEICAM 9906. We evaluate molecular subtypes predictive of prognosis\\u000a and paclitaxel response in this trial. Two molecular subtype classifications based on conventional immunohistochemical and\\u000a fluorescent in situ hybridization determinations were used: #1: Four groups segregated according to

Miguel Martín; Álvaro Rodríguez-Lescure; Amparo Ruiz; Emilio Alba; Lourdes Calvo; Manuel Ruiz-Borrego; Ana Santaballa; César A. Rodríguez; Carmen Crespo; Mar Abad; Severina Domínguez; Jesús Florián; Cristina Llorca; Miguel Méndez; María Godes; Ricardo Cubedo; Adolfo Murias; Norberto Batista; María José García; Rosalía Caballero; Enrique de Álava

2010-01-01

77

Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.  

PubMed

Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (?5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. PMID:24002934

Mittapalli, Rajendar K; Liu, Xinli; Adkins, Chris E; Nounou, Mohamed I; Bohn, Kaci A; Terrell, Tori B; Qhattal, Hussaini S; Geldenhuys, Werner J; Palmieri, Diane; Steeg, Patricia S; Smith, Quentin R; Lockman, Paul R

2013-11-01

78

Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity  

Microsoft Academic Search

The main objective of this study was to develop a polymeric drug delivery system for paclitaxel, intended to be intravenously administered, capable of improving the therapeutic index of the drug and devoid of the adverse effects of Cremophor® EL. To achieve this goal paclitaxel (Ptx)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-Nps) were prepared by the interfacial deposition method. The influence of

Cristina Fonseca; Sérgio Simões; Rogério Gaspar

2002-01-01

79

[Adenovirus-mediated interleukin-24 enhances the inhibitory effect of paclitaxel on the growth of lung cancer A549 cells].  

PubMed

Objective To investigate the effect of adenovirus-mediated interleukin-24 (Ad-IL-24) combined with paclitaxel on the growth of human lung cancer A549 cells in vitro. Methods A549 cells were treated with Ad-IL-24 alone, paclitaxel alone and Ad-IL-24 combined with paclitaxel, respectively. Their proliferation was detected by CCK-8 assay, and the changes of apoptosis and cell cycle were tested by flow cytometry. Results The treatment of Ad-IL-24 significantly inhibited the A549 cell growth and induced cell apoptosis. Compared with paclitaxel alone and Ad-IL-24 alone, the Ad-IL-24 plus paclitaxel treatment more evidently inhibited lung cancer cell growth and increased cell apoptosis rate, and induced G2/M phase arrest. Conclusion Ad-IL-24 infection can enhance the inhibitory effect of paclitaxel on lung cancer cell growth. PMID:25374078

Xu, Mingju; Li, Minmin; Yang, Jicheng; Guo, Jinjin; Sun, Wanbang

2014-11-01

80

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).  

PubMed

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients. PMID:24513692

Chhibber, A; Mefford, J; Stahl, E A; Pendergrass, S A; Baldwin, R M; Owzar, K; Li, M; Winer, E P; Hudis, C A; Zembutsu, H; Kubo, M; Nakamura, Y; McLeod, H L; Ratain, M J; Shulman, L N; Ritchie, M D; Plenge, R M; Witte, J S; Kroetz, D L

2014-08-01

81

Cost-Benefit Analysis of Nanoparticle Albumin-Bound Paclitaxel versus Solvent-Based Paclitaxel for the Treatment of Metastatic Breast Cancer in the United States  

NASA Astrophysics Data System (ADS)

Breast cancer is the second leading cause of death among women in the US. Although early detection and treatment help to increase survival rates, some unfortunate patients develop metastatic breast cancer that has no cure. Palliative treatment is the main objective in this group of patients in order to prolong life and reduce toxicities from interventions. In the advancement of treatment for metastatic breast cancer, solvent-based paclitaxel has been widely used. However, solvent-based paclitaxel often causes adverse reactions. Therefore, researchers have developed a new chemotherapy based on nanotechnology. One of these drugs is the Nanoparticle albumin-bound Paclitaxel. This nanodrug aims to increase therapeutic index by reducing adverse reactions from solvents and to improve efficacy of conventional cytotoxic chemotherapy. Breast cancer is a disease with high epidemiological and economic burden. The treatment of metastatic breast cancer has not only high direct costs but also high indirect costs. Breast cancer affects mass populations, especially women younger than 50 years of age. It relates to high indirect costs due to lost productivity and premature death because the majority of these patients are in the workforce. Because of the high cost of breast cancer therapies and short survival rates, the question is raised whether the costs and benefits are worth paying or not. Due to the rising costs in healthcare and new financing policies that have been developed to address this issue, economic evaluation is an important aspect of the development and use of any new interventions. To guide policy makers on how to allocate limited healthcare resources in the most efficient and effective manner, many economic evaluation methods can be used to measure the costs, benefits, and impacts of healthcare innovations. Currently, economic evaluation and health outcomes studies have focused greatly on cost-effectiveness and cost-utility analysis. However, the previous studies had some limitations because they were conducted from a narrow perspective such as payer and provider point of views. The studies also considered only direct costs in their analysis. In fact, conducting economic evaluations from a narrow perspective and leaving out indirect costs might undermine the true benefit of the interventions for society. A cost-benefit analysis measures all costs and benefits in monetary units. It incorporates both health outcomes gained from individuals and the value gained to society in order to maximize the usage of resources effectively. This thesis conducted a cost-benefit analysis to compare nab-paclitaxel and generic paclitaxel in treating metastatic breast cancer from a societal perspective in the United States. The results showed that nab-paclitaxel is a cost-benefit strategy regardless of the different costs and benefits due to the extra 3 years of living it provides. In all models, when nab-paclitaxel was compared to generic paclitaxel, nab-paclitaxel showed cost-benefit to society. However, the results of generic paclitaxel were dependent on the total medical costs. Performing a cost-benefit analysis of nab-paclitaxel from a societal perspective is important to understand the true benefit of interventions. Furthermore, considering both direct and indirect costs, as well as benefits, of this drug is vital because the economic profile of nab-paclitaxel would be improved.

Vichansavakul, Kittaya

82

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel.  

PubMed

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used clinically for the treatment of ovarian and breast cancer. Due to its aqueous insolubility it is administered dissolved in ethanol and Cremophor EL (polyethoxylated castor oil), which has serious side effects. In order to eliminate this vehicle, in previous work we entrapped paclitaxel in conventional and in polyethylene glycol coated liposomes. However, in neither formulation did we obtain satisfactory entrapment efficiency. In this study we increased the paclitaxel concentration entrapped in liposomes by incorporating different water-soluble prodrugs, such as the 2'-succinyl, 2'-methylpyridinium acetate and 2'-mPEG ester paclitaxel derivatives, in the lipid vesicles. Liposomes containing 2'-mPEG (5000)-paclitaxel showed the best performance in terms of stability, entrapment efficiency and drug concentration (6.5 mgml(-1)). The in vitro cytotoxic activity of this liposomal prodrug was similar to that of the parent drug. The pharmacokinetic parameters for the free and for the liposomal prodrugs fitted a bi-exponential plasma disposition. The most important change in pharmacokinetic values of the prodrug vs. the free drug liposomal formulations was t(1/2)beta, plasma lifetime, which was longer in liposomes containing 2'-mPEG (5000)-paclitaxel. PMID:10640588

Ceruti, M; Crosasso, P; Brusa, P; Arpicco, S; Dosio, F; Cattel, L

2000-01-01

83

Nab-paclitaxel: potential for the treatment of advanced pancreatic cancer  

PubMed Central

Advanced pancreatic adenocarcinoma is a deadly disease and is considered incurable. For the past two decades, gemcitabine remained the major chemotherapeutic drug with modest clinical benefit. Many chemotherapy and targeted agents were combined with gemcitabine but failed to demonstrate improvement in pancreatic cancer (PC) survival. Taxanes (paclitaxel, docetaxel) were introduced in the clinic as anti-microtubule agents and showed activity against PC cells in vitro; however, clinical efficacy was limited. Nab-paclitaxel (Abraxane) is an albumin-bound paclitaxel that has shown clinical activity in advanced breast and lung cancer. Recently, nab-paclitaxel was tested in a large Phase III clinical trial in combination with gemcitabine for the treatment of advanced PC. The data showed that the addition of nab-paclitaxel improved the response rate (7% in gemcitabine alone versus 23% in combination), progression-free survival (from 3.7 months to 5.5 months), and overall survival from 6.7 months to 8.5 months, compared to single agent gemcitabine. Through this review, we provide the preclinical and clinical progress in the development of nab-paclitaxel for the treatment of metastatic PC. PMID:24523592

Al-Hajeili, Marwan; Azmi, Asfar S; Choi, Minsig

2014-01-01

84

A new 2?,5?,10?,14?-tetraacetoxy-4(20),11-taxadiene (SIA) derivative overcomes paclitaxel resistance by inhibiting MAPK signaling and increasing paclitaxel accumulation in breast cancer cells.  

PubMed

Tumor resistance due to multiple mechanisms seriously hinders the efficacy of chemotherapy drugs such as paclitaxel. The most widely studied P-glycoprotein inhibitors still have limited ability to reverse resistance in the clinic. In this study, NPB304, a novel Sinenxan A (SIA) derivative, was found to significantly sensitize resistant breast cancer cells to paclitaxel in vitro and in vivo. Treatment with NPB304 increased paclitaxel-induced apoptosis in a p53-dependent manner through PARP cleavage. Importantly, NPB304 enhanced the antitumor effect of paclitaxel in resistant breast tumor xenografts in nude mice without significantly affecting weight loss. NPB304 regulated cell resistance through inhibition of MAPK pathway components, including p-ERK and p-p38. Moreover, NPB304 increased paclitaxel accumulation by affecting P-gp function. In addition to increasing Rhodamine 123 accumulation, NPB304 promoted bidirectional permeability but decreased the efflux ratio of paclitaxel in a Caco-2 monolayer model, thereby increasing the intracellular concentration of paclitaxel. Similarly, NPB304 increased the concentration of paclitaxel in the resistant tumor tissue. Hence, NPB304 is a novel compound that promotes the sensitization of resistant cells to paclitaxel through multiple mechanisms and has the potential for use in combination therapies to treat resistant breast cancer. PMID:25093335

Mei, Mei; Xie, Dan; Zhang, Yi; Jin, Jing; You, Feng; Li, Yan; Dai, Jungui; Chen, Xiaoguang

2014-01-01

85

Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture.  

PubMed

Peripheral neuropathy (PN) is a debilitating and dose-limiting side effect of treatment with the chemotherapeutic agent, paclitaxel. Understanding the effects of paclitaxel on sensory neuronal function and the signaling pathways which mediate these paclitaxel-induced changes in function are critical for the development of therapies to prevent or alleviate the PN. The effects of long-term administration of paclitaxel on the function of sensory neurons grown in culture, using the release of the neuropeptide calcitonin gene-related peptide (CGRP) as an endpoint of sensory neuronal function, were examined. Dorsal root ganglion cultures were treated with low (10 nM) and high (300 nM) concentrations of paclitaxel for 1, 3, or 5 days. Following paclitaxel treatment, the release of CGRP was determined using capsaicin, a TRPV1 agonist; allyl isothiocyanate (AITC), a TRPA1 agonist; or high extracellular potassium. The effects of paclitaxel on the release of CGRP were stimulant-, concentration-, and time-dependent. When neurons were stimulated with capsaicin or AITC, a low concentration of paclitaxel (10nM) augmented transmitter release, whereas a high concentration (300 nM) reduced transmitter release in a time-dependent manner; however, when high extracellular potassium was used as the evoking stimulus, all concentrations of paclitaxel augmented CGRP release from sensory neurons. These results suggest that paclitaxel alters the function of sensory neurons in vitro, and suggest that the mechanisms by which paclitaxel alters neuronal function may include functional changes in TRP channel activity. The described in vitro model will facilitate future studies to identify the signaling pathways by which paclitaxel alters neuronal sensitivity. PMID:24374060

Pittman, Sherry K; Gracias, Neilia G; Vasko, Michael R; Fehrenbacher, Jill C

2014-03-01

86

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer  

Microsoft Academic Search

The microtubule-targeting antineoplastic agent, paclitaxel, is highly efficacious against a wide spectrum of human cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize cancer cells to paclitaxel can enhance the therapeutic effect of this drug. We have previously shown that curcumin, a natural polyphenol, enhances paclitaxel-induced cytotoxicity

C N Sreekanth; S V Bava; E Sreekumar; R J Anto

2011-01-01

87

Effect of water content of organic solvent on microwave-assisted extraction efficiency of paclitaxel from plant cell culture  

Microsoft Academic Search

A microwave-assisted extraction (MAE) method was used to recover the anticancer agent paclitaxel from plant cell cultures,\\u000a and the extraction efficiency of the paclitaxel was determined using various organic solvents (acetone, chloroform, ethanol,\\u000a methanol, and methylene chloride) and solvent concentrations. Methanol provided the highest recovery of paclitaxel (?93%)\\u000a and resulted in the most severe rupturing of the biomass surface during

Ji-Yeon Lee; Jin-Hyun Kim

88

A mucoadhesive in situ gel delivery system for paclitaxel.  

PubMed

MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen's phosphate buffer (pH 7.4) at 37 degrees C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61% +/- 0.19%, 12.0% +/- 0.98%, 31.7% +/- 0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drug-loaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1% +/- 4.35%, 44.2% +/- 6.35%, and 97.1% +/- 1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell. PMID:16796370

Jauhari, Saurabh; Dash, Alekha K

2006-01-01

89

Combined modality radioimmunotherapy: synergistic effect of Paclitaxel and additive effect of Bevacizumab  

PubMed Central

Introduction This study was undertaken to investigate the effect of Paclitaxel and Bevacizumab on the therapeutic efficacy of 90Y-labeled B3 mAb, directed against Ley antigen, for the treatment of Ley-positive A431 tumors implanted s.c. in the right hind flank of nude mice. Methods When the tumor size reached ~200 mm3, the mice received a single dose of i.v. 90Y-labeled B3 (60 ?Ci/150 ?g or 100 ?Ci/150 ?g B3), i.p. Paclitaxel (40 mg/kg), or i.v. Bevacizumab (5 mg/kg) for monotherapy. To investigate the effect of combined therapies on survival, the mice were treated with two or three agents in the following combinations: 90Y-B3 on day 0 and Paclitaxel on day 1; Bevacizumab on ?1 day and 90Y-B3 on day 0; Bevacizumab on ?1 day and Paclitaxel on day 1; Bevacizumab, 90Y-B3, and Paclitaxel each at 1-day intervals. The mice with no treatment were used as a control. The tumor volume at 1,000 mm3 was used as a surrogate endpoint of survival. Results Compared to control animals, Paclitaxel delayed tumor growth with a significantly longer median survival time (P < 0.001) whereas Bevacizumab alone showed a less pronounced effect on a median survival time (P = 0.18). 90Y-B3 increased the median survival time in a dose dependent manner (P < 0.05). The combined therapy of Bevacizumab with Paclitaxel produced a trend toward an increase of the median survival time compared to Paclitaxel alone (P = 0.06), whereas Bevacizumab combined with 90Y-B3 showed a statistically insignificant increase in the median survival time compared to 90Y-B3 alone (P = 0.25). The tumor sizes of all animals in these groups reached the surrogate end point of survival by day 35. In contrast, the combined therapy involving 90Y-B3 with Paclitaxel showed a striking synergistic effect in shrinking tumors and prolonging the survival time (P < 0.001); on day 120, 3 of 9 mice (33%) and 6 of 6 mice (100%) were alive without tumor when treated with 60 ?Ci 90Y-B3 and 100 ?Ci 90Y-B3, respectively. The addition of Bevacizumab treatment one day before the combined therapy of 60 ?Ci 90Y-B3 with Paclitaxel did not produce a statistically significant increase in survival when compared to the 90Y-B3 with Paclitaxel (P > 0.10). Fluorescence microscopy analysis indicated that Paclitaxel increased, whereas Bevacizumab decreased the accumulation and penetration of Alexa Fluor 647-B3 into tumor microenvironment compared to the control (P < 0.05). Conclusion Our findings on the Paclitaxel effect support a hypothesis that the increased tumor accumulation and penetration of 90Y-B3 as well as the high radio-sensitization of tumor cells by Paclitaxel may be the major factors responsible for the synergistic effect of the combined therapy involving 90Y-B3 with Paclitaxel. PMID:22172384

Jang, B. S.; Lee, S. -M.; Kim, H. S.; Shin, I. S.; Razjouyan, F.; Wang, S.; Yao, Z.; Pastan, I.; Dreher, M. R.; Paik, C. H.

2011-01-01

90

Chemical conjugation of muramyl dipeptide and paclitaxel to explore the combination of immunotherapy and chemotherapy for cancer  

Microsoft Academic Search

Paclitaxel (Taxol®) conjugated to muramyl dipeptide (MDP) is described. Biological testing showed that the conjugation of\\u000a MDP at 2?-O-paclitaxel (2?-\\u000a O\\u000a -MTC-01) not only has antitumor activity, but also have immunoenhancement capacity. Compared with paclitaxel or MDP alone or with\\u000a a mixture of paclitaxel + MDP, 2?-\\u000a O\\u000a -MTC-01 significantly increases the production and expression of TNF-? and IL-12 from

Xuqin Li; Junli Yu; Song Xu; Nan Wang; Hongzhen Yang; Zheng Yan; Guifang Cheng; Gang Liu

2008-01-01

91

Rationalization of paclitaxel insensitivity of yeast ?-tubulin and human ?III-tubulin isotype using principal component analysis  

PubMed Central

Background The chemotherapeutic agent paclitaxel arrests cell division by binding to the hetero-dimeric protein tubulin. Subtle differences in tubulin sequences, across eukaryotes and among ?-tubulin isotypes, can have profound impact on paclitaxel-tubulin binding. To capture the experimentally observed paclitaxel-resistance of human ?III tubulin isotype and yeast ?-tubulin, within a common theoretical framework, we have performed structural principal component analyses of ?-tubulin sequences across eukaryotes. Results The paclitaxel-resistance of human ?III tubulin isotype and yeast ?-tubulin uniquely mapped on to the lowest two principal components, defining the paclitaxel-binding site residues of ?-tubulin. The molecular mechanisms behind paclitaxel-resistance, mediated through key residues, were identified from structural consequences of characteristic mutations that confer paclitaxel-resistance. Specifically, Ala277 in ?III isotype was shown to be crucial for paclitaxel-resistance. Conclusions The present analysis captures the origin of two apparently unrelated events, paclitaxel-insensitivity of yeast tubulin and human ?III tubulin isotype, through two common collective sequence vectors. PMID:22849332

2012-01-01

92

Paclitaxel-induced hyposensitivity to nociceptive chemical stimulation in mice can be prevented by treatment with minocycline.  

PubMed

Development of peripheral neuropathy, which can present as painful neuropathy or loss of sensation, sometimes limit the use of paclitaxel in the treatment of solid tumors such as breast cancer. Previous studies reported development of thermal hyperalgesia in mice treated with paclitaxel. In this study an automated flinch detection system for the formalin test (20??l of 5% formalin injected subcutaneously into the paw dorsum) was used to evaluate chemical nociception in BALB/c mice treated with paclitaxel 2?mg/kg alone or coadministered with minocycline 50?mg/kg, intraperitoneally for 5 consecutive days. Reaction latency to thermal stimuli (hot-plate) was also measured. Injection of formalin resulted in biphasic paw flinches; phase 1 (1-9 minutes) and phase 2 (10-40 minutes). Treatment with paclitaxel reduced cumulative flinches in both phases 1 and 2 by 28% and 43%, respectively at day 7. However, treatment with paclitaxel also induced thermal hyperalgesia. Co-administration of paclitaxel with minocycline prevented development of both paclitaxel-induced hyposensitivity to chemical nociception and thermal hyperalgesia. In conclusion, the results indicate paclitaxel induces chemical hyposensitivity and thermal hyperalgesia in mice. Minocycline protected against paclitaxel-induced chemical hyposensitivity and thermal hyperalgesia, thus, providing further support of the usefulness of the drug in prevention of chemotherapy-induced neuropathy. PMID:25335491

Masocha, Willias

2014-01-01

93

Paclitaxel-induced hyposensitivity to nociceptive chemical stimulation in mice can be prevented by treatment with minocycline  

PubMed Central

Development of peripheral neuropathy, which can present as painful neuropathy or loss of sensation, sometimes limit the use of paclitaxel in the treatment of solid tumors such as breast cancer. Previous studies reported development of thermal hyperalgesia in mice treated with paclitaxel. In this study an automated flinch detection system for the formalin test (20??l of 5% formalin injected subcutaneously into the paw dorsum) was used to evaluate chemical nociception in BALB/c mice treated with paclitaxel 2?mg/kg alone or coadministered with minocycline 50?mg/kg, intraperitoneally for 5 consecutive days. Reaction latency to thermal stimuli (hot-plate) was also measured. Injection of formalin resulted in biphasic paw flinches; phase 1 (1–9 minutes) and phase 2 (10–40 minutes). Treatment with paclitaxel reduced cumulative flinches in both phases 1 and 2 by 28% and 43%, respectively at day 7. However, treatment with paclitaxel also induced thermal hyperalgesia. Co-administration of paclitaxel with minocycline prevented development of both paclitaxel-induced hyposensitivity to chemical nociception and thermal hyperalgesia. In conclusion, the results indicate paclitaxel induces chemical hyposensitivity and thermal hyperalgesia in mice. Minocycline protected against paclitaxel-induced chemical hyposensitivity and thermal hyperalgesia, thus, providing further support of the usefulness of the drug in prevention of chemotherapy-induced neuropathy. PMID:25335491

Masocha, Willias

2014-01-01

94

A Phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors  

PubMed Central

Background Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. Results Twenty-nine heavily pretreated patients [median 3 (0–7)] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). A trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4–67 cycles, median 10); two patients had minor responses. Patients and methods Eligible patients with solid tumors received micronized CAI daily (150–250 mg PO) and paclitaxel intravenously q3weeks (175–250 mg/m2), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics and disease outcome. Conclusions The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m2 q3weeks, respectively. The combination is tolerable and has potential antitumor activity. PMID:19738417

Azad, Nilofer; Perroy, Alyssa; Gardner, Erin; Imamura, Chiyo K.; Graves, Cynthia; Sarosy, Gisele A.; Minasian, Lori; Kotz, Herbert; Raggio, Miranda; Figg, William D.; Kohn, Elise C.

2011-01-01

95

Inhibition of Hec1 expression enhances the sensitivity of human ovarian cancer cells to paclitaxel  

PubMed Central

Aim: Hec1, a member of the Ndc80 kinetochore complex, is highly expressed in cancers. The aim of this study was to explore the role and mechanism of action of Hec1 with respect to the cytotoxicity of paclitaxel in ovarian cancer. Methods: Thirty ovarian cancer samples and 6 normal ovarian samples were collected. Hec1 expression in these samples was determined with immunohistochemistry. Ovarian cancer cell lines A2780, OV2008, C13K, SKOV3, and CAOV3 and A2780/Taxol were examined. Cell apoptosis and cell cycle analysis were detected with flow cytometric technique. siRNA was used to delete Hec1 in the cells. The expression of related mRNAs and proteins was measured using RT-PCR and Western blot analysis, respectively. Results: Hec1 expression was significantly higher in ovarian cancer samples than in normal ovarian samples, and was associated with paclitaxel-resistance and poor prognosis. Among the 6 ovarian cancer cell lines examined, Hec1 expression was highest in paclitaxel-resistant A2780/Taxol cells, and lowest in A2780 cells. Depleting Hec1 in A2780/Taxol cells with siRNA decreased the IC50 value of paclitaxel by more than 10-fold (from 590±26.7 to 45.6±19.4 nmol/L). Depleting Hec1 in A2780 cells had no significant effect on the paclitaxel sensitivity. In paclitaxel-treated A2780/Taxol cells, depleting Hec1 significantly increased the cleaved PARP and Bax protein levels, and decreased the Bcl-xL protein level. Conclusion: Hec1 overexpression is associated with the progression and poor prognosis of ovarian cancer. Inhibition of Hec1 expression can sensitize ovarian cancer cells to paclitaxel. PMID:23474708

Mo, Qing-qing; Chen, Ping-bo; Jin, Xin; Chen, Qian; Tang, Lan; Wang, Bei-bei; Li, Ke-zhen; Wu, Peng; Fang, Yong; Wang, Shi-xuan; Zhou, Jian-feng; Ma, Ding; Chen, Gang

2013-01-01

96

Thermosensitive and Mucoadhesive Sol-Gel Composites of Paclitaxel/Dimethyl-?-Cyclodextrin for Buccal Delivery  

PubMed Central

The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O-methyl)-?-cyclodextrin (DM?CD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4°C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37°C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127-based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel. PMID:25275485

Kang, Bong-Seok; Ng, Choon Lian; Davaa, Enkhzaya; Park, Jeong-Sook

2014-01-01

97

Paclitaxel sensitivity of breast cancer cells requires efficient mitotic arrest and disruption of Bcl-xL/Bak interaction.  

PubMed

Taxanes are being used for the treatment of breast cancer. However, cancer cells frequently develop resistance to these drugs with the subsequent recurrence of the tumor. MDA-MB-231 and T-47D breast cancer cell lines were used to assess the effect of paclitaxel treatment on apoptosis and cell cycle, the possible mechanisms of paclitaxel resistance as well as the enhancement of paclitaxel-induced apoptosis based on its combination with phenylethyl isothiocyanate (PEITC). T-47D cells undergo apoptosis in response to paclitaxel treatment. The induction of apoptosis was associated with a robust mitotic arrest and the disruption of Bcl-xL/Bak interaction. By contrary, MDA-MB-231 cells were insensitive to paclitaxel-induced apoptosis and this was associated with a high percentage of cells that slip out of paclitaxel-imposed mitotic arrest and also with the maintenance of Bcl-xL/Bak interaction. The sequential treatment of MDA-MB-231 cells with PEITC followed by paclitaxel inhibited the slippage induced by paclitaxel and increased the apoptosis induction achieved with any of the drugs alone. In breast cancer tissues, high Bcl-xL expression was correlated with a shorter time of disease-free survival in patients treated with a chemotherapeutic regimen that contains paclitaxel, in a statistically significant way. Thus, resistance to paclitaxel in MDA-MB-231 cells is related to the inability to disrupt the Bcl-xL/Bak interaction and increased slippage. In this context, the combination of a drug that induces a strong mitotic arrest, such as paclitaxel, with another that inhibits slippage, such as PEITC, translates into increased apoptotic induction. PMID:22076480

Flores, M Luz; Castilla, Carolina; Ávila, Rainiero; Ruiz-Borrego, Manuel; Sáez, Carmen; Japón, Miguel A

2012-06-01

98

E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines  

PubMed Central

The CDK/Rb/E2F pathway is commonly disrupted in lung cancer, and thus, it is predicted that blocking the E2F pathway would have therapeutic potential. To test this hypothesis, we have examined the activity of HLM006474 (a small molecule pan-E2F inhibitor) in lung cancer cell lines as a single agent and in combination with other compounds. HLM006474 reduces the viability of both SCLC and NSCLC lines with a biological IC50 that varies between 15 and 75 µM, but with no significant difference between the groups. Combination of HLM006474 with cisplatin and gemcitabine demonstrate little synergy; however, HLM006474 synergizes with paclitaxel. Surprisingly, we discovered that brief treatment of cells with HLM006474 led to an increase of E2F3 protein levels (due to de-repression of these promoter sites). Since paclitaxel sensitivity has been shown to correlate with E2F3 levels, we hypothesized that HLM006474 synergy with paclitaxel may be mediated by transient induction of E2F3. To test this, H1299 cells were depleted of E2F3a and E2F3b with siRNA and treated with paclitaxel. Assays of proliferation showed that both siRNAs significantly reduced paclitaxel sensitivity, as expected. Taken together, these results suggest that HLM006474 may have efficacy in lung cancer and may be useful in combination with taxanes. PMID:24831239

Kurtyka, Courtney A.; Chen, Lu; Cress, W. Douglas

2014-01-01

99

Synergistic interaction of paclitaxel and curcumin with cyclodextrin polymer complexation in human cancer cells.  

PubMed

The use of cytotoxic chemotherapic agents is the most common method for the treatment of metastatic cancers. Poor water solubility and low efficiency of chemotherapic agents are among the major hurdles of effective chemotherapy treatments. Curcumin and paclitaxel are well-known chemotherapic agents with poor water solubility and undesired side effects. In this study, a novel drug nanocarrier system was formulated by encapsulating curcumin and paclitaxel in poly(?-cyclodextrin triazine) (PCDT) for the therapy of four cancer models; ovarian, lung, prostate, and breast cancer. Cell viability and colony formation assays revealed enhanced curcumin cytotoxicity upon complexation. Annexin V apoptotic studies showed that the PCDT complexation improved curcumin induced apoptosis in human ovarian cancer cell lines A2780 and SKOV-3, human nonsmall cell lung carcinoma cell line H1299, and human prostate cancer line DU-145, while no significant effect was observed with paclitaxel/PCDT complexation. The bioactivity of combining curcumin and paclitaxel was also investigated. A synergism was found between curcumin and paclitaxel, particularly when complexed with PCDT on A2780, SKOV-3, and H1299 cancer cell lines. PMID:23730903

Boztas, Ali O; Karakuzu, Ozgur; Galante, Gabriela; Ugur, Zafer; Kocabas, Fatih; Altuntas, Cengiz Z; Yazaydin, A Ozgur

2013-07-01

100

Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles.  

PubMed

The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel. PMID:24670687

Zasadil, Lauren M; Andersen, Kristen A; Yeum, Dabin; Rocque, Gabrielle B; Wilke, Lee G; Tevaarwerk, Amye J; Raines, Ronald T; Burkard, Mark E; Weaver, Beth A

2014-03-26

101

Photodistributed erythema multiforme: paclitaxel-related, photosensitive conditions in patients with cancer.  

PubMed

Paclitaxel (Taxol) is an intravenously administered antineoplastic agent derived from the yew tree, Taxus brevifolia, whose mechanism of action involves inhibition of mitosis. Some of the mucocutaneous reactions to the drug that have been observed include alopecia, mucositis, hypersensitivity reactions (with erythema and urticaria), nail changes, changes occurring at intravenous sites, and radiation recall dermatitis. Less commonly, acral erythema, erythema multiforme, pustular dermatitis, and scleroderma-like changes have been described. A female patient who was receiving adjuvant weekly paclitaxel for the treatment of intraductal breast carcinoma developed photodistributed erythema multiforme and onycholysis after sun exposure to the affected areas. Including this woman, paclitaxel-associated photosensitve conditions have only been reported in 9 female oncology patients: onycholysis (5), erythema multiforme and onycholysis (2), photo-recall phenomenon (1), and subacute cutaneous lupus erythematosus (1). The patients were either receiving treatment for breast carcinoma (8) or lung cancer (1). The skin lesions developed on sun-exposed areas, usually after the patient had received several weekly doses of paclitaxel, and resolved following discontinuation of the drug. Several of the patients were subsequently able to receive additional cycles of paclitaxel without recurrence of their drug-associated photosensitive conditions by concurrently using photoprotection to prevent additional sun exposure to the previously affected sites during treatment. PMID:19180897

Cohen, Philip R

2009-01-01

102

Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles  

PubMed Central

The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, the majority of mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs due to chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future anti-mitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel. PMID:24670687

Zasadil, Lauren M.; Andersen, Kristen A.; Yeum, Dabin; Rocque, Gabrielle B.; Wilke, Lee G.; Tevaarwerk, Amye J.; Raines, Ronald T.; Burkard, Mark E.; Weaver, Beth A.

2014-01-01

103

MiR-634 sensitizes nasopharyngeal carcinoma cells to paclitaxel and inhibits cell growth both in vitro and in vivo  

PubMed Central

Resistance to chemotherapy is one of the key causal factors in cancer death and increasing evidence has revealed that microRNAs (miRNAs) are involved in chemoresistance in many kinds of human cancers. Paclitaxel has been used for treatment of advanced nasopharyngeal carcinoma (NPC); however, treatment failure often occurs due to development of acquired paclitaxel resistance. In this study, based on miRNA microarray screening and qRT-PCR validation, we found six differentially expressed miRNAs in our induced paclitaxel-resistant NPC CNE-1/Taxol cells. Furthermore, we clarified the role of miR-634, most significantly downregulated in the paclitaxel-resistant CNE-1/Taxol, in regulating the paclitaxel sensitivity in NPC cells. We restored miR-634 expression in the CNE-1/Taxol cells by lentivirus infection, and found restoration of miR-634 re-sensitized the CNE-1/Taxol cells to paclitaxel in vitro by MTT assay and colony formation assay. In xenograft mouse model, we found that miR-634 inhibited tumor growth and enhanced paclitaxel sensitivity. Thus, our findings provide important information for the development of targeted gene therapy for reversing paclitaxel resistance in NPC.

Peng, Xiaowei; Cao, Peiguo; He, Dong; Han, Shuang; Zhou, Jianda; Tan, Guolin; Li, Wei; Yu, Fenghui; Yu, Jianjun; Li, Zan; Cao, Ke

2014-01-01

104

A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma  

Microsoft Academic Search

Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is undefined. We evaluated a combination of capecitabine, carboplatin, and paclitaxel with RT in a phase I study. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received capecitabine, carboplatin, and paclitaxel

Brian G.. Czito; Chris R. Kelsey; Herbert I. Hurwitz; Chris G. Willett; Michael A. Morse; Gerard C. Blobe; Nishan H. Fernando; Thomas A. D’Amico; David H. Harpole; Wanda R. N. Honeycutt; Daohai Yu; Johanna C. Bendell

2007-01-01

105

Phase II study with paclitaxel for the treatment of advanced inoperable non-small cell lung cancer  

Microsoft Academic Search

Paclitaxel is a plant product isolated from the bark of the Western yew (Taxus brevifolia) that promotes the formation and stabilization of microtubules. This leads to growth arrest in the G2\\/M phase of the cell cycle. Paclitaxel has demonstrated significant antineoplastic activity in different tumor types, most notably in ovarian and breast carcinoma. In two Phase II trials (Eastern Cooperative

Ulrich Gatzemeier; Marlene Heckmayr; Renate Neuhauss; Ingrid Schlüter; Joachim V. Pawel; Horst Wagner; Andreas Dreps

1995-01-01

106

In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel.  

PubMed

Paclitaxel (Taxol), a diterpenoid isolated from Taxus brevifolia, is effective against several murine tumors, and is one of the most exciting anticancer molecules currently available. Due to its low solubility in water, it is clinically administered with polyethoxylated castor oil (Cremophor EL), which causes serious side effects. Inclusion of paclitaxel in solid lipid nanoparticles (SLNs) has proved to be a good approach to eliminate the need for Cremophor EL and improve the drug's antitumor efficacy. This paper describes the development of two types of long-circulating SLNs as colloidal carriers for paclitaxel. SLNs are constituted mainly of bioacceptable and biodegradable lipids. In vitro release kinetics showed that the release was very slow, the release of paclitaxel from F68-SLN is linear, and the release of paclitaxel from Brij78-SLN followed the Weibull equation. Pharmacokinetics was evaluated in KM mice after injection of paclitaxel formulated in Cremophor EL or in Brij78-SLN and F68-SLN. Encapsulation of paclitaxel in both SLNs produced marked differences compared with the free drug pharmacokinetics. F68-SLN and Brij78-SLN are long-circulating (t 1/2 beta, 10.06 and 4.88 h, respectively) compared with paclitaxel injection (t 1/2 beta, 1.36 h). PMID:11724235

Chen, D B; Yang, T Z; Lu, W L; Zhang, Q

2001-11-01

107

Use of a cholesterol-rich emulsion that binds to low-density lipoprotein receptors as a vehicle for paclitaxel.  

PubMed

A cholesterol-rich emulsion (LDE) is taken up by malignant cells which over-express low-density lipoprotein (LDL) receptors and thus may be used as a carrier for drugs directed against neoplastic cells. In this study, we associated the antineoplastic agent paclitaxel to LDE and analysed the new formulation's incorporation efficiency, chemical and physical stability, cellular uptake and cytostatic activity against a neoplastic cell line and the acute toxicity to rats. A paclitaxel incorporation efficiency of approximately 75% was achieved when paclitaxel was mixed with LDE at a 6:1 lipid-to-drug molar ratio. The association of paclitaxel with LDE increased by 54% the mean diameter of the emulsion particles but did not damage the paclitaxel chemical structure as analysed by HPLC. Results from gradient ultracentrifugation and Sephadex G25 gel filtration indicated that the binding of the drug to the emulsion was stable. It was shown that the cellular uptake and the cytotoxic activity of LDE-paclitaxel by a neoplastic cell line (NCI-H292 cells) was indeed mediated by the LDL receptors. The antiproliferative activity of LDE-paclitaxel against NCI-H292 cells was less than that of a commercial paclitaxel preparation (50% inhibitory concentration, IC50 = 2.60 and 0.45 microM, respectively). This difference, however, can be ascribed to the in-vitro anti-proliferative activity of the commercial paclitaxel vehicle Cremophor EL; when Cremophor EL was added to the cultures with LDE-paclitaxel, the IC50 value was reduced to 0.45 microM, attaining that of the commercial paclitaxel preparation. The tolerability of LDE-paclitaxel in rats was remarkable, such that its lethal dose (LD50) was ten-fold greater than that of the commercial formulation (LD50 = 324 and 31.8 mg kg(-1), respectively). Therefore, LDE-paclitaxel association is stable and the cytostatic activity of the drug is preserved while its toxicity to rats is small. By diminishing the side effects and directing paclitaxel to neoplastic tissues, LDE may be useful as adjuvant in chemotherapy with this drug. PMID:12078992

Rodrigues, Debora G; Covolan, Cristiane C; Coradi, Silvana T; Barboza, Renato; Maranhão, Raul C

2002-06-01

108

Targeting of albumin-embedded paclitaxel nanoparticles to tumors  

PubMed Central

We have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA, and LyP-1 (CGQKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands expressing its receptor, p32. Self-assembled mixed micelles carrying the homing peptide and the label on different subunits accumulated in the same areas of tumors as LyP-1-abraxane, showing that Lyp-1 can deliver intact nanoparticles into extravascular sites. Untargeted, FAM-abraxane was detected in the form of a faint meshwork in tumor interstitium. LyP-1-abraxane produced a statistically highly significant inhibition of tumor growth compared to untargeted abraxane. These results show that nanoparticles can be effectively targeted into extravascular tumor tissue and that targeting can enhance the activity of a therapeutic nanoparticle. PMID:18829396

Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Kastantin, Mark; Black, Matthew; Missirlis, Dimitris; Tirrell, Matthew; Ruoslahti, Erkki

2010-01-01

109

Praziquantel synergistically enhances paclitaxel efficacy to inhibit cancer cell growth.  

PubMed

The major challenges we are facing in cancer therapy with paclitaxel (PTX) are the drug resistance and severe side effects. Massive efforts have been made to overcome these clinical challenges by combining PTX with other drugs. In this study, we reported the first preclinical data that praziquantel (PZQ), an anti-parasite agent, could greatly enhance the anticancer efficacy of PTX in various cancer cell lines, including PTX-resistant cell lines. Based on the combination index value, we demonstrated that PZQ synergistically enhanced PTX-induced cell growth inhibition. The co-treatment of PZQ and PTX also induced significant mitotic arrest and activated the apoptotic cascade. Moreover, PZQ combined with PTX resulted in a more pronounced inhibition of tumor growth compared with either drug alone in a mouse xenograft model. We tried to investigate the possible mechanisms of this synergistic efficacy induced by PZQ and PTX, and we found that the co-treatment of the two drugs could markedly decrease expression of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic protein. Our data further demonstrated that down-regulation of XIAP was required for the synergistic interaction between PZQ and PTX. Together, this study suggested that the combination of PZQ and PTX may represent a novel and effective anticancer strategy for optimizing PTX therapy. PMID:23251610

Wu, Zhen Hua; Lu, Ming-ke; Hu, Long Yu; Li, Xiaotong

2012-01-01

110

Inhibition of paclitaxel-induced decreases in calcium signaling.  

PubMed

Peripheral neuropathy is one of the most severe and irreversible side effects caused by treatment from several chemotherapeutic drugs, including paclitaxel (Taxol®) and vincristine. Strategies are needed that inhibit this unwanted side effect without altering the chemotherapeutic action of these drugs. We previously identified two proteins in the cellular pathway that lead to Taxol-induced peripheral neuropathy, neuronal calcium sensor-1 (NCS-1) and calpain. Prolonged treatment with Taxol induces activation of calpain, degradation of NCS-1, and loss of intracellular calcium signaling. This paper has focused on understanding the molecular basis for prevention of peripheral neuropathy by testing the effects of addition of two candidate compounds to the existing chemotherapeutic drug regime: lithium and ibudilast. We found that the co-administration of either lithium or ibudilast to neuroblastoma cells that were treated with Taxol or vincristine inhibited activation of calpain and the reductions in NCS-1 levels and calcium signaling associated with these chemotherapeutic drugs. The ability of Taxol to alter microtubule formation was unchanged by the addition of either candidate compound. These results allow us to suggest that it is possible to prevent the unnecessary and irreversible damage caused by chemotherapeutic drugs while still maintaining therapeutic efficacy. Specifically, the addition of either lithium or ibudilast to existing chemotherapy treatment protocols has the potential to prevent chemotherapy-induced peripheral neuropathy. PMID:22988235

Benbow, Jennifer H; Mann, Taylor; Keeler, Camille; Fan, Chengpeng; Hodsdon, Michael E; Lolis, Elias; DeGray, Brenda; Ehrlich, Barbara E

2012-11-01

111

Strategy of directly employing paclitaxel to construct vesicles.  

PubMed

A class of aza-arm modified ?-cyclodextrins were found to be able to trap paclitaxel (PTX), an effective but strongly hydrophobic anticancer drug, to form novel "supramolecular amphiphiles", which can further self-assemble into vesicular structures in aqueous solution. The obtained vesicles were characterized in detail by transmission electron microscopy (TEM), scanning electron microscopy (SEM), cryogenic transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS). The mechanism of the vesicular formation was suggested on the basis of the experimental results of nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and thermal analysis. The effects to the vesicular formation by changing the host molecules and solvents were also studied. The vesicles will disappear upon the introduction of Cu(2+) into the vesicular system, during the procedure of which, PTX will be released meanwhile. We believe that our research will provide a new strategy of directly employing special drugs to construct microvehicles to carry other targeted molecules. PMID:23194107

Sun, Tao; Yan, Hui; Liu, Guangcun; Hao, Jingcheng; Su, Jie; Li, Shangyang; Xing, Pengyao; Hao, Aiyou

2012-12-20

112

Inhibition of Paclitaxel-induced Decreases in Calcium Signaling*  

PubMed Central

Peripheral neuropathy is one of the most severe and irreversible side effects caused by treatment from several chemotherapeutic drugs, including paclitaxel (Taxol®) and vincristine. Strategies are needed that inhibit this unwanted side effect without altering the chemotherapeutic action of these drugs. We previously identified two proteins in the cellular pathway that lead to Taxol-induced peripheral neuropathy, neuronal calcium sensor-1 (NCS-1) and calpain. Prolonged treatment with Taxol induces activation of calpain, degradation of NCS-1, and loss of intracellular calcium signaling. This paper has focused on understanding the molecular basis for prevention of peripheral neuropathy by testing the effects of addition of two candidate compounds to the existing chemotherapeutic drug regime: lithium and ibudilast. We found that the co-administration of either lithium or ibudilast to neuroblastoma cells that were treated with Taxol or vincristine inhibited activation of calpain and the reductions in NCS-1 levels and calcium signaling associated with these chemotherapeutic drugs. The ability of Taxol to alter microtubule formation was unchanged by the addition of either candidate compound. These results allow us to suggest that it is possible to prevent the unnecessary and irreversible damage caused by chemotherapeutic drugs while still maintaining therapeutic efficacy. Specifically, the addition of either lithium or ibudilast to existing chemotherapy treatment protocols has the potential to prevent chemotherapy-induced peripheral neuropathy. PMID:22988235

Benbow, Jennifer H.; Mann, Taylor; Keeler, Camille; Fan, Chengpeng; Hodsdon, Michael E.; Lolis, Elias; DeGray, Brenda; Ehrlich, Barbara E.

2012-01-01

113

Polymerizable disulfide paclitaxel prodrug for controlled drug delivery.  

PubMed

A polymerizable disulfide paclitaxel (PTX) prodrug was synthesized by the consequential esterification reactions of 3,3'-dithiodipropionic acid (DTPA), a disulfide compound containing two active carboxyl groups, with 2-hydroxyethyl methacrylate (HEMA) and PTX. The structure of the prodrug was confirmed by (1)H NMR characterization. Then, the polymerizable prodrug was copolymerized with poly(ethylene glycol) methyl ether methacrylate (PEGMEA) to obtain a copolymer with hydrophilic PEG side chains and PTX covalently linked onto the backbone via disulfide bonds. The loading content of PTX was 23%. In aqueous solution, this copolymer prodrug could self-assemble into micelles, with hydrophobic PTX as the cores and hydrophilic PEG-segment as the shells. In vitro cell assay demonstrated that this copolymer prodrug showed more apparent cytotoxicity to cancer cells than to human normal cells. After incubation for 48h, the cell viability of HEK-293 cells (human embryo kidney cells) at 0.1?g/mL PTX still remained more than 90%, however, that of HeLa cells (human cervical cancer cells) decreased to 52%. PMID:25280719

Ding, Yi; Chen, Wulian; Hu, Jianhua; Du, Ming; Yang, Dong

2014-11-01

114

Synergistic Effect of COX-2 Inhibitor on Paclitaxel-Induced Apoptosis in the Human Ovarian Cancer Cell Line OVCAR-3  

PubMed Central

Purpose Celecoxib, a highly selective cyclooxygenase-2 inhibitor, regulates apoptosis of several types of human cancer cells. The purpose of this study was to investigate whether celecoxib in combination with paclitaxel modulates apoptosis of ovarian cancer cells, and to identify the signal pathway by which celecoxib mediates apoptosis. Materials and Methods OVCAR-3 cells were exposed to paclitaxel (20 µM) in the absence or presence of celecoxib (10 µM). Cell viability was evaluated using a Cell Counting Kit-8 assay. Apoptosis was evaluated using Annexin-V/7-aminoactinomycin D staining and a cellular DNA fragmentation enzyme-linked immunosorbent assay. Caspase-3, -9, and cleavage of poly ADP-ribose polymerase (PARP) were determined by western blotting. Expression of nuclear factor-?B (NF-?B) and vascular endothelial growth factor (VEGF) and Akt activation were assessed using reverse transcriptase-polymerase chain reaction and western blotting. Results Celecoxib enhanced paclitaxel-induced growth inhibition of OVCAR-3 cells. Celecoxib significantly increased paclitaxel-induced apoptosis of OVCAR-3 cells. Pretreatment with celecoxib also increased activation of caspase-9, -3 and cleaved PARP following paclitaxel-treatment. Exposure of OVCAR-3 cells to celecoxib in combination with paclitaxel resulted in downregulation of NF-?B activation and VEGF expression. Furthermore, combining celecoxib and paclitaxel inhibited phosphorylation of Akt. Conclusion OVCAR-3 cells were sensitized to paclitaxel-induced apoptosis by celecoxib through downregulation of NF-?B and Akt activation, suggesting that celecoxib may work synergistically with paclitaxel to inhibit different targets and ultimately produce anticancer effects. Combining celecoxib with paclitaxel may prove beneficial in the clinical treatment of ovarian cancer. PMID:24520227

Kim, Hee Jung; Yim, Ga Won; Nam, Eun Ji

2014-01-01

115

Quasi-Complete Response of Classic Kaposi's Sarcoma Treated with Weekly Paclitaxel  

PubMed Central

Classic Kaposi's sarcoma (CKS) is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean origin. Patients with CKS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon but may occur in the late stages of the disease. Patients with extensive KS can be treated with systemic chemotherapy. A number of drugs approved for treatment of AIDS-associated KS, especially Paclitaxel, have activity against CKS after failure of prior therapy. We report a patient treated with weekly Paclitaxel, as initial chemotherapy, for CKS presenting with multiple visceral involvement and having a contraindication for Bleomycin. The patient had quasi-complete response after three months of chemotherapy suggesting that weekly Paclitaxel might be effective as a first-line therapy for classical type KS with visceral involvement. PMID:23476845

Benbrahim, Zineb; Arifi, Samia; Benhammane, Hafida; Inani, Kaoutar; Gallouj, Salim; Meziane, Meriem; Mernissi, Fatima Zahra; Mellas, Nawfel; El Mesbahi, Omar

2013-01-01

116

Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes.  

PubMed

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by the FDA for the treatment of ovarian and breast cancers. Due to its low solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side effects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to eliminating this vehicle and improving the drug's antitumor efficacy. We prepared different conventional and PEGylated liposomes containing paclitaxel and determined encapsulation efficiency, physical stability and drug leakage in human plasma. The best conventional liposome formulation was composed of ePC/PG 9:1, while for PEGylated liposomes the best composition was ePC/PG/CHOL/PEG(5000)-DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage than the corresponding conventional liposomes and to have lower drug release in human plasma at 37 degrees C. In vitro cytotoxic activities were evaluated on HT-29 human colon adenocarcinoma and MeWo melanoma cell lines. After 2 and 48 h, conventional liposomes had the same cytotoxicity as free paclitaxel, while PEGylated liposomes were as active as free drug, only after 48 h. Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v. injection of paclitaxel, formulated in Cremophor EL or in conventional or in PEGylated liposomes. Encapsulation of paclitaxel in conventional liposomes produced marked differences over the free drug pharmacokinetics. PEGylated liposomes were long-circulating liposomes, with an increased t(1/2) beta 48.6 h, against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies showed a considerable decrease in drug uptake in MPS-containing organs (liver and spleen) at 0.5 and 3 h after injection with PEGylated compared to conventional liposomes. PMID:10640577

Crosasso, P; Ceruti, M; Brusa, P; Arpicco, S; Dosio, F; Cattel, L

2000-01-01

117

The effect of paclitaxel on the radiosensitivity of gynecological tumor cells  

Microsoft Academic Search

Background  Paclitaxel, a natural product from Taxus brevifolia, is a microtubule stabilizing agent, which has been shown to block different\\u000a cells in the G2\\/M phase of the cell cycle and consequently, to modulate their radioresponsiveness. Our aim was to test the\\u000a cytotoxic and radiosensitizing potential of paclitaxel, with respect to different gynecological tumors with varying radiosensitivities.\\u000a \\u000a \\u000a \\u000a Material and Method  We performed clonogenic

M. Rave-Fränk; H. Meden; A. Jäschke; A. Tänzer; O. Boghun; R. Fietkau

1997-01-01

118

End-binding protein 1 stimulates paclitaxel sensitivity in breast cancer by promoting its actions toward microtubule assembly and stability.  

PubMed

Paclitaxel is a microtubule-targeting agent widely used for the treatment of many solid tumors. However, patients show variable sensitivity to this drug, and effective diagnostic tests predicting drug sensitivity remain to be investigated. Herein, we show that the expression of end-binding protein 1 (EB1), a regulator of microtubule dynamics involved in multiple cellular activities, in breast tumor tissues correlates with the pathological response of tumors to paclitaxel-based chemotherapy. In vitro cell proliferation assays reveal that EB1 stimulates paclitaxel sensitivity in breast cancer cell lines. Our data further demonstrate that EB1 increases the activity of paclitaxel to cause mitotic arrest and apoptosis in cancer cells. In addition, microtubule binding affinity analysis and polymerization/depolymerization assays show that EB1 enhances paclitaxel binding to microtubules and stimulates the ability of paclitaxel to promote microtubule assembly and stabilization. These findings thus reveal EB1 as a critical regulator of paclitaxel sensitivity and have important implications in breast cancer chemotherapy. PMID:24748116

Luo, Youguang; Li, Dengwen; Ran, Jie; Yan, Bing; Chen, Jie; Dong, Xin; Liu, Zhu; Liu, Ruming; Zhou, Jun; Liu, Min

2014-06-01

119

A randomized phase II trial comparing every 3-weeks carboplatin\\/paclitaxel with every 3-weeks carboplatin and weekly paclitaxel in advanced non-small cell lung cancer  

Microsoft Academic Search

Background: The optimal schedule of taxane administration has been an area of active interest in several recent clinical trials. Methods: To address a pure schedule question, we randomized 161 patients with advanced stage IIIB or IV non-small-cell lung cancer (NSCLC) to either paclitaxel 225 mg\\/m2 every 3 weeks · 4 cycles or 75 mg\\/m2\\/week · 12 (cumulative dose on each

M. A. Socinski; A. Ivanova; K. Bakri; J. Wall; M. Q. Baggstrom; T. A. Hensing; A. Mears; M. Tynan; J. Beaumont; A. H. Peterman; H. B. Niell

2005-01-01

120

Validated HPLC Method for the Determination of Paclitaxel-related Substances in an Intravenous Emulsion Loaded with a Paclitaxel-Cholesterol Complex  

PubMed Central

A high-performance liquid chromatography method was developed for the determination of related substances in an intravenous emulsion loaded with a paclitaxel–cholesterol complex. The separation was achieved using Agilent Eclipse XDB-C18 column (150×4.6 mm, 3.5 ?m), which was kept at 40°. The gradient mobile phase consisted of acetonitrile and water with a flow rate of 1.2 ml/min. The ultraviolet detection wavelength was set at 227 nm. The preparation of the sample solution began with the addition of anhydrous sodium sulphate to break the emulsion. Then, methanol and ethyl ether were added to pick up the drug and remove the accessories of the emulsion by extraction and centrifugation. Finally, paclitaxel was enriched by a nitrogen blow method and resolved with a mixture of methanol:glacial acetic acid (200:1). The method was proven to be selective, sensitive, robust, linear, repeatable, accurate and suitable for the determination of paclitaxel-related substances in the emulsion formulations, and the major degradation products in the potential pharmaceutical product were 7-epipaclitaxel and 10-deacetylpaclitaxel. PMID:24591742

Xia, X. J.; Peng, J.; Zhang, P. X.; Jin, D. J.; Liu, Y. L.

2013-01-01

121

Paclitaxel and TRAIL Synergize to Kill Paclitaxel-resistant Small Cell Lung Cancer Cells through a Caspase-independent Mechanism Mediated through AIF  

PubMed Central

Background Small cell lung cancer (SCLC) is the most aggressive form of lung cancer with poor disease outcome. Chemotherapeutic agent paclitaxel (PA) is commonly used as a second-line treatment in SCLC, but response rates are low. Materials and Methods 86M1 SCLC cells were treated in the presence or absence of Paclitaxel and TRAIL or the combination for 24 hours. Western blot analysis was utilized to examine protein expression, cell surface protein expression and membrane integrity were elucidated by flow cytometry, and immunofluorescence microscopy was used to demonstrate translocation of proteins to the cell nucleus. Results Human 86M1 SCLC cells were found to be resistant to PA killing in vitro. This resistance is mediated by up-regulation of pro-survival protein BCL-xl. However, PA also increases surface expression of death receptors 4 and 5 (DR4 and DR5, respectively). The death receptors’ ligand increased SCLC killing by PA through an apparent caspase-independent route involving activation/translocation of AIF. Conclusion The addition of TRAIL to PA can potentiate apoptosis in a relatively PA-resistant SCLC line (specifically 86M1 cells). More importantly, we are the first to report an active method of resistance to paclitaxel in SCLC via BCL-xl up-regulation. PMID:21965726

HUNTER, TERRI B.; MANIMALA, NEIL J.; LUDDY, KIMBERLY A.; CATLIN, TRACY; ANTONIA, SCOTT J.

2014-01-01

122

Evaluation of combined bevacizumab and intraperitoneal carboplatin or paclitaxel therapy in a mouse model of ovarian cancer  

Microsoft Academic Search

Purpose  To evaluate the pharmacokinetics of bevacizumab following IP and IV administration, and to investigate combined bevacizumab\\u000a therapy (IP or IV) with IP paclitaxel or carboplatin in a mouse model of ovarian cancer.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Bevacizumab pharmacokinetics were investigated following IV or IP dosing, and mice bearing peritoneal A2780 xenografts were\\u000a treated with vehicle, IV or IP bevacizumab, IP paclitaxel, IP paclitaxel with

Dhaval K. Shah; Jean Veith; Ralph J. Bernacki; Joseph P. Balthasar

123

Acquisition of Paclitaxel Resistance Is Associated With a More Aggressive and Invasive Phenotype in Prostate Cancer  

PubMed Central

Drug resistance is a major limitation to the successful treatment of advanced prostate cancer (PCa). Patients who have metastatic, castration-resistant PCa (mCRPC) are treated with chemotherapeutics. However, these standard therapy modalities culminate in the development of resistance. We established paclitaxel resistance in a classic, androgen-insensitive mCRPC cell line (DU145) and, using a suite of molecular and biophysical methods, characterized the structural and functional changes in vitro and in vivo that are associated with the development of drug resistance. After acquiring paclitaxel-resistance, cells exhibited an abnormal nuclear morphology with extensive chromosomal content, an increase in stiffness, and faster cytoskeletal remodeling dynamics. Compared with the parental DU145, paclitaxel-resistant (DU145-TxR) cells became highly invasive and motile in vitro, exercised greater cell traction forces, and formed larger and rapidly growing tumors in mouse xenografts. Furthermore, DU145-TxR cells showed a discrete loss of keratins but a distinct gain of ZEB1, Vimentin and Snail, suggesting an epithelial-to-mesenchymal transition. These findings demonstrate, for the first time, that paclitaxel resistance in PCa is associated with a trans-differentiation of epithelial cell machinery that enables more aggressive and invasive phenotype and portend new strategies for developing novel biomarkers and effective treatment modalities for PCa patients. PMID:23192682

Kim, John J.; Yin, Bo; Christudass, Christhunesa S.; Terada, Naoki; Rajagopalan, Krithika; Fabry, Ben; Lee, Danielle Y.; Shiraishi, Takumi; Getzenberg, Robert H.; Veltri, Robert W.; An, Steven S.; Mooney, Steven M.

2014-01-01

124

Paclitaxel coating of the luminal surface of hemodialysis grafts with effective suppression of  

E-print Network

on the outer surface. Methods: A peristaltic pump and a double-solvent (water and acetone) system were used of hemodialysis grafts is effective in suppressing neointimal hyperplasia in the graft and vascular anastomosis). Compared with the control group, paclitaxel inner-coated vascular grafts significantly suppressed

Park, Jong-Sang

125

Molecular Mechanisms of Paclitaxel Resistance and Resveratrol Sensitivity in MDA-MB-231 Breast Cancer Cells  

E-print Network

Molecular Mechanisms of Paclitaxel Resistance and Resveratrol Sensitivity in MDA-MB-231 Breast to the parent line. It has been suggested that the polyphenol natural compound, resveratrol, which has been sensitive to resveratrol treatment. We observed that treatment with 10-100 µM concentrations of resveratrol

Zhou, Yaoqi

126

Cisplatin and paclitaxel target significant long noncoding RNAs in laryngeal squamous cell carcinoma.  

PubMed

The objectives of this study were to identify specific long noncoding RNAs (lncRNAs) in laryngeal squamous cell carcinoma (LSCC) and to clarify the function of cisplatin and paclitaxel on the confirmed laryngeal cancer lncRNAs. Fifty-four pairs of laryngeal tumor and adjacent normal tissue were collected. Candidate lncRNAs were searched in authorized databases. The significant lncRNAs were identified and confirmed through high-output real-time PCR. Chemotherapy assay evaluated the influences of cisplatin and paclitaxel on the significant lncRNAs. Thirty-seven cancer-related candidate lncRNAs were selected. Three up-expressed and two down-expressed significant lncRNAs were identified and confirmed. The expressions of lncRNA CDKN2B-AS1, HOTAIR and MALAT1 were dramatically reduced with the increasing concentration of cisplatin and paclitaxel and also lengthening of the treatment duration. Cisplatin and paclitaxel have target function on significant lncRNAs in LSCC, which presents novel molecular targets to cure LSCC patients and also leads an orientation for developing new drugs. PMID:25257554

Chen, Hui; Xin, Yuan; Zhou, Liang; Huang, Jia-Meng; Tao, Lei; Cheng, Lei; Tian, Jie

2014-11-01

127

Establishment of opioid-induced rewarding effects under oxaliplatin- and Paclitaxel-induced neuropathy in rats.  

PubMed

The rewarding effects of ?-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used ?-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of ?-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug-induced neuropathic pain. Nevertheless, no information is available regarding whether ?-receptor agonists produce psychological dependence under chemotherapeutic drug-induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of ?-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of ?-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of ?-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on ?-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain. PMID:25141998

Mori, Tomohisa; Kanbara, Tomoe; Harumiya, Masato; Iwase, Yoshiyuki; Masumoto, Aki; Komiya, Sachiko; Nakamura, Atsushi; Shibasaki, Masahiro; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Suzuki, Tsutomu

2014-09-20

128

Improved paclitaxel and baccatin III production in suspension cultures of Taxus media.  

PubMed

A cell suspension culture of Taxus media was established from a stable callus line of this species. The growth rate and production of paclitaxel and baccatin III of this cell suspension were significantly increased during the shake flask culture in its respective optimum media for cell growth and product formation, which were selected after assaying 24 different culture media. The highest yields of paclitaxel (2.09 mg L(-1)) and baccatin III (2.56 mg L(-1)) in the production medium rose (factors of 7.0 and 3.0, respectively) in the presence of methyljasmonate (220 microg g(-1) FW). When the elicitor was added together with mevalonate (0.38 mM) and N-benzoylglycine (0.2 mM), the increase in the yields of paclitaxel and baccatin III was even higher (factors of 8.3 and 4.0, respectively). Thereafter, a two-stage culture for cell suspension was carried out using a 5-l stirred bioreactor running for 36 days, the first stage being in the cell growth medium until cells entered their stationary growth phase (12 days) and the second stage being in the production medium supplemented with the elicitor and two putative precursors in the concentrations indicated above. Under these conditions, 21.12 mg L(-1) of paclitaxel and 56.03 mg L(-1) of baccatin III were obtained after 8 days of culture in the production medium. PMID:12052053

Cusidó, Rosa M; Palazón, Javier; Bonfill, Mercedes; Navia-Osorio, Alberto; Morales, Carmen; Piñol, M Teresa

2002-01-01

129

Use of the tubulin bound paclitaxel conformation for structure-based rational drug design.  

PubMed

A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts. PMID:15797218

Geney, Raphaël; Sun, Liang; Pera, Paula; Bernacki, Ralph J; Xia, Shujun; Horwitz, Susan B; Simmerling, Carlos L; Ojima, Iwao

2005-03-01

130

[A case of advanced breast cancer successfully treated with paclitaxel and toremifene therapy].  

PubMed

We report a case of advanced breast cancer with skin ulceration and bleeding (T4bN3bM0: Stage IIIC) achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 38-year-old woman with slight anemia who had ulcerative breast lump with skin ulcer. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesteron receptor, and negative for HER2/neu protein expression. She received 6 cycles of tri-weekly FEC (C: 500 mg, E: 60 mg, F: 500 mg/m2) and 16 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The anemia and the bleeding from the tumor disappeared after FEC chemotherapy. The response for breast tumor after paclitaxel and toremifene therapy was evaluated as partial response, and the infraclavicular, subpectoral, and interpectoral lymph nodes metastasis disappeared. Muscle-preserving radical mastectomy (Bt + Ax: Auchincloss) with skin transplantation was performed. She had no recurrence during one year after the operation. Paclitaxel and Toremifene therapy was effective for advanced breast tumor, and can improve a patient QOL and the clinical outcomes in Stage IIIC advanced breast cancer. PMID:19106576

Sakurai, Kenichi; Enomoto, Katsuhisa; Tani, Mayumi; Kitajima, Akira; Amano, Sadao; Shiono, Motomi

2008-11-01

131

Effects of emulsifiers on the controlled release of paclitaxel (Taxol ®) from nanospheres of biodegradable polymers  

Microsoft Academic Search

Paclitaxel (Taxol®) is an antineoplastic drug effective for various cancers especially ovarian and breast cancer. Due to its high hydrophobicity, however, an adjuvant such as Cremophor EL has to be used in its clinical administration, which causes serious side-effects. Nanospheres of biodegradable polymers could be an ideal solution. This study investigates the effects of various emulsifiers on the physical\\/chemical properties

Si-shen Feng; Guofeng Huang

2001-01-01

132

Screening of the needles of different yew species and cultivars for paclitaxel and related taxoids  

Microsoft Academic Search

The needles of several yew species and cultivars were analysed by high-pressure liquid chromatography for paclitaxel, 10-deacetylpaclitaxel, cephalomannine, baccatin III, 10-deacetylbaccatin III and brevifoliol. About 750 samples were collected from five different locations in the Netherlands and the UK. The results of this screening show a large variation in taxane content between the different species and cultivars. The content of

Erik L. M van Rozendaal; Gerrit P Lelyveld; Teris A van Beek

2000-01-01

133

Initiation, Growth and Immobilisation of Cell Cultures of Taxus spp. for Paclitaxel Production  

Microsoft Academic Search

Paclitaxel (Taxol), a cytotoxic diterpene initially isolated from the bark of Taxus brevifolia (Pacific yew), has been approved for cancer treatment. Since total chemical synthesis is not economical, plant biotechnology can offer an alternative route for the production of this drug. Callus cultures were initiated from different explants of Taxus x media and Taxus cuspidata on various media using different

CHI WAI TANG; Eman Zalat; Ferda Mavituna

134

Negative Impact of Paclitaxel Crystallization on Hydrogels and Novel Approaches for  

E-print Network

32 Negative Impact of Paclitaxel Crystallization on Hydrogels and Novel Approaches for Anticancer the intravenously administration of the drug, process termed as chemotherapy. This technique has brought many. Based in facts we point a delicate issue, Taxol crystallization in hydrogels and its negative impact

Deymier, Pierre

135

Activity of Gemcitabine in Patients with Advanced Ovarian Cancer: Responses Seen Following Platinum and Paclitaxel  

Microsoft Academic Search

Thirty-eight women with epithelial ovarian cancer were treated with gemcitabine, a new antimetabolite. All had previously received platinum, and 27 had also received paclitaxel. Four patients had a partial response giving a response rate of 13% in assessable patients (n= 31) and 11% for all patients entered. Additionally, 6 patients had stable disease with >50% reduction in CA-125 for at

Jeremy D. Shapiro; Michael J. Millward; Danny Rischin; Michael Michael; Vicki Walcher; Prudence A. Francis; Guy C. Toner

1996-01-01

136

Coating with paclitaxel improves graft survival in a porcine model of haemodialysis graft stenosis  

Microsoft Academic Search

Background. Most commonly resulting from intimal hyperplasia at the venous anastomosis, stenosis leading to thrombosis is a major cause of failure of polytetra- fluoroethylene (PTFE) dialysis grafts. We recently reported that coating haemodialysis grafts with pacli- taxel could reduce neointimal hyperplasia. This study tested whether paclitaxel-coating could prolong graft survival in a porcine model. Methods. PTFE grafts were double-coated with

Byung Ha Lee; Jung Eun Lee; Kwang Woong Lee; Hye Yeong Nam; Hyun Jung Jeon; Young Ju Sung; Jong Sung Kim; Hyun Jung Lim; Jong-sang Park; Jai Young Ko; Dae Joong Kim

2007-01-01

137

Polymeric nanoparticles for the intracellular delivery of paclitaxel in lung and breast cancer  

NASA Astrophysics Data System (ADS)

Nanoparticles are useful for addressing many of the difficulties encountered when administering therapeutic compounds. Nanoparticles are able to increase the solubility of hydrophobic drugs, improve pharmacokinetics through sustained release, alter biodistribution, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues. The use of functional nanocarriers can also provide controlled intracellular delivery of a drug. To this end, we have developed functional pH-responsive expansile nanoparticles for the intracellular delivery of paclitaxel. The pH-responsiveness of these nanoparticles occurs due to a hydrophobic to hydrophilic transition of the polymer occurring under mildly acidic conditions. These polymeric nanoparticles were systematically evaluated for the delivery of paclitaxel in vitro and in vivo to improve local therapy for lung and breast cancers. Nanoparticles were synthesized using a miniemulsion polymerization process and were subsequently characterized and found to swell when exposed to acidic environments. Paclitaxel was successfully encapsulated within the nanoparticles, and the particles exhibited drug release at pH 5 but not at pH 7.4. In addition, the uptake of nanoparticles was observed using flow cytometry, and the anticancer efficacy of the paclitaxel-loaded nanoparticles was measured using cancer cell lines in vitro. The potency of the paclitaxel-loaded nanoparticles was close to that of free drug, demonstrating that the drug was effectively delivered by the particles and that the particles could act as an intracellular drug depot. Following in vitro characterization, murine in vivo studies demonstrated the ability of the paclitaxel-loaded responsive nanoparticles to delay recurrence of lung cancer and to prevent establishment of breast cancer in the mammary fat pads with higher efficacy than paclitaxel alone. In addition, the ability of nanoparticles to migrate up to 40 cm through lymphatic channels to local lymph nodes was demonstrated using near infrared imaging in a large animal model. Continued investigation of functional nanoparticles, like the system described here for lung and breast cancer, will facilitate the development of new materials that meet the varied and demanding needs in chemotherapy, and may afford new treatment options for the local and metastatic control of many forms of cancer.

Zubris, Kimberly Ann Veronica

138

Digitoxin activates EGR1 and synergizes with paclitaxel on human breast cancer cells  

PubMed Central

Background: Numerous studies have suggested that digitalis derivatives promise to be superior to existing adjuvant therapy for breast cancer as to effects and side-effects. In the present study, we have used gene expression analysis to determine the molecular action of digitoxin on breast cancer cells and assessed digitoxin’s ability to synergize with the chemotherapy agent paclitaxel with respect to inhibition of cell proliferation Materials and Methods: We treated (Her2 overexpressing, ER low) MDA-MB-453 human breast cancer cells with digitoxin at four doses {20 ng/ml (26 nM) to 1 ?g/ml} and collected RNA at 6 h and 24 h for gene expression analysis. To examine the effects on ER positive cells, we treated MCF7 cells with digitoxin at 1 ?g/ml and collected RNA for RT-PCR analysis. In addition, we assayed the growth inhibitory effect of low doses of digitoxin combined with paclitaxel and determined combination index values. Results: To reveal primary effects, we examined digitoxin’s effect 6 h post-treatment with the highest dose, 1?g/ml, and found upregulation of the stress response genes EGR-1 and NAB2, lipid biosynthetic genes and the tumor suppressor gene p21, and downregulation of the mitotic cell cycle gene CDC16 and the replication gene PolR3B. RT-PCR analysis validated effects on stress response, apoptotic and cell cycle genes on MDA-MB-453 and MCF7 cells. Western blot analysis confirmed induction of EGR1 protein at 1 h and ATF3 at 24 h. Paclitaxel, as well as digitoxin, inhibited the in vitro activity of the purified Na+-K+-ATPase; digitoxin enhanced the growth inhibitory effects of paclitaxel on Her2 overexpressing breast cancer cells. Conclusions: Our studies show the potential of digitoxin to prevent and treat breast cancer and indicate that the combination of digitoxin and paclitaxel is a promising treatment for ER negative breast cancer. These findings are the first to alert physicians to the possible dangers to patients who take a combination of digitoxin and paclitaxel. The potential dangers ensuing when paclitaxel and digitoxin are combined are dependent on the dose of digitoxin. PMID:21139994

Einbond, Linda Saxe; Wu, Hsan-au; Su, Tao; Chang, Tangel; Panjikaran, Maya; Wang, Xiaomei; Goldsberry, Sarah

2010-01-01

139

Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells.  

PubMed

The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors. PMID:16059735

Ehrlichova, Marie; Vaclavikova, Radka; Ojima, Iwao; Pepe, Antonella; Kuznetsova, Larisa V; Chen, Jin; Truksa, Jaroslav; Kovar, Jan; Gut, Ivan

2005-07-01

140

Genetic inactivation and pharmacological blockade of sigma-1 receptors prevent paclitaxel-induced sensory-nerve mitochondrial abnormalities and neuropathic pain in mice  

PubMed Central

Background Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (?1R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities. In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the ?1R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (?1R knockout mice) and pharmacological (?1R antagonist) approaches. Results Paclitaxel administration to wild-type (WT) mice produced cold- and mechanical-allodynia, and an increase in the frequency of swollen and vacuolated mitochondria in myelinated A-fibers, but not in C-fibers, of the saphenous nerve. Behavioral and mitochondrial alterations were marked at 10 days after paclitaxel-administration and had resolved at day 28. In contrast, paclitaxel treatment did not induce allodynia or mitochondrial abnormalities in ?1R knockout mice. Moreover, the prophylactic treatment of WT mice with BD-1063 also prevented the neuropathic pain and mitochondrial abnormalities induced by paclitaxel. Conclusions These results suggest that activation of the ?1R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, ?1R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy. PMID:24517272

2014-01-01

141

Raman confocal microscopy and AFM combined studies of cancerous cells treated with Paclitaxel  

NASA Astrophysics Data System (ADS)

Paclitaxel interferes with the normal function of microtubule breakdown, induces apoptosis in cancer cells and sequesters free tubulin. As this drug acts also on other cell mechanisms it is important to monitor its accumulation in the cell compartments. The intracellular spreading of the drug was followed using a WITEC 300R confocal Raman microscope equipped with a CCD camera. Hence Atomic force microscopy (an MFP3D- Asylum Research AFM) in imaging and force mode was used to determine the morphological and mechanical modifications induced on living cells. These studies were performed on living epithelial MCF-7 breast cancer cells. Paclitaxel was added to cell culture media for 3, 6 and 9 hours. Among the specific paclitaxel Raman bands we selected the one at 1670 cm-1 because it is not superposed by the spectrum of the cells. Confocal Raman images are formed by monitoring this band, the NH2 and the PO4 band. Paclitaxel slightly accumulates in the nucleus forming patches. The drug is also concentrated in the vicinity of the cell membrane and in an area close to the nucleus where proteins accumulate. Our AFM images reveal that the treated cancerous MCF-7 cells keep the same size as the non treated ones, but their shape becomes more oval. Cell's elasticity is also modified: a difference of 2 kPa in the Young Modulus characterizes the treated MCF-7 mammary cancerous cell. Our observations demonstrate that paclitaxel acts not only on microtubules but accumulates also in other cell compartments (nucleus) where microtubules are absent.

Derely, L.; Collart Dutilleul, P.-Y.; Michotte de Welle, Sylvain; Szabo, V.; Gergely, C.; Cuisinier, F. J. G.

2011-03-01

142

Design, Synthesis and Biological Assessment of a Triazine Dendrimer with Approximately 16 Paclitaxel Groups and 8 PEG Groups  

E-print Network

to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation

Annunziata, Onofrio

143

Dosimetric predictors of radiation esophagitis in patients treated for non-small-cell lung cancer with carboplatin\\/paclitaxel\\/radiotherapy  

Microsoft Academic Search

Purpose: To establish dosimetric predictors of radiation esophagitis (RE) in patients treated with a combination of carboplatin, paclitaxel, and radiotherapy.Methods and Materials: Three-dimensional radiotherapy plans of 26 patients with non-small-cell lung cancer who received 50–60 Gy of radiotherapy concurrently with weekly administration of carboplatin (AUC 2) and paclitaxel (40–45 mg\\/m2) were reviewed in conjunction with RE. The factors analyzed included

Saeko Hirota; Kayoko Tsujino; Masahiro Endo; Yoshikazu Kotani; Miyako Satouchi; Tetsuji Kado; Yoshio Hishikawa; Kayoko Obayashi; Yoshiki Takada; Michio Kono; Mitsuyuki Abe

2001-01-01

144

Randomized Trial of Paclitaxel Plus Supportive Care Versus Supportive Care for Patients With Advanced Non-Small-Cell Lung Cancer  

Microsoft Academic Search

Background: In phase II trials, paclitaxel has been shown to have antitumor activity in patients with advanced non-small- cell lung cancer (NSCLC). However, the survival and qual- ity-of-life (QOL) benefits of paclitaxel used as a single agent compared with supportive care alone have not been assessed in a randomized clinical trial. Methods: A total of 157 pa- tients with stage

Malcolm Ranson; Neville Davidson; Marianne Nicolson; Stephen Falk; Jim Carmichael; Pedro Lopez; Heather Anderson; Nancy Gustafson; Allison Jeynes; Giles Gallant; Terri Washington; Nick Thatcher

2000-01-01

145

Oxycodone Induces Overexpression of P-Glycoprotein (ABCB1) and Affects Paclitaxel's Tissue Distribution in Sprague Dawley Rats  

PubMed Central

Previous studies suggest that P-glycoprotein (P-gp) modulates the PK/PD of many compounds including opioid agonists and chemotherapeutic agents. The objective of this study was to assess the P-gp affinity status of oxycodone, the P-gp expression, and the paclitaxel’s tissue distribution in oxycodone-treated rats. P-gp ATPase assay, Caco-2 transepithelial permeability studies, and mdr1a/b (?/?) mice were used to assess the P-gp affinity status of oxycodone. P-gp expression was determined by Western blot analysis while [14C] paclitaxel’s distributions in the liver, kidney, brain, and plasma tissues were determined by liquid scintillation counter. Oxycodone stimulated the P-gp ATPase activity in a concentration-dependant manner. The Caco-2 secretory transport of oxycodone was reduced from 3.64 ×10?5 to 1.96 × 10?5 cm/s (p <0.05) upon preincubation with the P-gp inhibitor, verapamil. The brain levels of oxycodone in mdr1a/b (+/+) were not detectable (<15 ng/mL) while in mdr1a/b (?/?) the average levels were 115 ± 39 ng/mL. The P-gp protein levels were increased by 1.3–4.0 folds while paclitaxel’s tissue distributions were decreased by 38–90% (p <0.05) in oxycodone-treated rats. These findings display that oxycodone is a P-gp substrate, induces overexpression of P-gp, and affects paclitaxel’s tissue distribution in a manner that may influence its chemotherapeutic activity. PMID:17593551

HASSAN, HAZEM E.; MYERS, ALAN L.; LEE, INSONG J.; COOP, ANDREW; EDDINGTON, NATALIE D.

2012-01-01

146

Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate).  

PubMed

Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a (1)H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a (1)H-NMR study in D2O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell-bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery. PMID:25288916

Kim, Hyun Yul; Ryu, Je Ho; Chu, Chong Woo; Son, Gyung Mo; Jeong, Young-Il; Kwak, Tae-Won; Kim, Do Hyung; Chung, Chung-Wook; Rhee, Young Ha; Kang, Dae Hwan; Kim, Hyung Wook

2014-01-01

147

Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate)  

PubMed Central

Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a 1H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a 1H-NMR study in D2O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell-bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery. PMID:25288916

2014-01-01

148

Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF7 breast cancer cells  

Microsoft Academic Search

Paclitaxel (Taxol®) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This

Antony Chadderton; David J. Villeneuve; Stefan Gluck; Angie F. Kirwan-Rhude; Brian R. Gannon; David E. Blais; Amadeo M. Parissenti

2000-01-01

149

Preparation and characterization of poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel  

Microsoft Academic Search

Microspheres of a new kind of copolymer, poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA), are proposed in the present work for clinical administration of an antineoplastic drug paclitaxel with hypothesis that incorporation of a hydrophilic PEG segment within the hydrophobic PLA might facilitate the paclitaxel release. Paclitaxel-loaded PLA–PEG–PLA microspheres of various compositions were prepared by the solvent extraction\\/evaporation method. Characterization of the

Gang Ruan; Si-Shen Feng

2003-01-01

150

Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype.  

PubMed

In an attempt to define the molecular changes associated with the paclitaxel-resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell line, SKOV-3TR, was established through stepwise selection in increasing paclitaxel concentrations. SKOV-3TR was cross- resistant to doxorubicin and vincristine and overexpressed multidrug resistance gene 1 but not multidrug resistance associated protein. SKOV-3TR and the paclitaxel-sensitive SKOV-3 parent line were characterized using human cDNA array technology that examined expression of a wide variety of genes involved in cell growth, signal transduction, cell death, and immune function. cDNA probes from reverse transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to identify genes differentially expressed in the paclitaxel-resistant cells. Of 588 different human cDNA transcripts compared, 6 genes were found to be markedly decreased, and 12 genes increased in the resistant subline. Northern analysis and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over- or underexpressed in SKOV-3TR. In addition, at least eight of the genes were found differentially expressed in several other paclitaxel- and/or doxorubicin-resistant cell lines, both those with increased multidrug resistance expression and those without. Included in the set of overexpressed genes were the cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic protein 1. ELISA assays confirm that mRNA overexpression of these cytokine/chemokines was associated with the increased secretion of these molecules in the tissue culture supernatant. Evaluation of supernatants from an expanded collection of paclitaxel- and Adriamycin-resistant cell lines demonstrated that all of the resistant lines had significant overexpression of at least one cytokine/chemokine as compared with their drug-sensitive parent line. The overexpression of these cytokines seemed to be stable and associated with a drug-resistant phenotype with only a modest induction of cytokine expression in the parent line with short-term paclitaxel exposure. These findings suggest that the development of paclitaxel resistance is accompanied by multiple changes in gene expression including stable alterations in selective chemokine and cytokine expression. The role these associated genetic changes have in the drug-resistant phenotype is discussed. PMID:10589757

Duan, Z; Feller, A J; Penson, R T; Chabner, B A; Seiden, M V

1999-11-01

151

Silencing of astrin induces the p53-dependent apoptosis by suppression of HPV18 E6 expression and sensitizes cells to paclitaxel treatment in HeLa cells.  

PubMed

Astrin is a microtubule-associated protein and localizes with mitotic spindles in the M-phase. We silenced the expression of astrin protein and tested the cell viability in response to paclitaxel treatment in paclitaxel-sensitive and paclitaxel-resistant cells. We found that the absence of astrin by siRNA resulted in the activation of a p53-dependent apoptosis, which elevated pro-apoptotic Bax expression and increased the activity of caspase-3 in astrin-depleted cells. The HPV18 E6 transcription was found to be inhibited along with the increase expression of p53. Intriguingly, the expression of astrin decreased in paclitaxel-sensitive HeLa cells but remained steady in paclitaxel-resistant cells in response to paclitaxel treatment. Furthermore, we identified that the depletion of astrin caused more cell death both in paclitaxel-sensitive and -resistant cells in combination with paclitaxel treatment. These findings suggest that the silencing of astrin induce a p53-dependent apoptosis and has an additive effect on paclitaxel treatment. PMID:16546135

Yang, Yuh-Cheng; Hsu, Yun-Ting; Wu, Chao-Chih; Chen, Hsiang-Ting; Chang, Mau-Sun

2006-05-01

152

Nanoparticle albumin-bound paclitaxel in a patient with locally advanced breast cancer and taxane-induced skin toxicity: a case report  

PubMed Central

Introduction Taxanes have demonstrated effectiveness in the treatment of breast cancer, the most common type of cancer in women. The toxicity profile of taxanes (including skin toxicities) induces dose adjustment, delay, or discontinuation, which prevents a sufficient dose intensity to achieve a response. Nanoparticle albumin-bound paclitaxel, a solvent-free form of paclitaxel, prevents toxicities and reduces the pharmacokinetic interferences between paclitaxel and other drugs. Case presentation We describe the case of a 55-year-old Caucasian woman with locally advanced breast cancer treated with neoadjuvant therapy who developed secondary skin toxicity due to delayed hypersensitivity to taxanes. She received Adriamycin® (doxorubicin), cyclophosphamide and docetaxel and developed toxicity that promoted treatment delay and a switch to weekly paclitaxel. After the third and fourth weeks of treatment, paclitaxel toxicities also induced treatment delay and paclitaxel was switched to nanoparticle albumin-bound paclitaxel. She completed the five planned nanoparticle albumin-bound paclitaxel cycles with acceptable tolerability (including persistent grade 2 neuropathy) and without dose delay or adjustments. Clinical response was achieved although pathological response was not good. Conclusions Nanoparticle albumin-bound paclitaxel treatment is a good option for patients with breast cancer with taxanes-related skin toxicity. This drug allows the treatment to be completed with acceptable tolerance in our case. PMID:24386978

2014-01-01

153

Fabrication of Micro and Nanoparticles of Paclitaxel-loaded Poly L Lactide for Controlled Release using Supercritical Antisolvent Method: Effects of Thermodynamics and Hydrodynamics  

E-print Network

This paper presents the fabrication of controlled release devices for anticancer drug paclitaxel using supercritical antisolvent method. The thermodynamic and hydrodynamic effects during supercritical antisolvent process ...

Lee, Lai Yeng

154

Electrocoating of stainless steel coronary stents for extended release of paclitaxel.  

PubMed

Nonbiodegradable polymer coating based on N-(2-carboxyethyl)pyrrole (PPA) and butyl ester of PPA (BuOPy) were successfully electrodeposited on a stainless steel stent surface using cyclic voltammetry. Chemical composition of the coating was examined by X-ray photoelectron spectroscopy. Polymer stability was examined by immersing the coated stent into 1:1 solution of fetal calf serum:seline solution up to 1 year and implantation subcutaneously in mouse for 1 week. Morphology changes were then recorded by scanning electron microscopy. Paclitaxel loading was carried out by immersion into drug solution and its release was detected by HPLC. The results show that thin (single micrometers), uniform coating with various morphology and hydrophobicity can be created by electrochemical deposition. The polymer did not show significant histopathological or morphological changes in vitro and in vivo. The surface properties allow loading appropriate amounts of paclitaxel and release it slowly up to a month. PMID:18306316

Okner, R; Oron, M; Tal, N; Nyska, A; Kumar, N; Mandler, D; Domb, A J

2009-02-01

155

Screening of the needles of different yew species and cultivars for paclitaxel and related taxoids.  

PubMed

The needles of several yew species and cultivars were analysed by high-pressure liquid chromatography for paclitaxel, 10-deacetylpaclitaxel, cephalomannine, baccatin III, 10-deacetylbaccatin III and brevifoliol. About 750 samples were collected from five different locations in the Netherlands and the UK. The results of this screening show a large variation in taxane content between the different species and cultivars. The content of paclitaxel and 10-deacetylbaccatin III varied from 0 to 500 micrograms/g and 0 to 4800 micrograms/g dried needles, respectively. Brevifoliol was found in a very high concentration in Taxus brevifolia. 10-Deacetylpaclitaxel, cephalomannine and baccatin III were found in concentrations ranging from 0 to 500 micrograms/g dried needles. PMID:10703062

van Rozendaal, E L; Lelyveld, G P; van Beek, T A

2000-02-01

156

Detection of apoptosis caused by anticancer drug paclitaxel in MCF-7 cells by confocal Raman microscopy  

NASA Astrophysics Data System (ADS)

Confocal Raman Microscopy, a non-invasive, label free imaging technique is used to study apoptosis in living MCF-7 cells. The images are based on Raman spectra of cells components. K-mean clustering was used to determine mitochondria position in cells and cytochrome c distribution inside the cells was based on correlation analysis. Cell apoptosis is defined as cytochrome c diffusion in cytoplasm. Co-localization of cytochrome c is found within mitochondria after three hours of incubation with 10 ?M paclitaxel. Our results demonstrate that the presence of paclitaxel at this concentration in the culture media for 3 hours does not induce apoptosis of MCF7 cells via a caspase independent pathway.

Salehi, H.; Middendorp, E.; Végh, A.-G.; Ramakrishnan, S.-K.; Gergely, C.; Cuisinier, F. J. G.

2013-02-01

157

Confocal Raman data analysis enables identifying apoptosis of MCF-7 cells caused by anticancer drug paclitaxel  

NASA Astrophysics Data System (ADS)

Confocal Raman microscopy is a noninvasive, label-free imaging technique used to study apoptosis of live MCF-7 cells. The images are based on Raman spectra of cells components, and their apoptosis is monitored through diffusion of cytochrome c in cytoplasm. K-mean clustering is used to identify mitochondria in cells, and correlation analysis provides the cytochrome c distribution inside the cells. Our results demonstrate that incubation of cells for 3 h with 10 ?M of paclitaxel does not induce apoptosis in MCF-7 cells. On the contrary, incubation for 30 min at a higher concentration (100 ?M) of paclitaxel induces gradual release of the cytochrome c into the cytoplasm, indicating cell apoptosis via a caspase independent pathway.

Salehi, Hamideh; Middendorp, Elodie; Panayotov, Ivan; Dutilleul, Pierre-Yves Collard; Vegh, Attila-Gergely; Ramakrishnan, Sathish; Gergely, Csilla; Cuisinier, Frederic

2013-05-01

158

2'-Behenoyl-Paclitaxel Conjugate Containing Lipid Nanoparticles for the Treatment of Metastatic Breast Cancer  

PubMed Central

The aim of these studies was to develop a novel 2’-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in-vitro and in-vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. PMID:22902506

Ma, Ping; Benhabbour, S. Rahima; Feng, Lan; Mumper, Russell J

2012-01-01

159

Development and evaluation of paclitaxel loaded PLGA:poloxamer blend nanoparticles for cancer chemotherapy.  

PubMed

This investigation described the development of novel PLGA:poloxamer blend nanoparticles for intravenous administration of paclitaxel in order to limit the cremophor-associated adverse effects. The developed formulation was well-characterized using various techniques including scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. The nanoparticles had an average particle size around 180nm and zeta potential of -22.7mV. The in vitro release study of nanoparticles exhibited biphasic release pattern. The non-hemolytic potential of the nanoparticles indicated the suitability of the developed formulation for intravenous administration. The PLGA:poloxamer blend nanoparticles showed significantly improved cytotoxicity in cell lines (MCF-7 and Colo-205), as compared to free drug. Further, the developed formulation was stable under the accelerated storage conditions. In conclusion, the results indicated that the developed polymeric formulation is a novel and potential alternative for the paclitaxel delivery. PMID:24942992

Gupta, Prem N; Jain, Sharad; Nehate, Chetan; Alam, Noor; Khare, Vaibhav; Dubey, Ravindra Dhar; Saneja, Ankit; Kour, Smit; Singh, Shashank K

2014-08-01

160

Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway.  

PubMed

Mesothelin, a secreted protein, is overexpressed in some cancers, but its exact function remains unclear. The aim of the present study was to evaluate the possible function of mesothelin. Real-time PCR, RT (reverse transcription)-PCR, cytotoxicity assays, proliferative assays, apoptotic assays by Hoechst staining, detection of active caspases 3 and 7 by flow cytometric analysis, and immunoprecipitation and immunoblotting were performed. Cancer tissues in paclitaxel-resistant ovarian cancer patients expressed higher levels of mesothelin as assessed using real-time PCR than paclitaxel-sensitive ovarian cancer patients (the mean crossing point value change of mesothelin was 26.9+/-0.4 in the resistant group and 34.3+/-0.7 for the sensitive group; P<0.001). Mesothelin also protected cells from paclitaxel-induced apoptosis. The protein expression of Bcl-2 family members, such as Bcl-2 and Mcl-1, was significantly increased regardless of whether cells were treated with exogenous mesothelin or were mesothelin-transfectants. Furthermore, mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 1/2 for enhancing MAPK (mitogen-activated protein kinase) activity. The anti-apoptotic ability was suppressed and the expression of Bcl-2 family in response to mesothelin was altered by inhibiting PI3K activity, but not by inhibiting MAPK activity. Thus mesothelin can inhibit paclitaxel-induced cell death mainly by involving PI3K signalling in the regulation of Bcl-2 family expression. Mesothelin is a potential target in reducing resistance to cytotoxic drugs. PMID:19747165

Chang, Ming-Cheng; Chen, Chi-An; Hsieh, Chang-Yao; Lee, Chien-Nan; Su, Yi-Ning; Hu, Yu-Hao; Cheng, Wen-Fang

2009-12-15

161

Optimization of productivity in solvent gradient simulated moving bed for paclitaxel purification  

Microsoft Academic Search

The isocratic and solvent gradient SMBs for paclitaxel purification were optimized to maximize productivity under constraints of product purities and zone flow rate. The solvent composition in the feed and in the desorbent, zone flow rates, and switching time were optimized using non-dominated sorting genetic algorithm with elitism and jumping genes (NSGA-II-JG) and rate model simulations. The highest productivity is

Sungyong Mun; Nien-Hwa Linda Wang

2008-01-01

162

Methylseleninic Acid Enhances Paclitaxel Efficacy for the Treatment of Triple-Negative Breast Cancer  

Microsoft Academic Search

A major challenge in breast cancer therapy is the lack of an effective therapeutic option for a particularly aggressive subtype of breast cancer, triple-negative breast cancer. Here we provide the first preclinical evidence that a second-generation selenium compound, methylseleninic acid, significantly enhances the anticancer efficacy of paclitaxel in triple-negative breast cancer. Through combination-index value calculation, we demonstrated that methylseleninic acid

Yanfeng Qi; Xueqi Fu; Zhenggang Xiong; Haitao Zhang; Steven M. Hill; Brian G. Rowan; Yan Dong

2012-01-01

163

Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel  

Microsoft Academic Search

Understanding the molecular events that lead to paclitaxel (TX) resistance is necessary to identify effective means to prevent\\u000a chemoresistance. Previously, results from our lab revealed that secretory clusterin (CLU) form positively mediates TX response\\u000a in ovarian cancer cells. Thus, we had interest to study the role of another non-secreted form (intracellular clusterin (i-CLU))\\u000a in chemo-response. Here, we provide evidences that

Mohamed Kamel Hassan; Hidemichi Watari; Saverio Bettuzzi; Noriaki Sakuragi

164

Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines  

SciTech Connect

Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of survivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin dose-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating an essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that in turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer.

Ho, T.-F. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Medical Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan (China); Peng, Y.-T.; Chuang, S.-M.; Lin, S.-C.; Feng, B.-L. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Lu, C.-H. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Yu, W.-J. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Chang, J.-S. [Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (China); Sustainable Environment Research Center, National Cheng Kung University, Tainan, Taiwan (China)], E-mail: changjs@mail.ncku.edu.tw; Chang, C.-C. [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China)], E-mail: chia_che@dragon.nchu.edu.tw

2009-03-01

165

Endostatin gene therapy enhances the efficacy of paclitaxel to suppress breast cancers and metastases in mice  

Microsoft Academic Search

Chemotherapy combined with antiangiogenic therapy is more effective than chemotherapy alone. The aim of this study was to\\u000a investigate whether endostatin, a potent anti-angiogenic agent, could enhance the efficacy of paclitaxel to combat breast\\u000a cancer. An expression plasmid encoding mouse endostatin (End-pcDNA3.1) was constructed, which produced intense expression\\u000a of endostatin and inhibited angiogenesis in the chorioallantoic membrane assay. 4T1 breast

Jie Li; Xuesong Dong; Zongzhen Xu; Xian Jiang; Hongchi Jiang; Geoffrey W Krissansen; Xueying Sun

2008-01-01

166

Long Circulating Lectin Conjugated Paclitaxel Loaded Magnetic Nanoparticles: A New Theranostic Avenue for Leukemia Therapy  

Microsoft Academic Search

Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs

Abhalaxmi Singh; Fahima Dilnawaz; Sanjeeb Kumar Sahoo

2011-01-01

167

Syngeneic Mouse Model of Epithelial Ovarian Cancer: Effects of Nanoparticulate Paclitaxel, Nanotax®  

Microsoft Academic Search

In 2006, it has been estimated that 20,180 women in the United States will be diagnosed with ovarian cancer, and 15,310 women\\u000a will die from the disease (1). Although advances have occurred in treatment strategies, success remains limited (1). The median\\u000a overall survival for patients with advanced ovarian cancer and receiving the current standards of treatment (surgery and paclitaxel\\/platinum\\u000a chemotherapy)

Katherine F. Roby; Fenghui Niu; Roger A. Rajewski; Charles Decedue; Bala Subramaniam; Paul F. Terranova

168

PACLITAXEL SENSITIVITY CORRELATES WITH P53 STATUS AND DNA FRAGMENTATION, BUT NOT G2\\/M ACCUMULATION  

Microsoft Academic Search

Purpose: The antitumor agent paclitaxel (Taxolt) has been shown to arrest cells in mitosis through microtubule stabilization and to induce apoptosis. The tumor suppressor gene p53 is implicated in the regulation of cell cycle checkpoints and can mediate apoptotic cell death. Although initial studies demonstrated that various DNA-damaging agents can induce p53, more recent studies have also shown p53 induction

EILEEN RAKOVITCH; WILFREDO MELLADO; ERIC J. HALL; D. PHIL; TEJ K. PANDITA; SATIN SAWANT; CHARLES R. GEARD

1999-01-01

169

Influence of drug formulation on OATP1B-mediated transport of paclitaxel.  

PubMed

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P<0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. PMID:24755470

Nieuweboer, Annemieke J M; Hu, Shuiying; Gui, Chunshan; Hagenbuch, Bruno; Ghobadi Moghaddam-Helmantel, Inge M; Gibson, Alice A; de Bruijn, Peter; Mathijssen, Ron H J; Sparreboom, Alex

2014-06-01

170

Nab-paclitaxel for the management of triple-negative metastatic breast cancer: a case study  

PubMed Central

The optimal sequence of systemic chemotherapy in metastatic breast cancer (MBC) is unknown. We report the case of a woman who was successfully treated with nanoparticle albumin-bound (nab)-paclitaxel for triple negative MBC in our institution. In November 2008, a 48-year-old woman underwent surgical treatment for a triple negative invasive ductal breast cancer and subsequently received adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide and radiotherapy. Sixteen months after surgery, she presented with a left chest wall metastatasis. The patient received combination therapy with conventional paclitaxel (90mg/m² weekly for 3 out of 4 weeks [QW 3/4]) and bevacizumab (10mg/kg every 2 weeks [Q2W]) as first-line treatment for MBC (six cycles; March to September 2010) and achieved a partial response at the metastatic site. Bevacizumab monotherapy was continued until disease progression (April 2011) with the development of a single infraclavicular lymph node metastasis and an increase in the dimensions of the left chest wall lesion. From May to December 2011, the patient received nab-paclitaxel 260mg/m² every 3 weeks (Q3W) as second-line treatment (11 cycles). After three cycles, the left chest wall lesion and the infraclavicular lymph node metastasis were undetectable and the patient was considered to have achieved a complete response. Treatment was well tolerated with no significant toxicity or need for dose reduction. Given our case, here we review the clinical evidence and discuss the potential role of nab-paclitaxel for the treatment of triple negative MBC, a subgroup typically characterized as having aggressive disease and limited treatment options. PMID:25115342

De Placido, Sabino; De Angelis, Carmine

2015-01-01

171

Paclitaxel-loaded PEGylated PLGA-based nanoparticles: In vitro and in vivo evaluation  

Microsoft Academic Search

The purpose of this study was to develop Cremophor® EL-free nanoparticles loaded with Paclitaxel (PTX), intended to be intravenously administered, able to improve the therapeutic index of the drug and devoid of the adverse effects of Cremophor® EL. PTX-loaded PEGylated PLGA-based were prepared by simple emulsion and nanoprecipitation.The incorporation efficiency of PTX was higher with the nanoprecipitation technique. The release

Fabienne Danhier; Nathalie Lecouturier; Benoît Vroman; Christine Jérôme; Jacqueline Marchand-Brynaert; Olivier Feron; Véronique Préat

2009-01-01

172

A Novel Technique for Loading of Paclitaxel-PLGA Nanoparticles onto ePTFE Vascular Grafts  

Microsoft Academic Search

The major cause of hemodialysis vascular access dysfunction (HVAD) is the occurrence of stenosis followed by thrombosis at venous anastomosis sites due to the aggressive development of venous neointimal hyperplasia. Local delivery of antiproliferative drugs may be effective in inhibiting hyperplasia without causing systemic side effects. We have previously demonstrated that paclitaxel-coated expanded poly(tetrafluoroethylene) (ePTFE) grafts, by a dipping method,

Hyun Jung Lim; Hye Yeong Nam; Byung Ha Lee; Dae Joong Kim; Jai Young Ko; Jong-sang Park

2007-01-01

173

Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles loaded with Paclitaxel  

Microsoft Academic Search

Paclitaxel (PTX)-loaded PEGylated PLGA-based nanoparticles (NP) have been previously described as more effective in vitro and in vivo than Taxol®. The aim of this study was to test the hypothesis that our PEGylated PLGA-based nanoparticles grafted with the RGD peptide or RGD-peptidomimetic (RGDp) would target the tumor endothelium and would further enhance the anti-tumor efficacy of PTX. The ligands were

Fabienne Danhier; Benoît Vroman; Nathalie Lecouturier; Nathalie Crokart; Vincent Pourcelle; Hélène Freichels; Christine Jérôme; Jacqueline Marchand-Brynaert; Olivier Feron; Véronique Préat

2009-01-01

174

The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation  

PubMed Central

Background Microtubule stabilizers suppress microtubule dynamics and, at the lowest antiproliferative concentrations, disrupt the function of mitotic spindles, leading to mitotic arrest and apoptosis. At slightly higher concentrations, these agents cause the formation of multiple mitotic asters with distinct morphologies elicited by different microtubule stabilizers. Results We tested the hypothesis that two classes of microtubule stabilizing drugs, the taxanes and the taccalonolides, cause the formation of distinct aster structures due, in part, to differential effects on microtubule dynamics. Paclitaxel and the taccalonolides suppressed the dynamics of microtubules formed from purified tubulin as well as in live cells. Both agents suppressed microtubule dynamic instability, with the taccalonolides having a more pronounced inhibition of microtubule catastrophe, suggesting that they stabilize the plus ends of microtubules more effectively than paclitaxel. Live cell microscopy was also used to evaluate the formation and resolution of asters after drug treatment. While each drug had similar effects on initial formation, substantial differences were observed in aster resolution. Paclitaxel-induced asters often coalesced over time resulting in fewer, larger asters whereas numerous compact asters persisted once they were formed in the presence of the taccalonolides. Conclusions We conclude that the increased resistance of microtubule plus ends to catastrophe may play a role in the observed inability of taccalonolide-induced asters to coalesce during mitosis, giving rise to the distinct morphologies observed after exposure to these agents. PMID:24576146

2014-01-01

175

Model-Based Meta-Analysis for Quantifying Paclitaxel Dose Response in Cancer Patients  

PubMed Central

Model-based meta-analysis of dose response is a sophisticated method to guide dose and regimen selection. In this report, the effects of paclitaxel dose and regimen (weekly or every 3 weeks) on the efficacy and safety in cancer patients were quantified by model-based meta-analysis of 29 monotherapy trials. Logistic regression models were developed to assess the relationship between dose and objective response rate or neutropenia rate. Survival models were developed to assess the relationship between dose and overall survival or progression-free survival. Paclitaxel efficacy (e.g., objective response rate, median overall survival, and progression-free survival) is correlated with average dose per week (mg/m2/week), whereas safety (e.g., neutropenia rate) is correlated with dose per administration (mg/m2). Weekly paclitaxel regimen at 65–80?mg/m2 is supported to have comparable to better efficacy and lower neutropenia incidence than an every-3-week regimen at 175?mg/m2. PMID:24850445

Lu, D; Joshi, A; Li, H; Zhang, N; Ren, M M; Gao, Y; Wada, R; Jin, J Y

2014-01-01

176

[A case of recurrent breast cancer with carcinomatous pleurisy responding to bevacizumab and paclitaxel therapy].  

PubMed

A 57-year-old woman who had undergone muscle-preserving radical mastectomy at the age of 38 presented with a 5 cm mass in front of the breastbone. She was diagnosed as having recurrent breast cancer( estrogen receptor[ ER] positive, progesterone receptor[ PgR] positive, human epidermal growth factor receptor[ HER] -2 negative) by core needle biopsy. She received an aromatase inhibitor (AI) and showed partial response. At the age of 54, PgR status became negative. At the age of 55, the recurrent tumor increased in size, and the patient received 50 Gy of radiation therapy for its treatment and AI administration was continued. At the age of 57, tumor marker levels increased and detailed examination revealed that the recurrent tumor had increased in size and carcinomatous pleurisy was noted. Bevacizumab and paclitaxel therapy was initiated. Tumor marker levels decreased and the pleural fluid disappeared in 2 weeks. After 3 courses, positron emission tomography( PET) -computed tomography( CT) showed a reduction in the tumor size and a decrease in fluorodeoxyglucose (FDG) uptake. Bevacizumab and paclitaxel therapy could be effective for the treatment of patients with recurrent breast cancer with a life-threatening status, after hormone therapy failure. Bevacizumab and paclitaxel could be effective as first- line chemotherapy because of its good treatment efficiency. PMID:24394121

Sato, Yuya; Nakagawa, Tsuyoshi; Sato, Takanobu; Nagahara, Makoto; Sugihara, Kenichi

2013-11-01

177

Long Circulating Lectin Conjugated Paclitaxel Loaded Magnetic Nanoparticles: A New Theranostic Avenue for Leukemia Therapy  

PubMed Central

Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs were functionalized with lectin glycoprotein which resulted in higher cellular uptake and lower IC50 value suggesting the efficacy of targeted delivery of paclitaxel. Both pac-MNPs and lectin conjugated pac-MNPs have a prolonged circulation time in serum suggesting increased bioavailability and therapeutics index of paclitaxel in vivo. Further, the molecular mechanism pertaining to pac-induced cytotoxicity was analyzed by studying the involvement of different apoptotic pathway proteins by immunoblotting and quantitative PCR. Our study revealed simultaneous activation of JNK pathway leading to Bcr-Abl instability and the extrinsic apoptotic pathway after pac-MNPs treatment in two Bcr-Abl positive cell lines. In addition, the MRI data suggested the potential application of MNPs as imaging agent. Thus our in vitro and in vivo results strongly suggested the pac-MNPs as a future prospective theranostic tool for leukemia therapy. PMID:22110595

Singh, Abhalaxmi; Dilnawaz, Fahima; Sahoo, Sanjeeb Kumar

2011-01-01

178

[Two advanced gastric cancer cases with peritoneal metastases successfully treated by s-1/paclitaxel combination therapy].  

PubMed

Two unresectable advanced gastric cancer cases with peritoneal metastases were successfully treated by the combination therapy of S-1 and paclitaxel. S-1 (1.25m(2): 80 mg/day, 1.25m(2)-1.50m(2)<:120 mg/day) was administered orally for 14 consecutive days followed by 14 days rest and a 2-hour infusion of paclitaxel (50 mg/m(2)) was administered on day 1 and 15 of each course. Treatment was repeated every 4 weeks unless disease progression or severe adverse effects were observed. Case 1: 65-year-old male (performance status: PS 3) with type 1 gastric cancer with malignant ascites. Case 2: 66-year-old male (PS3) with peritoneal metastases whose primary gastric lesion was surgically resected. Partial response was obtained in the former and complete response in the latter. Combination therapy of S-1 and paclitaxel can be highly recommended for patients with inoperable gastric cancer with poor PS. PMID:19542719

Ina, Kenji; Furuta, Ryuichi; Kataoka, Takae; Nishio, Tomoko; Nagao, Seiji; Kayukawa, Satoshi; Masaki, Ayako; Ando, Takafumi; Goto, Hidemi

2009-06-01

179

Solubility enhancement of paclitaxel using a linear-dendritic block copolymer.  

PubMed

The solubilising capacities of micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly(butylene oxide) (B)-poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent-loading method compared with the conventional solution-loading method. The solubility of paclitaxel was increased 3700-fold by micellar encapsulation in a 2% (w/v) BE-PAMAM copolymer solution at 37°C using this solubilisation technique. Dynamic light scattering and transmission electron microscopy studies indicated a transition of spherical to worm-like micelles of the BE copolymer induced by the encapsulation of drug molecules. A sustained release of encapsulated drug was observed, with approximately 80% and 60% paclitaxel being released from 2% (w/v) solutions of BE and BE-PAMAM respectively after 24h of dialysis at 37°C. PMID:23651641

Zhou, Zhengyuan; D'Emanuele, Antony; Attwood, David

2013-08-16

180

Dose-Dense Epirubicin and Cyclophosphamide Followed by Weekly Paclitaxel in Node-Positive Breast Cancer  

PubMed Central

Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement in node-positive breast cancer patients but the optimal dose schedule has still remained undetermined. Objectives. The feasibility of dose-dense epirubicin in combination with cyclophosphamide (EC) followed by weekly paclitaxel as adjuvant chemotherapy in node-positive breast cancer patients was investigated. Methods. All patients were treated with epirubicin (100?mg/m2) and cyclophosphamide (600?mg/m2) every two weeks for four cycles with daily Pegfilgrastim (G-CSF) that was administered 3–10 days after each cycle of epirubicin and cyclophosphamide infusion which followed by (80?mg/m2) paclitaxel for twelve consecutive weeks. Results. Sixty consecutive patients were analyzed, of whom 57 patients (95%) completed the regimen and no case of toxicity-related death was observed. Grade 3/4 hematologic toxicity was uncommon and the most common grade 3/4 nonhematological adverse event was neuropathy disorders. Conclusions. Dose-dense epirubicin and cyclophosphamide followed by weekly paclitaxel with G-CSF support is a well-tolerated and feasible regimen in node-positive breast cancer patients without serious complications. PMID:25276426

Mirzaei, Hamid Reza; Mohammadi Yeganeh, Ladan; Jafari Naeini, Sepideh; Bikdeli, Pegah; Hajian, Parastoo

2014-01-01

181

A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative laboratory studies.  

PubMed

Head and neck cancer is a major cause of cancer-related deaths. In general, early stage head and neck cancers are effectively treated with either radiation or surgery. More advanced tumors often require combined-modality therapy with both radiation therapy and surgery. Recent investigations indicate that the addition of chemotherapy may be helpful. One of the newer chemotherapy agents that appears to have significant activity against head and neck cancer is paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Paclitaxel, originally derived from the western yew Taxus brevifolia, acts by increasing the stability of microtubules and preventing mitosis. Recent evidence indicates that the microtubule system is vital to the release of various cytokines and that modulation of cytokine release may play a major role in the drug's antitumor activity. We report a phase II trial of paclitaxel in patients with head and neck cancer, not only to evaluate its clinical effects, but also to study its effect on cytokine release. We assessed interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha production by using a sensitive enzyme-linked immunosorbent assay to assess the serum of patients receiving paclitaxel and to detect cytokine release in vitro. The objective response rate was 36%, with 12% complete responses and 24% partial responses. No IL-1 beta or tumor necrosis factor-alpha was detected in patient serum at any time during the infusion of paclitaxel or after overnight incubation with patient monocytes. No proIL-1 beta was detected in in vitro cultures of paclitaxel-treated patient monocytes. When monocytes were stimulated with endotoxin, IL-1 beta production was greatest at 48 hours, suggesting that paclitaxel can prime cells to produce greater quantities of cytokines after a second stimulus. PMID:7597432

Smith, R E; Thornton, D E; Allen, J

1995-06-01

182

Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia  

PubMed Central

Background Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemokines in pain hypersensitivity, but little is know about their roles in chemotherapy-induced peripheral neuropathy. In the present study, we investigated the role of CC-chemokine ligand 3 (CCL3) in the spinal cord in the development and maintenance of mechanical allodynia using a rat model of paclitaxel-induced neuropathy. Findings Repeated intravenous administration of paclitaxel induced a marked decrease in paw withdrawal threshold in response to mechanical stimulation (mechanical allodynia). In these rats, the number of microglia in the spinal dorsal horn (SDH) was significantly increased. Paclitaxel-treated rats showed a significant increase in the expression of mRNAs for CCL3 and its receptor CCR5 in the SDH. Intrathecal administration of a CCL3-neutralizing antibody not only attenuated the development of paclitaxel-induced mechanical allodynia but also reversed its maintenance. Paclitaxel also upregulated expression of purinoceptor P2X7 receptors (P2X7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2X7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia. Conclusions Our findings suggest a contribution of CCL3 and P2X7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy. PMID:25127716

2014-01-01

183

Increased Spinal Cord Na+-K+-2Cl- Cotransporter-1 (NKCC1) Activity Contributes to Impairment of Synaptic Inhibition in Paclitaxel-induced Neuropathic Pain.  

PubMed

Microtubule-stabilizing agents, such as paclitaxel (Taxol), are effective chemotherapy drugs for treating many cancers, and painful neuropathy is a major dose-limiting adverse effect. Cation-chloride cotransporters, such as Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) and K(+)-Cl(-) cotransporter-2 (KCC2), critically influence spinal synaptic inhibition by regulating intracellular chloride concentrations. Here we show that paclitaxel treatment in rats significantly reduced GABA-induced membrane hyperpolarization and caused a depolarizing shift in GABA reversal potential of dorsal horn neurons. However, paclitaxel had no significant effect on AMPA or NMDA receptor-mediated glutamatergic input from primary afferents to dorsal horn neurons. Paclitaxel treatment significantly increased protein levels, but not mRNA levels, of NKCC1 in spinal cords. Inhibition of NKCC1 with bumetanide reversed the paclitaxel effect on GABA-mediated hyperpolarization and GABA reversal potentials. Also, intrathecal bumetanide significantly attenuated hyperalgesia and allodynia induced by paclitaxel. Co-immunoprecipitation revealed that NKCC1 interacted with ?-tubulin and ?-actin in spinal cords. Remarkably, paclitaxel increased NKCC1 protein levels at the plasma membrane and reduced NKCC1 levels in the cytosol of spinal cords. In contrast, treatment with an actin-stabilizing agent had no significant effect on NKCC1 protein levels in the plasma membrane or cytosolic fractions of spinal cords. In addition, inhibition of the motor protein dynein blocked paclitaxel-induced subcellular redistribution of NKCC1, whereas inhibition of kinesin-5 mimicked the paclitaxel effect. Our findings suggest that increased NKCC1 activity contributes to diminished spinal synaptic inhibition and neuropathic pain caused by paclitaxel. Paclitaxel disrupts intracellular NKCC1 trafficking by interfering with microtubule dynamics and associated motor proteins. PMID:25253692

Chen, Shao-Rui; Zhu, Lihong; Chen, Hong; Wen, Lei; Laumet, Geoffroy; Pan, Hui-Lin

2014-11-01

184

miR-17-5p Downregulation Contributes to Paclitaxel Resistance of Lung Cancer Cells through Altering Beclin1 Expression  

PubMed Central

Non- small- cell lung cancer (NSCLC) is one of the most leading causes of cancer-related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3?-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression. PMID:24755562

Chatterjee, Abhisek; Chattopadhyay, Dhrubajyoti; Chakrabarti, Gopal

2014-01-01

185

Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line.  

PubMed

Ovarian cancer is currently the most lethal gynecological malignancy in the United States. Although effective therapies exist, the acquisition of multidrug resistance within persisting tumor cells renders curative therapies elusive for the majority of women with ovarian cancer. In an attempt to better define the evolution of paclitaxel resistance, three SKOV-3 sublines were selected during successive rounds of exposure to increasing paclitaxel concentrations. The sublines were selected to represent early (0.003 micro M), intermediate (0.03 micro M), and late (0.3 micro M) paclitaxel resistance. RNA from these cell lines, SKOV-3(0.003TR), SKOV-3(0.03TR), and SKOV-3(0.3TR), as well as the parent cell line SKOV-3, was analyzed by cDNA array to evaluate transcript expression profiles. Arrays were performed using Affymetrix HG-U95Av2 arrays, which contain probes for approximately 9600 known human genes. Signal intensities were calculated by Microarray Suite 5.0 (Affymetrix, Santa Clara, CA). Expression patterns were analyzed by Affymetrix Data Mining Tool 3.0 with filtering of expression patterns for fold change in expression (maximum divided by minimum expression value/gene) and for variation of expression (maximum minus minimum expression value/gene). This analysis dismissed approximately 11,000 of approximately 12,000 expression patterns. The remaining approximately 1000 expression patterns were normalized and segregated into 20 partitions of a self-organizing map (SOM). The resulting SOM discriminates between genes, which are differentially expressed in early versus intermediate versus late paclitaxel resistance. For example, multidrug resistance 1 transcript expression is not elevated in SKOV-3(0.003TR) as compared with parental SKOV-3 but demonstrates elevated expression in SKOV-3(0.03TR) and SKOV-3(0.3TR). In contrast, SOM analysis demonstrates early (SKOV-3(0.003TR)) transcriptional changes in a wide variety of genes, including gene families involved in cell growth/maintenance, cell structure, signal transduction, and inflammatory response. The use of array analysis with SOMs in sublines with progressive paclitaxel resistance can successfully define an evolution of resistance. Such an analysis may be useful at defining candidate gene families involved in the early-drug resistance phenotype. PMID:12727840

Lamendola, Diana E; Duan, Zhenfeng; Yusuf, Rushdia Z; Seiden, Michael V

2003-05-01

186

Folic acid-coupled nano-paclitaxel liposome reverses drug resistance in SKOV3/TAX ovarian cancer cells.  

PubMed

Chemotherapy could be used as an effective treatment for ovarian cancer and subsequent peritoneal metastasis. Administration of chemoagents in a targeted manner may bring the advantage of higher efficiency and lower drug resistance. In the present study, folate receptor (FR)-targeted nano-paclitaxel formulations were generated and tested for cytotoxicity in a peritoneal xenograft model of paclitaxel-resistant ovarian cancer and SKOV3/TAX cell lines. Immunocytochemical staining confirmed the expression of FR in both SKOV3 and SKOV3/TAX cells. The enrichment of the folic acid-coupled PEGylated nano-paclitaxel liposome (FA-NP) in FR-positive cells was visualized with fluorescence. The uptake of the FA-NP peaked at 4 h and was more robust than nontargeted PEGylated nano-paclitaxel liposome (NP). FA-NP but not NP markedly inhibited the growth of ovarian cancer cells and induced a two-fold increase in the doubling time. The cytotoxic effects of FA-NP were more potent than NP in both SKOV3 cells [50% of inhibition concentration (IC50), 5.67 vs. 50.2 ?g/ml, FA-NP vs. NP] and SKOV3/TAX cells (IC50, 0.38 vs. >200 ?g/ml, FA-NP vs. NP). FA-NP caused more G2-M cell cycle arrest and apoptotic changes in ovarian cancer cells than NP or regular paclitaxel. However, these effects were blunted in the presence of free FA, which competitively inhibited the receptor-mediated uptake of FA-NP particles. Intraperitoneal (i.p.) administration of FA-NP but not regular paclitaxel, NP, or vehicle significantly prolonged the survival and reduced tumor nodule number (2.9±0.3) in BALB/c nude mice. FA-NP also markedly enhanced the percentage of apoptotic cells in peritoneal xenografts of paclitaxel-resistant ovarian cancer cells (44.6±8.5 vs. 3.2±1.1% for vehicle, 22.4±5.9% for regular paclitaxel, and 35.2±7.7% for NP; P<0.05). However, intravenous administration of FA-NP at the same dose failed to induce apoptosis (20.1±6.2%; P<0.05) and inhibit tumor nodule number to the same extent as intraperitoneal administration. FA-NP reversed the drug resistance in paclitaxel-resistant SKOV3/TAX ovarian cancer cells both in vitro and in vivo. Localized and targeted administration of the FR-targeted chemoagents might prolong the survival time in patients with drug-resistant ovarian cancer. PMID:24275314

Tong, Lingxia; Chen, Wei; Wu, Jing; Li, Hongxia

2014-03-01

187

Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.  

PubMed

Transforming growth factor (TGF)-? has been shown to play a central role in the development of tubulointerstitial fibrosis, which can be corrected via treatment with paclitaxel. The biology of microRNA (miR) can be modulated by paclitaxel. We hypothesized that paclitaxel may attenuate renal fibrosis in a rat model of remnant kidney disease by inhibiting TGF-? induced-miRs. Rats in groups of 12 were subjected to 5/6 nephrectomy and received low-dose intraperitoneal injection of paclitaxel. Renal functions were assessed at 8 weeks. The TGF-? signalling cascade and ECM proteins were evaluated by real-time polymerase chain reaction (TRT-PCR) and immunofluorescence microscopy. Animals with remnant kidneys developed hypertension, which was not relieved with paclitaxel treatment. However, paclitaxel treatment resulted in dampening the proteinuric response, reduction in serum BUN, creatinine levels and urine protein : creatinine ratio and normalization of creatinine clearance. These effects were accompanied by the inhibition of Smad2/3 activation, attenuation of renal fibrosis and normalization of integrin-linked kinase (ILK), COL(I)A1, COL(IV)A2 and ?-SMA expression. Also, paclitaxel down-regulated the expression of miR-192, miR-217 and miR -377, while miR-15 was up-regulated in the remnant kidney. In vitro, in tubular epithelial cells (NRK-52E), paclitaxel also inhibited TGF-?1-induced Smad2/3 activation and normalized ILK, COL(I)A1, COL(IV)A2 and ?-SMA expression. Furthermore, ChIP analyses indicated that Taxol suppressed Smad3-mediated miR-192 transcriptional activity. Over-expression of miR-192 in NRK-52E mimicked the changes seen in the remnant kidney, while inclusion of miR-192 inhibitor in the culture medium blocked TGF-?1-induced COL(I)A1 and COL(IV)A2 expression, while ILK and ?-SMA were unaffected. These data suggest that low-dose paclitaxel ameliorates renal fibrosis via modulating miR-192 pathobiology and TGF-?/Smad signalling. PMID:21984124

Sun, Lin; Zhang, Dongshan; Liu, Fuyou; Xiang, Xudong; Ling, Guanghui; Xiao, Li; Liu, Yinghong; Zhu, Xuejing; Zhan, Ming; Yang, Yeyi; Kondeti, Vinay K; Kanwar, Yashpal S

2011-11-01

188

Cancer cell sensitization and improved treatment efficacy by combined sodium butyrate and paclitaxel formulations is cancer-type specific.  

PubMed

We queried whether cancer treatment by combinations of paclitaxel and butyrate - free or formulated in drug delivery systems - can improve therapeutic responses compared to each drug alone. Combination treatments were conducted with HT-29 and HeLa cells, as representatives of differentiation-induced and cell-death-induced cancer lines, respectively. Pre-treatment of the HT-29 cells with butyrate (at doses inducing differentiation), followed by butyrate+paclitaxel generated changes in cell cycle profile, increased the level of dead cells beyond that of each drug alone, and allowed reduction in paclitaxel doses. A similar combination treatment of HeLa cells was detrimental, indicating that whether the combination is beneficial or not is cancer-type specific. We hypothesize that while butyrate-treated HT-29 cells became sensitive to paclitaxel-induced Fas-mediated apoptosis, butyrate-adapted HeLa cells became apoptosis-resistant. We next tested the same drug combination on HT-29 cells, but each drug in a specific tumor-targeted carrier. The combination of drug carriers outperformed an equidose combination of the free drugs, showing potential to achieve high therapeutic responses (even in drug-resistant cells) at significantly lower and detergent-free paclitaxel doses, which should allow for reduction in adverse effects and risks of toxicity. PMID:24370842

Rivkin, Ilia; Cohen, Keren; Bod, Tal; Argov, Mirit; Margalit, Rimona

2014-01-30

189

Pluronic-poly (acrylic acid)-cysteine/Pluronic L121 mixed micelles improve the oral bioavailability of paclitaxel.  

PubMed

Abstract The aim of the study is to synthesize a thiolated Pluronic copolymer, Pluronic-poly (acrylic acid)-cysteine copolymer, to construct a mixed micelle system with the Pluronic-poly (acrylic acid)-cysteine copolymer and Pluronic L121 (PL121) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel. Compared with Pluronic-poly (acrylic acid)-cysteine micelles, drug-loading capacity of Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles was increased from 0.4 to 2.87%. In vitro release test indicated that Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles exhibited a pH sensitivity. The permeability of drug-loaded micelles in the intestinal tract was studied with an in situ perfusion method in rats. The presence of verapamil and Pluronic both improved the intestinal permeability of paclitaxel, which further certified the inhibition effect of thiolated Pluronic on P-gp. In pharmacokinetic study, the area under the plasma concentration-time curve (AUC0??) of paclitaxel-loaded mixed micelles was four times greater than that of the paclitaxel solution (p?paclitaxel. PMID:23971495

Zhao, Yanli; Li, Yanli; Ge, Jianjun; Li, Na; Li, Ling-Bing

2014-11-01

190

Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer  

PubMed Central

Background A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel. Methods The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively. Results The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol. Conclusion Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications. PMID:22605931

Xiao, Wenwu; Luo, Juntao; Jain, Teesta; Riggs, John W; Tseng, Harry P; Henderson, Paul T; Cherry, Simon R; Rowland, Douglas; Lam, Kit S

2012-01-01

191

Spotlight on Paclitaxel in Ovarian Cancer The full text of this article was published in PharmacoEconomics 2001; 19 (12): 1227-1259  

Microsoft Academic Search

Paclitaxel belongs to the group of antitumor agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomized phase III clinical trials. When used in combination with cisplatin for first-line treatment of advanced ovarian cancer, it is superior to cyclophosphamide\\/cisplatin, with gains in median survival of around 1 year. Paclitaxel plus carboplatin has similar efficacy

Melissa Young; Greg L. Plosker

2002-01-01

192

Characterization of cell death events induced by anti-neoplastic drugs cisplatin, paclitaxel and 5-fluorouracil on human hepatoma cell lines: Possible mechanisms of cell resistance  

Microsoft Academic Search

Two different hepatoma cell lines were incubated for 48h with chemotherapeutic drugs cisplatin, paclitaxel and 5-FU to determine their ability to induce cytotoxicity and DNA fragmentation as well as to modify the expression of some cell death-related genes that could be involved in the resistance to therapy. We observed that cisplatin and paclitaxel induced cytotoxicity, but significant differences between both

O. Brenes; F. Arce; O. Gätjens-Boniche; C. Díaz

2007-01-01

193

Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines  

PubMed Central

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0–2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 × IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 × IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70–89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine–paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences. © 2000 Cancer Research Campaign PMID:10993656

Kroep, J R; Giaccone, G; Tolis, C; Voorn, D A; Loves, W J P; Groeningen, C J van; Pinedo, H M; Peters, G J

2000-01-01

194

Effect of elicitors and a biogenetic precursor on paclitaxel production in cell suspension cultures of Taxus cuspidata var. nana.  

PubMed

To stimulate the production of taxol (paclitaxel) by cell suspension cultures of Taxus cuspidata var. nana, two kinds of elicitors and a biogenetic precursor were used in F4G4 culture medium. Paclitaxel production was enhanced by each elicitor as well as by the biogenetic precursor and by a combination of the two elicitors or one elicitor and the biogenetic precursor. The amount ofpaclitaxel produced (16.6 mg L(-1)) was greatest when the cell suspension cultures were conducted in F4G4 medium containing chito-heptaose (8 mg L(-1)) and jasmonic acid (21 mg L(-1)). The productivity was enhanced 4.1 fold compared to the control. The amount of paclitaxel produced was increased by supplying air to the cultures, though the productivity depended on the amount of air supplied. However, no enhancement of production was observed when a combination of air and chito-heptaose was provided to the cell suspension cultures. PMID:19090188

Tachinbana, Sanro; Muranaka, Toshio; Itoh, Kazutaka

2007-09-01

195

Successful Chemotherapy with Nab-Paclitaxel in a Heavily Treated Non-Small Cell Lung Cancer Patient: A Case Report  

PubMed Central

Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers. A 69-year-old female with postoperatively recurrent NSCLC was treated weekly with nanoparticle-albumin-bound paclitaxel (nab-paclitaxel) monotherapy every 4 weeks as a tenth line chemotherapy, and stable disease was achieved by seven cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including febrile neutropenia and peripheral neuropathy, were severe, and thus she was able to tolerate this salvage chemotherapy. To our knowledge this is the first report of the efficacy of nab-paclitaxel monotherapy in a heavily treated NSCLC patient. PMID:25076891

Ishihara, Mikiko; Igawa, Satoshi; Maki, Sachiyo; Harada, Shinya; Kusuhara, Seiichiro; Niwa, Hideyuki; Otani, Sakiko; Sasaki, Jiichiro; Jiang, Shi-Xu; Masuda, Noriyuki

2014-01-01

196

Inhibition of Lipolysis by Mercaptoacetate and Etomoxir Specifically Sensitize Drug-Resistant Lung Adenocarcinoma Cell to Paclitaxel  

PubMed Central

Chemoresistance is a major cause of treatment failure in patients with lung cancer. Although the extensive efforts have been made in overcoming chemoresistance, the underlying mechanisms are still elusive. Cancer cells reprogram cellular metabolism to satisfy the demands of malignant phenotype. To reveal roles of cancer metabolism in regulating chemoresistance, we profiled the metabolic characteristics in paclitaxel-resistant lung cancer cells by flux assay. Glucose and oleate metabolism were significantly different between resistant and non-resistant cells. In addition, targeting metabolism as a strategy to overcome drug resistance was investigated using specific metabolic inhibitors. Inhibition of glycolysis and oxidative phosphorylation by 2-deoxyglucose and malonate, respectively, potentiated the effects of paclitaxel on nonresistant lung adenocarcinoma cells but not paclitaxel-resistant cells. By contrast, inhibition of lipolysis by mercaptoacetate or etomoxir synergistically inhibited drug-resistant lung adenocarcinoma cell proliferation. We conclude that lipolysis inhibition potentially be a therapeutic strategy to overcome drug resistance in lung cancer. PMID:24040298

Zhou, Xiang; Zhang, Teng; Zhao, Li; Miao, Ping; Song, Shaoli; Sun, Xiaoguang; Liu, Jianjun; Zhao, Xiaoping; Huang, Gang

2013-01-01

197

Cellular aggregation is a key parameter associated with long term variability in paclitaxel accumulation in Taxus suspension cultures  

PubMed Central

Plant cell cultures provide a renewable source for synthesis and supply of commercially valuable plant-derived products, particularly for secondary metabolites. However, instability in product yields over multiple passages has hampered the efficient and sustainable use of this technology. Paclitaxel accumulation in Taxus cell suspension culture was quantified over multiple passages and correlated to mean aggregate size, extracellular sugar level, ploidy, and cell cycle distribution. Paclitaxel levels varied approximately 6.9-fold over the six-month timeframe investigated. Of all of the parameters examined, only mean aggregate size correlated with paclitaxel accumulation, where a significant negative correlation (r = ? 0.75, p < 0.01) was observed. These results demonstrate the relevance of measuring, and potentially controlling, aggregate size during long term culture passages, particularly for plant suspensions where industrially relevant secondary metabolites are not pigmented to enable rapid culture selection. PMID:23439858

Patil, Rohan A.; Kolewe, Martin E.; Roberts, Susan C.

2012-01-01

198

Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing  

PubMed Central

Background The efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery is still unknown. Methods and results The pharmacokinetic profile and differences in drug concentration (vessel surface vs arterial wall) of two different paclitaxel coating formulations (3?µg/mm2) displaying opposite solubility characteristics (CC=crystalline vs AC=amorphous) were tested in vivo and compared with paclitaxel-eluting stents (PES). Also, the biological effect of both PCB formulations on vascular healing was tested in the porcine coronary injury model. One hour following balloon inflation, both formulations achieved similar arterial paclitaxel levels (CC=310 vs AC=245?ng/mg; p=NS). At 24?h, the CC maintained similar tissue concentrations, whereas the AC tissue levels declined by 99% (p<0.01). At this time point, arterial levels were 20-fold (CC) and 5-fold (AC) times higher compared to the PES group (p<0.05). At 28?days, arterial levels retained were 9.2% (CC) and 0.04% (AC, p<0.01) of the baseline levels. Paclitaxel concentration on the vessel surface was higher in the CC at 1 (CC=36.7% vs AC=13.1%, p<0.05) and 7?days (CC=38.4% vs AC=11%, p<0.05). In addition, the CC induced higher levels of neointimal inhibition, fibrin deposition and delayed healing compared with the AC group. Conclusions The presence of paclitaxel deposits on the vessel surface driving diffusion into the arterial tissue in a time-dependent fashion supports the mechanism of action of PCB. This specific pharmacokinetic behaviour influences the patterns of neointimal formation and healing. PMID:25332821

Granada, Juan F; Stenoien, Mark; Buszman, Piotr P; Tellez, Armando; Langanki, Dan; Kaluza, Greg L; Leon, Martin B; Gray, William; Jaff, Michael R; Schwartz, Robert S

2014-01-01

199

Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model  

Microsoft Academic Search

Purpose  We compared the safety, toxicity, biocompatibility and anti-tumour efficacy of a novel chitosan-egg phosphatidylcholine (ePC)\\u000a implantable drug delivery system that provides controlled and sustained release of paclitaxel (PTXePC) versus commercial paclitaxel formulated in Cremophor EL (PTXCrEL).\\u000a \\u000a \\u000a \\u000a Methods  Toxicity studies were conducted in healthy CD-1 female mice, whereas efficacy studies were performed in the SKOV-3 xenograft\\u000a model of ovarian cancer. Treatments consisted

Vessela Vassileva; Justin Grant; Raquel De Souza; Christine Allen; Micheline Piquette-Miller

2007-01-01

200

Comparison of Cell Death-inducing Effect of Novel Taxane SB-T-1216 and Paclitaxel in Breast Cancer Cells  

PubMed Central

Background In this study, the effect of novel taxane SB-T-1216 and paclitaxel were compared on drug-sensitive MDA-MB-435 and drug-resistant NCI/ADR-RES human breast cancer cells. Materials and Methods Cell growth and survival were evaluated after 96-hour incubation with tested concentrations of taxanes. The effect on the formation of microtubule bundles was assessed employing fluorescence microscopy and on the cell cycle employing flow cytometric analysis. The activity of caspases was assessed employing commercial colorimetric kits. Results The IC50 (concentration resulting in 50% of living cells in comparison with the control) of SB-T-1216 in drug-sensitive cells was 0.6 nM versus 1 nM for paclitaxel. However, the IC50 of SB-T-1216 in drug-resistant cells was 1.8 nM versus 300 nM for paclitaxel. Both SB-T-1216 and paclitaxel at death-inducing concentrations induced the formation of microtubule bundles in drug-sensitive as well as drug-resistant cells. Cell death induced in drug-sensitive and drug-resistant cells by paclitaxel was associated with the accumulation of cells in the G2/M phase. On the contrary, cell death induced by SB-T-1216 took place without the accumulation of cells in the G2/M phase but with a decreased number of G1 cells and the accumulation of hypodiploid cells. Both SB-T-1216 and paclitaxel activated caspase-3, caspase-9, caspase-2 and caspase-8 in drug-sensitive as well as drug-resistant cells. Conclusion Cell death induced by both paclitaxel and novel taxane SB-T-1216 in breast cancer cells is associated with caspase activation and with the formation of interphase microtubule bundles. Novel taxane SB-T-1216, but not paclitaxel, seems to be capable of inducing cell death without the accumulation of cells in the G2/M phase. PMID:19661300

KOVAR, JAN; EHRLICHOVA, MARIE; SMEJKALOVA, BARBORA; ZANARDI, ILARIA; OJIMA, IWAO; GUT, IVAN

2010-01-01

201

Neurosteroid 3?-androstanediol efficiently counteracts paclitaxel-induced peripheral neuropathy and painful symptoms.  

PubMed

Painful peripheral neuropathy belongs to major side-effects limiting cancer chemotherapy. Paclitaxel, widely used to treat several cancers, induces neurological symptoms including burning pain, allodynia, hyperalgesia and numbness. Therefore, identification of drugs that may effectively counteract paclitaxel-induced neuropathic symptoms is crucial. Here, we combined histopathological, neurochemical, behavioral and electrophysiological methods to investigate the natural neurosteroid 3?-androstanediol (3?-DIOL) ability to counteract paclitaxel-evoked peripheral nerve tissue damages and neurological symptoms. Prophylactic or corrective 3?-DIOL treatment (4 mg/kg/2 days) prevented or suppressed PAC-evoked heat-thermal hyperalgesia, cold-allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased thermal and mechanical pain thresholds of PAC-treated rats. Electrophysiological studies demonstrated that 3?-DIOL restored control values of nerve conduction velocity and action potential peak amplitude significantly altered by PAC-treatment. 3?-DIOL also repaired PAC-induced nerve damages by restoring normal neurofilament-200 level in peripheral axons and control amount of 2',3'-cyclic-nucleotide-3'-phosphodiesterase in myelin sheaths. Decreased density of intraepidermal nerve fibers evoked by PAC-therapy was also counteracted by 3?-DIOL treatment. More importantly, 3?-DIOL beneficial effects were not sedation-dependent but resulted from its neuroprotective ability, nerve tissue repairing capacity and long-term analgesic action. Altogether, our results showing that 3?-DIOL efficiently counteracted PAC-evoked painful symptoms, also offer interesting possibilities to develop neurosteroid-based strategies against chemotherapy-induced peripheral neuropathy. This article shows that the prophylactic or corrective treatment with 3?-androstanediol prevents or suppresses PAC-evoked painful symptoms and peripheral nerve dysfunctions in rats. The data suggest that 3?-androstanediol-based therapy may constitute an efficient strategy to explore in humans for the eradication of chemotherapy-induced peripheral neuropathy. PMID:24260511

Meyer, Laurence; Patte-Mensah, Christine; Taleb, Omar; Mensah-Nyagan, Ayikoe Guy

2013-01-01

202

Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature.  

PubMed

Antiangiogenic cancer therapy can be achieved through the targeted delivery of antiangiogenic agents to the endothelial cells of tumor neovasculature. In the present study, we developed a drug delivery system (DDS), nanoparticles conjugated with K237-(HTMYYHHYQHHL) peptides for tumor neovasculature targeting drug delivery. Paclitaxel, a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. We synthesized the aldehyde poly(ethylene glycol)-poly(lactide) (aldehyde-PEG-PLA) block copolymer by ring opening polymerization. The nanoparticles loading paclitaxel (PTX-NP) were fabricated using the O/W emulsion and evaporation technique. K237 ligand, a peptide that can bind to the KDR receptors predominantly expressed on the surface of tumor neovasculature endothelial cells with high affinity and specificity and inhibit the VEGF-KDR angiogenic signal pathway, was conjugated to the aldehyde group of PEG chain using the N-terminal PEGylation technique. The K237 conjugated paclitaxel-loaded nanoparticles (K237-PTX-NP) had a hydrodynamic diameter of 150 nm. The K237 density on nanoparticle surface was 474 and the mean distance between two neighboring PEG chains linked to K237 peptide was 12 nm. The K237 conjugated nanoparticles could be significantly internalized by human umbilical vein endothelial cells (HUVEC) through the K237-KDR interaction, and this facilitated uptake led to the expected enhanced antiangiogenic activity shown by HUVEC proliferation, migration and tube formation compared to cells treated with the commercial formulation Taxol and PTX-NP. The long-circulating property and the K237 ligand of K237-PTX-NP warranted rapid, long-term, and accurate in vivo tumor neovasculature targeting, and thereafter the significant apoptosis of tumor neovasculature endothelial cells and necrosis of tumor tissues of MDA-MB-231 breast tumors implanted in female BLAB/c nude mice. This nanoparticulate DDS offers a new strategy for paclitaxel chemotherapy application and it could also be used to carry other chemotherapeutic drugs, genes, and proteins with antiangiogenic activity for antiangiogenic cancer therapy. PMID:20053444

Yu, De-Hong; Lu, Qin; Xie, Jing; Fang, Chao; Chen, Hong-Zhuan

2010-03-01

203

Synthesis and characterization of polymeric nanospheres loaded with the anticancer drug paclitaxel and magnetic particles  

NASA Astrophysics Data System (ADS)

We describe the preparation (by nanoprecipitation) and characterization of nanospheres (NPs) for magnetic drug targeting made of a magnetic fluid with poly(ethylene glycol), poly( D, L-lactic- co-glycolic acid) (PLGA), and the anticancer drug paclitaxel (Taxol ®). Infrared spectroscopy confirmed the incorporation of the drug in the PLGA NPs, which were also characterized in terms of morphology, size (typical diameter 200-250 nm) and colloidal stability in aqueous solutions of NaCl. Drug release and in vivo toxicity experiments of the prepared samples were performed. Their stability, magnetic properties (superparamagnetism), and lethal dose were found to be acceptable for the proposed application in cancer therapy.

Závišová, Vlasta; Koneracká, Martina; Mú?ková, Marta; Kop?anský, Peter; Tomašovi?ová, Natália; Lancz, Gábor; Timko, Milan; Pätoprstá, Božena; Bartoš, Peter; Fabián, Martin

2009-05-01

204

Paclitaxel-coated balloons in refractory nonanastomostic airway stenosis following lung transplantation.  

PubMed

Airway stenosis represents the commonest airway complication following lung transplantation, affecting between 7% and 18% of patients. Existing treatment options offer limited efficacy and can cause additional patient morbidity. Paclitaxel-coated balloons (PCB) have proved effective in managing postinterventional coronary artery re-stenosis. In a first-in-man study, we evaluated similar PCBs in refractory nonanastomotic airway stenosis in 12 patients. Following a single application, luminal patency was maintained in 50% at 270 days. No significant peri-interventional or early postinterventional complications occurred. Given these encouraging initial findings, further studies appear warranted. PMID:25055720

Greer, M; Fuehner, T; Warnecke, G; Noack, H; Heilmann, T; Haverich, A; Welte, T; Gottlieb, J

2014-10-01

205

Vasculitis resulting from a superficial femoral artery angioplasty with a paclitaxel-eluting balloon.  

PubMed

Drug-eluting balloons (DEBs) coated with the antiproliferative agent paclitaxel may improve primary patency by reducing recurrent luminal stenosis. A proportion of the active drug and excipient coating are known to embolize distally, but until now, there have been no reports of adverse events resulting from their use. We report an unusual case of a painful nodular, biopsy specimen-proven vasculitic rash that afflicted the ipsilateral lower limb of a patient after superficial femoral artery treatment with a DEB. This adverse event may have implications for the use of DEB in this and other vascular territories. PMID:23642919

Thomas, Shannon D; McDonald, Robert R A; Varcoe, Ramon L

2014-02-01

206

Interleukin6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity  

Microsoft Academic Search

Purpose  This study was conducted to investigate the potential neuroprotective effect of IL-6 on chemotherapy induced neuropathy (CIN).\\u000a IL-6 was compared to four-methylcatechol (4-MC)-a known inducer of NGF secretion previously shown to exhibit neuroprotective\\u000a effects in CIN models.\\u000a \\u000a \\u000a \\u000a Methods  \\u000a Three CIN models were used; two in rats (cisplatin and vincristine) and one in mice (paclitaxel). IL-6 was delivered in four different

Noelle Callizot; Emile Andriambeloson; Jonathan Glass; Michel Revel; Pamela Ferro; Rocco Cirillo; Pierre-Alain Vitte; Michel Dreano

2008-01-01

207

Cdk2 acts upstream of mitochondrial permeability transition during paclitaxel-induced apoptosis  

Microsoft Academic Search

Sequential activation of cyclin-dependent kinases (Cdks) controls mammalian cell cycle. Here we demonstrate that the upregulation\\u000a of cyclin-dependent kinase 2 (Cdk2) activity coincides with the loss of mitochondrial membrane potential (MMP) in paclitaxel-induced\\u000a apoptosis. Ectopic expression of the dominant negative Cdk2 (Cdk2-dn) and a specific Cdk2 inhibitor, p21\\u000a WAF1\\/CIP1\\u000a , effectively suppresses the loss of MMP, the release of cytochrome

Xiao-Xi Guo; Hanna Kim; Yang Li; Hyungshin Yim; Seung Ki Lee; Ying-Hua Jin

2011-01-01

208

Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain.  

PubMed

Paclitaxel chemotherapy is limited by a long-lasting painful neuropathy that lacks an effective therapy. In this study, we tested the hypothesis that paclitaxel may release mast cell tryptase, which activates protease-activated receptor 2 (PAR2) and, subsequently, protein kinases A and C, resulting in mechanical and thermal (both heat and cold) hypersensitivity. Correlating with the development of neuropathy after repeated administration of paclitaxel, mast cell tryptase activity was found to be increased in the spinal cord, dorsal root ganglia, and peripheral tissues in mice. FSLLRY-amide, a selective PAR2 antagonist, blocked paclitaxel-induced neuropathic pain behaviors in a dose- and time-dependent manner. In addition, blocking downstream signaling pathways of PAR2, including phospholipase C (PLC), protein kinase A (PKA), and protein kinase C? (PKC), effectively attenuated paclitaxel-induced mechanical, heat, or cold hypersensitivity. Furthermore, sensitized pain response was selectively inhibited by antagonists of transient receptor potential (TRP) V1, TRPV4, or TRPA1. These results revealed specific cellular signaling pathways leading to paclitaxel-induced neuropathy, including the activation of PAR2 and downstream enzymes PLC, PKC?, and PKA and resultant sensitization of TRPV1, TRPV4, and TRPA1. Targeting one or more of these signaling molecules may present new opportunities for the treatment of paclitaxel-induced neuropathy. PMID:21763756

Chen, Y; Yang, C; Wang, Z J

2011-10-13

209

Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway  

PubMed Central

Paclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin, and to enhance early apoptosis and growth inhibition in MyD88+ EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88+ EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88+ EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling, and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-?B pathway. PMID:24452475

Huang, Jian-Ming; Zhang, Guo-Nan; Shi, Yu; Zha, Xiao; Zhu, Yi; Wang, Miao-Miao; Lin, Qing; Wang, Wen; Lu, Hai-Yan; Ma, Shi-Qi; Cheng, Jia; Deng, Bi-Fang

2014-01-01

210

Molecular mechanisms of paclitaxel and NM-3 on human gastric cancer in a severe combined immune deficiency mice orthotopic implantation model  

PubMed Central

AIM: To explore the molecular mechanisms of action of paclitaxel and NM-3 on human gastric cancer in severe combined immune deficiency (SCID) mice. METHODS: Human gastric cancer cells SGC-7901 were implanted into SCID mice and mice were treated with paclitaxel and NM-3. The effects of paclitaxel and NM-3 on apoptosis of human gastric cancer cells were analyzed using flow cytometry, TUNEL assays, and DNA fragment analyses. RESULTS: Apoptosis of SGC-7901 cells was successfully induced by paclitaxel, NM-3, and the combination of paclitaxel and NM-3 24 h after injection as shown by the presence of apoptotic hypodiploid peaks on the flow cytometer before G1-S and a characteristic apoptotic band pattern in the DNA electrophoresis. The apoptotic rate detected by TUNEL assay was found to be significantly higher in the paclitaxel/NM-3 compared to the control group (38.5% ± 5.14% vs 13.2% ± 1.75%, P < 0.01). CONCLUSION: Paclitaxel in combination with NM-3 is able to induce apoptosis of the human gastric cancer cells in SCID mice effectively and synergistically. PMID:17696236

Zhu, Jin-Shui; Song, Ming-Quan; Chen, Guo-Qiang; Li, Qin; Sun, Qun; Zhang, Qiang

2007-01-01

211

Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy.  

PubMed

Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin-taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin-paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin-taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication. PMID:22895509

Roulstone, V; Twigger, K; Zaidi, S; Pencavel, T; Kyula, J N; White, C; McLaughlin, M; Seth, R; Karapanagiotou, E M; Mansfield, D; Coffey, M; Nuovo, G; Vile, R G; Pandha, H S; Melcher, A A; Harrington, K J

2013-05-01

212

A Dicarboxylic Fatty Acid Derivative of Paclitaxel for Albumin Assisted Drug Delivery  

PubMed Central

Paclitaxel is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize paclitaxel (PTX) by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (~5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor bearing mice, [3H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 hours. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23-h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics. PMID:22674061

Hackett, Michael J.; Joolakanti, Shyamsunder; Hartranft, Megan E.; Guley, Patrick C.; Cho, Moo J.

2013-01-01

213

Two Cases of Mastectomy after Paclitaxel + Bevacizumab Therapy for Locally Advanced Breast Cancer  

PubMed Central

Introduction Locally advanced breast cancer (LABC) deteriorates the quality of life (QOL) of the affected patients. Combination chemotherapy or extended chemotherapy is considered to help to shrink local lesions. Case 1 A 71-year-old female with a history of tympanitis and cystitis with methicillin-resistant Staphylococcus aureus (MRSA) visited our hospital. There was a tumor of 7 cm in diameter in her right breast with skin ulceration. Paclitaxel + bevacizumab therapy was started, and after five cycles of therapy, a mastectomy with axillary dissection was performed. Chemotherapy with anthracycline was avoided for fear of activating the MRSA. After the operation, the patient's wound opened. However, it naturally epithelialized. Case 2 A 41-year-old female visited our hospital due to a tumor of 8 cm in diameter in her right breast with skin ulceration. Four cycles of paclitaxel + bevacizumab therapy were started, and her tumor almost disappeared during the first cycle. Then, doxorubicin + cyclophosphamide therapy was performed for four cycles, and a mastectomy with axillary dissection was performed. Her postoperative course was good. Discussion Chemotherapy with bevacizumab or extended chemotherapy is generally not considered to contribute to a survival improvement. However, such therapy contributes in increasing the response to chemotherapy, and should be considered for patients with LABC to shrink the local lesions and improve the QOL. PMID:24932175

Shinoda, Chika; Mori, Ryutaro; Nagao, Yasuko

2014-01-01

214

Effects of Paclitaxel on EGFR Endocytic Trafficking Revealed Using Quantum Dot Tracking in Single Cells  

PubMed Central

Paclitaxel (PTX), a chemotherapeutic drug, affects microtubule dynamics and influences endocytic trafficking. However, the mechanism and the dynamics of altered endocytic trafficking by paclitaxel treatment in single living cells still remain elusive. By labeling quantum dots (QDs) to the epidermal growth factor (EGF), we continuously tracked the endocytosis and post-endocytic trafficking of EGF receptors (EGFRs) in A549 cells for a long time interval. A single-cell analysis method was introduced to quantitatively study the dynamics of endocytic trafficking. Compared with the control cells, the velocity of directed motion was reduced by 30% due to the suppression of high speed movements of EGF-QDs along the microtubules in PTX-treated cells. The endocytic trafficking in PTX-treated cells was mainly via super-diffusive mode of motion, whereas in control cells, it was mostly via sub-diffusive mode of motion. Moreover, PTX shortened endosomal trafficking and prevented EGF-QDs from moving to the perinuclear area via the rapid delivery of EGF-QDs into the peripheral lysosomes. The present study may shed light on the mechanism of the effect of PTX on the treatment of lung cancer. PMID:23029028

Li, Hui; Duan, Zhao-Wen; Xie, Ping; Liu, Yu-Ru; Wang, Wei-Chi; Dou, Shuo-Xing; Wang, Peng-Ye

2012-01-01

215

Evaluation of vitamin B12 effects on DNA damage induced by paclitaxel.  

PubMed

Paclitaxel (PAC) is an anticancer drug that has been shown to generate free radicals leading to irreversible cell injury. Vitamin B12 has antioxidative properties and can protect DNA from free radicals. In this study, we examined the possible genotoxic effect of PAC on DNA as well as the possible protective effect of vitamin B12 on DNA damage induced by paclitaxel. Sister chromatid exchanges (SCEs), chromosomal aberrations (CAs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were measured in cultured human blood lymphocytes treated with PAC (10 µM) and/or vitamin B12 (2.7 mg/mL). Our results showed that PAC significantly increased the frequencies of SCEs (p < 0.001) and CAs (p < 0.001) in human blood lymphocytes, as compared to controls. These DNA damages, caused by PAC drug, were prevented by pretreatment of cells with vitamin B12. In addition, we showed that PAC induced an increase in 8-OHdG, a marker of oxidative DNA damage, and that this increase was prevented by vitamin B12. Vitamin B12 seems to protect against genotoxicity induced by PAC in human blood lymphocytes. PMID:24215581

Alzoubi, Karem; Khabour, Omar; Khader, Manal; Mhaidat, Nizar; Al-Azzam, Sayer

2014-07-01

216

Rapid and sensitive liquid chromatographic method for determination of Paclitaxel from parenteral formulation and nanoparticles.  

PubMed

A simple and fast reversed phase liquid chromatographic method was developed for estimation of paclitaxel in commercially available parenteral formulation and nanoparticles. Separations were carried out using mobile phase consisting of acetonitrile and 20 mM potassium dihydrogen phosphate (45:55, v/v) on Lichrocart(®) C(18) analytical column at a flow rate of 1 ml/min and detection wavelength of 230 nm. The developed method exhibited linearity over an analytical range of 50-2000 ng/ml with regression equation, mean peak area= 137.58 concentration (ng/ml)+1765.94, (R(2) =0.9999). The method demonstrated selectivity with no interfering peaks eluting near the vicinity of drug peak. The method was found to be sensitive with detection and quantification limits of 7.57 ng/ml and 22.94 ng/ml. The method has shown consistent and good recoveries from parenteral formulation (100.06±0.86%) and nanoparticles (100.43±0.91%). The method was successfully employed for the analysis of in vitro release study samples of nanoparticle formulation. The method was also applied for determination of paclitaxel content in various pharmaceutical formulations. PMID:21218057

Kollipara, S; Bende, G; Saha, R N

2010-07-01

217

Release modeling and comparison of nanoarchaeosomal, nanoliposomal and pegylated nanoliposomal carriers for paclitaxel.  

PubMed

Breast cancer is the most prevalent cancer among women. Recently, delivering by nanocarriers has resulted in a remarkable evolution in treatment of numerous cancers. Lipid nanocarriers are important ones while liposomes and archaeosomes are common lipid nanocarriers. In this work, paclitaxel was used and characterized in nanoliposomal and nanoarchaeosomal form to improve efficiency. To increase stability, efficiency and solubility, polyethylene glycol 2000 (PEG 2000) was added to some samples. MTT assay confirmed effectiveness of nanocarriers on MCF-7 cell line and size measuring validated nano-scale of particles. Nanoarchaeosomal carriers demonstrated highest encapsulation efficiency and lowest release rate. On the other hand, pegylated nanoliposomal carrier showed higher loading efficiency and less release compared with nanoliposomal carrier which verifies effect of PEG on improvement of stability and efficiency. Additionally, release pattern was modeled using artificial neural network (ANN) and genetic algorithm (GA). Using ANN modeling for release prediction, resulted in R values of 0.976, 0.989 and 0.999 for nanoliposomal, pegylated nanoliposomal and nanoarchaeosomal paclitaxel and GA modeling led to values of 0.954, 0.951 and 0.976, respectively. ANN modeling was more successful in predicting release compared with the GA strategy. PMID:24867099

Movahedi, Fatemeh; Ebrahimi Shahmabadi, Hasan; Alavi, Seyed Ebrahim; Koohi Moftakhari Esfahani, Maedeh

2014-09-01

218

LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer  

PubMed Central

The Leucine Zipper Tumor Suppressor 1 (LZTS1) is a tumor suppressor gene, located at chromosome 8p22, which is frequently altered in human cancer. In normal tissue, its ubiquitous expression regulates cell mitosis by the stabilization of microtubule networks. LZTS1-deficient mouse embryonic fibroblasts have been shown to have an accelerated mitotic progression, and a higher resistance to taxanes, microtubule-stabilizing drugs. We investigate the role of Lzts1 in paclitaxel-resistance in breast cancer cells. Downregulation of Lzts1 expression significantly decreases sensitivity to paclitaxel in vitro. We further analyzed Lzts1 expression by immunohistochemistry in 270 primary breast cancer samples and 16 normal breast specimens. Lzts1 was significantly downregulated in breast cancer samples and its deregulation was associated with a higher incidence of tumor recurrence, and to a worse overall survival. Moreover, Lzts1-negative tumors were associated with unfavorable outcome after taxanes-based therapy. Thus our data suggest that Lzts1 deregulation is involved in breast cancer and its immunohistochemical evaluation may serve as a prognostic factor for breast cancer therapy PMID:24448468

Lovat, Francesca; Ishii, Hideshi; Schiappacassi, Monica; Fassan, Matteo; Barbareschi, Mattia; Galligioni, Enzo; Gasparini, Pierluigi; Baldassarre, Gustavo; Croce, Carlo M.; Vecchione, Andrea

2014-01-01

219

Facile preparation of paclitaxel loaded silk fibroin nanoparticles for enhanced antitumor efficacy by locoregional drug delivery.  

PubMed

Non-toxic, safe materials and preparation methods are among the most important factors when designing nanoparticles (NPs) for future clinical application. Here we report a novel and facile method encapsulating anticancer drug paclitaxel (PTX) into silk fibroin (SF), a biocompatible and biodegradable natural polymer, without adding any toxic organic solvents, surfactants or other toxic agents. The paclitaxel loaded silk fibroin nanoparticles (PTX-SF-NPs) with a diameter of 130 nm were formed in an aqueous solution at room temperature by self-assembling of SF protein, which demonstrated mainly silk I conformation in the NPs. In cellular uptake experiments, coumarin-6 loaded SF NPs were taken up efficiently by two human gastric cancer cell lines BGC-823 and SGC-7901. In vitro cytotoxicity studies demonstrated that PTX kept its pharmacological activity when incorporating into PTX-SF-NPs, while SF showed no cytotoxicity to cells. The in vivo antitumor effects of PTX-SF-NPs were evaluated on gastric cancer nude mice exnograft model. We found that locoregional delivery of PTX-SF-NPs demonstrated superior antitumor efficacy by delaying tumor growth and reducing tumor weights compared with systemic administration. Furthermore, the organs of mice in NP treated groups didn't show obvious toxicity, indicating the in vivo safety of SF NPs. These results suggest that SF NPs are promising drug delivery carriers, and locoregional delivery of SF NPs could be a potential future clinical cancer treatment regimen. PMID:24274601

Wu, Puyuan; Liu, Qin; Li, Rutian; Wang, Jing; Zhen, Xu; Yue, Guofeng; Wang, Huiyu; Cui, Fangbo; Wu, Fenglei; Yang, Mi; Qian, Xiaoping; Yu, Lixia; Jiang, Xiqun; Liu, Baorui

2013-12-11

220

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics  

PubMed Central

Within the mitotic spindle, there are multiple populations of microtubules with different turnover dynamics, but how these different dynamics are maintained is not fully understood. MCAK is a member of the kinesin-13 family of microtubule-destabilizing enzymes that is required for proper establishment and maintenance of the spindle. Using quantitative immunofluorescence and fluorescence recovery after photobleaching, we compared the differences in spindle organization caused by global suppression of microtubule dynamics, by treating cells with low levels of paclitaxel, versus specific perturbation of spindle microtubule subsets by MCAK inhibition. Paclitaxel treatment caused a disruption in spindle microtubule organization marked by a significant increase in microtubules near the poles and a reduction in K-fiber fluorescence intensity. This was correlated with a faster t1/2 of both spindle and K-fiber microtubules. In contrast, MCAK inhibition caused a dramatic reorganization of spindle microtubules with a significant increase in astral microtubules and reduction in K-fiber fluorescence intensity, which correlated with a slower t1/2 of K-fibers but no change in the t1/2 of spindle microtubules. Our data support the model that MCAK perturbs spindle organization by acting preferentially on a subset of microtubules, and they support the overall hypothesis that microtubule dynamics is differentially regulated in the spindle. PMID:19158381

Rizk, Rania S.; Bohannon, Kevin P.; Wetzel, Laura A.; Powers, James; Shaw, Sidney L.

2009-01-01

221

The enthalpies and kinetic of dissolution of diterpenoid derivative—paclitaxel in aqueous NaCl solutions at 309.5 K  

NASA Astrophysics Data System (ADS)

The enthalpies of dissolution of paclitaxel in normal saline were measured using a RD496-2000 Calvet Microcalorimeter at 309.65 K under atmospheric pressure. The differential enthalpy (?dif H m ) and molar enthalpy (?sol H m) of dissolution of paclitaxel innormal saline were determined. The corresponding kinetic equation described the dissolution process was elucidated to be d?/ dt = 10-3.57(1 - a)1.15. Moreover, the half-life, ?sol H m , ?sol G m and ?sol S m of the dissolution process were also obtained. This work will provide a potential reference for the clinical application of paclitaxel.

Chen, Qi; Zhao, Weiwei; Pu, Xiaohua

2013-08-01

222

Prostate Cancer Prostatic Dis . Author manuscript Pilot trial of adjuvant paclitaxel plus androgen deprivation for patients with  

E-print Network

Prostate Cancer Prostatic Dis . Author manuscript Page /1 7 Pilot trial of adjuvant paclitaxel plus androgen deprivation for patients with high-risk prostate cancer after radical prostatectomy: results unclear with no clear consensus for men with high-risk prostate cancer after radical prostatectomy. We

Boyer, Edmond

223

Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel.  

PubMed

PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an antimitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an antiangiogenesis therapy such as sunitinib or sorafinib. PMID:22843210

Wein, Alexander N; Liu, Shihui; Zhang, Yi; McKenzie, Andrew T; Leppla, Stephen H

2013-02-01

224

Stability of parenteral nanoemulsions loaded with paclitaxel: the influence of lipid phase composition, drug concentration and storage temperature.  

PubMed

Paclitaxel was loaded into licensed parenteral nutrition nanoemulsions (Clinoleic® and Intralipid®) using bath sonication, and the stability of the formulations was investigated following storage for two weeks at room temperature or at 4?°C. In general, Clinoleic droplets were smaller than Intralipid droplets, being around 255 and 285?nm, respectively, for blank and freshly loaded emulsions. Regardless of storage temperature, the Clinoleic exhibited a very slight or no increase in droplet size upon storage, whilst the droplet size of the Intralipid emulsion increased significantly. The droplet size of both emulsions was minimally affected by paclitaxel concentration within the range of 0, 1, 3 and 6?mg/ml. The pH of both emulsions markedly decreased upon storage at room temperature, which was possibly attributed to the production of fatty acids resulting from phospholipid hydrolysis. However, at 4?°C, the pH of Clinoleic emulsion was unaffected by storage or paclitaxel concentration while the Intralipid emulsion demonstrated a trend for pH reduction. Both nanoemulsions had a negative zeta potential, with the Clinoleic formulations having the highest charge, possibly explaining the better size stability of this emulsion. Overall, this study has shown that paclitaxel was successfully loaded into clinically licensed parenteral emulsions and that Clinoleic showed greater stability than the Intralipid. PMID:24093888

Kadam, Alisha N; Najlah, Mohammad; Wan, Ka-Wai; Ahmed, Waqar; Crean, St John; Phoenix, David A; Taylor, Kevin M G; Elhissi, Abdelbary M A

2014-12-01

225

Materials Science and Engineering A 438440 (2006) 11191123 Surface characteristics and biological properties of paclitaxel-embedding  

E-print Network

spectroscopy (XPS), high performance of liquid chromatography (HPLC) and platelet adhesion test. AFM results be eliminated from body as carbon dioxide and water, and PLGA has been increasingly used to delivery drugs [6 paper, paclitaxel-embedding PLGA coatings with a variable dosage were prepared. The surface

Zheng, Yufeng

226

Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment  

PubMed Central

A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-?-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment. PMID:24134303

2013-01-01

227

Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III ?-tubulin  

PubMed Central

Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III ?-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatin- and topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drug-resistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III ?-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III ?-tubulin. PMID:19423340

Pepe, Antonella; Sun, Liang; Zanardi, Ilaria; Wu, Xinyuan; Ferlini, Cristiano; Fontana, Gabriele; Bombardelli, Ezio; Ojima, Iwao

2009-01-01

228

Shape-controlled Paclitaxel nanoparticles with multiple morphologies: rod-shaped, worm-like, spherical, and fingerprint-like.  

PubMed

Although many nanocarriers have been developed to encapsulate paclitaxel (PTX), the drug loading and circulation time in vivo always are not ideal because of its rigid "brickdust" molecular structure. People usually concentrate their attention on the spherical nanocarriers, here paclitaxel nanoparticles with different geometries were established through the chemical modification of PTX, nanoprecipitation, and core-matched cargos. Previously we have developed rod-shape paclitaxel nanocrystals using block copolymer, pluronic F127. Unfortunately, the pharmacokinetic (PK) profile of PTX nanocrystals is very poor. However, when PTX was replaced by its prodrug, the geometry of the nanoparticles changed from rod-shaped to worm-like. The worm-like nanoparticles can be further changed to spherical nanoparticles using the nanoprecipitation method, and changed to fingerprint-like nanoparticles upon the addition of the core-matched PTX. The nanoparticles with nonspherical morphologies, including worm-like nanoparticles and fingerprint-like nanoparticles, offer significant advantages in regards to key PK parameters in vivo. More important, in this report the application of the core-matching technology in creating a core-matched environment capable of controlling the in vivo PK of paclitaxel was demonstrated, and it revealed a novel technique platform to construct nanoparticles and improve the poor PK profiles of the drugs. PMID:25188586

Wang, Yongjun; Wang, Dun; Fu, Qiang; Liu, Dan; Ma, Yan; Racette, Kelly; He, Zhonggui; Liu, Feng

2014-10-01

229

Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound Paclitaxel in pancreatic ductal adenocarcinoma.  

PubMed

Pancreatic stellate cells (PSC) have been recognized as the principal cells responsible for the production of fibrosis in pancreatic ductal adenocarcinoma (PDAC). Recently, PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBP; pamidronate or zoledronic acid), which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro, we observed that PSCs possess ?-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover, NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1), and type I collagen expression. NBPs also induced PSCs apoptosis and cell-cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine. Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. Mol Cancer Ther; 13(11); 2583-94. ©2014 AACR. PMID:25193509

Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N; Del C Monroig-Bosque, Paloma; Philip, Bincy; Rashed, Mohammed H; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M; Sood, Anil K; Logsdon, Craig; Lopez-Berestein, Gabriel

2014-11-01

230

Well-defined, size-tunable, multi-functional micelles for efficient paclitaxel delivery for cancer treatment  

PubMed Central

We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptakes of the smaller paclitaxel-loaded micelles (17–60 nm) by the tumor, and the larger micelles (150 nm) by the liver and lung. The toxicity and anti-tumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol® and Abraxane®. PMID:20536174

Luo, Juntao; Xiao, Kai; Li, Yuanpei; Lee, Joyce S.; Shi, Lifang; Tan, Yih-Horng; Xing, Li; Cheng, R. Holland; Liu, Gang-Yu; Lam, Kit S.

2010-01-01

231

Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer  

Microsoft Academic Search

Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with non- small cell lung cancer (NSCLC) that express EGFR. We re- cently published a phase I study of weekly matuzumab plus paclitaxel. This therapy was well tolerated and showed clinical responses in the majority of patients. Although matu- zumab displays potent antitumor activity in some

Marcus M. Schittenhelm; Christian Kollmannsberger; Karin Oechsle; Amy Harlow; Jason Morich; Friedemann Honecker; Raffael Kurek; Stephan Storkel; Lothar Kanz; Christopher L. Corless; Kwok-Kin Wong; Carsten Bokemeyer; Michael C. Heinrich

2009-01-01

232

Pharmacokinetics, biodistribution, efficacy and safety of N-octyl- O-sulfate chitosan micelles loaded with paclitaxel  

Microsoft Academic Search

Paclitaxel (Taxol®, PTX) is a promising anti-cancer drug and has been successfully used to treat a wide variety of cancers. Unfortunately, serious clinical side effects are associated with it, which are caused by PTX itself and non-aqueous vehicle containing Cremophor EL. Development of new formulation of PTX with better efficacy and fewer side effects is extremely urgent. In the present

Can Zhang; Guowei Qu; Yingji Sun; Xiaoli Wu; Zhong Yao; Qinglong Guo; Qilong Ding; Shengtao Yuan; Zilong Shen; Qineng Ping; Huiping Zhou

2008-01-01

233

Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment  

NASA Astrophysics Data System (ADS)

A system of novel nanoparticles of star-shaped cholic acid-core polylactide- d-?-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly( d, l-lactide- co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment.

Tang, Xiaolong; Cai, Shuyu; Zhang, Rongbo; Liu, Peng; Chen, Hongbo; Zheng, Yi; Sun, Leilei

2013-10-01

234

PLGA\\/TPGS Nanoparticles for Controlled Release of Paclitaxel: Effects of the Emulsifier and Drug Loading Ratio  

Microsoft Academic Search

Purpose. We successfully manufactured nanoparticles of biodegradable polymers for controlled release of paclitaxel. TPGS (d-a-tocopheryl polyethylene glycol 1000 succinate) could be a novel material to make nanoparticles of high drug encapsulation efficiency (EE) and desired physicochemical and pharmaceutical properties of the drug loaded nanoparticles. Among various controlling parameters in the process, the present work is to elucidate the effects of

Li Mu; Si-Shen Feng

2003-01-01

235

A novel controlled release formulation for the anticancer drug paclitaxel (Taxol ®): PLGA nanoparticles containing vitamin E TPGS  

Microsoft Academic Search

Paclitaxel (Taxol®) is one of the best antineoplastic drugs found from nature in the past decades. Like many other anticancer drugs, there are difficulties in its clinical administration due to its poor solubility. Therefore an adjuvant called Cremophor EL has to be employed, but this has been found to cause serious side-effects. However, nanoparticles of biodegradable polymers can provide an

L Mu; S. S Feng

2003-01-01

236

Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines-a phase II multipractice study  

PubMed Central

Background The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients. Methods Patients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m², administered in weeks 1–6 and 8–13). Results Twenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1–5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response?+?partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1–11.3) and 22 months (95% CI: 17–46). After alopecia, Common Toxicity Criteria grade ?2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related. Conclusions Weekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome. PMID:22559145

2012-01-01

237

A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma  

SciTech Connect

Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is undefined. We evaluated a combination of capecitabine, carboplatin, and paclitaxel with RT in a phase I study. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received capecitabine, carboplatin, and paclitaxel with RT (1.8 Gy daily to 50.4 Gy). After completion, patients were restaged and evaluated for surgery. Primary endpoints included determination of dose-limiting toxicities (DLT) and a recommended phase II dose, non-DLT, and preliminary radiographic and pathologic response rates. Results: Thirteen patients were enrolled (10 men, 3 women). All were evaluable for toxicity and efficacy. Two of 3 patients at dose level 1 (capecitabine 825 mg/m{sup 2} twice daily on RT days, carboplatin area under the curve (AUC) 2 weekly, paclitaxel 60 mg/m{sup 2} weekly) had DLT (both Grade 4 esophagitis). Of these 3, 2 underwent esophagectomy and had pathologic complete response (pCR). Ten patients were then enrolled at dose level -1 (capecitabine 600 mg/m{sup 2} twice daily, carboplatin AUC 1.5, paclitaxel 45 mg/m{sup 2}). Overall, 3 of 10 patients at dose level -1 developed DLT (2 Grade 3 esophagitis, 1 Grade 3 hypotension). Esophagectomy was performed in 6 of 10 patients. All patients had pathologic downstaging and 2 of 6 had pCR. Conclusions: The maximally tolerated/recommended phase II doses were capecitabine 600 mg/m{sup 2} twice daily, carboplatin AUC 1.5 weekly, and paclitaxel 45 mg/m{sup 2} weekly with RT to 50.4 Gy. In our small study, this regimen appears active but is accompanied by significant toxicities, primarily esophagitis.

Czito, Brian G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)]. E-mail: czito@radonc.duke.edu; Kelsey, Chris R. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Hurwitz, Herbert I. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); Willett, Chris G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Morse, Michael A. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); Blobe, Gerard C. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); Fernando, Nishan H. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); D'Amico, Thomas A. [Department of General Surgery, Duke University Medical Center, Durham, NC (United States); Harpole, David H. [Department of General Surgery, Duke University Medical Center, Durham, NC (United States); Honeycutt, Wanda R.N. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); Yu Daohai [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC (United States); Bendell, Johanna C. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States)

2007-03-15

238

Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel  

PubMed Central

Background Tumor promoters enhance tumor yield in experimental animals without directly affecting the DNA of the cell. Promoters may play a role in the development of cancer, as humans are exposed to them in the environment. In work based on computer-assisted microscopy and sophisticated classification methods, we showed that cells could be classified by reference to a database of known normal and cancerous cell phenotypes. Promoters caused loss of properties specific to normal cells and gain of properties of cancer cells. Other compounds, including colchicine, had a similar effect. Colchicine given together with paclitaxel, however, caused cells to adopt properties of normal cells. This provided a rationale for tests of microtubule inhibitor combinations in cancer patients. The combination of a depolymerizing and a stabilizing agent is a superior anti-tumor treatment. The biological basis of the effect is not understood. Results A single compound containing both colchicine and paclitaxel structures was synthesized. Colchicine is an alkaloid with a trimethoxyphenyl ring (ring A), a ring with an acetamide linkage (ring B), and a tropolone ring (ring C). Although rings A and C are important for tubulin-binding activity, the acetamide linkage on ring B could be replaced by an amide containing a glutamate linker. Alteration of the C-7 site on paclitaxel similarly had little or no inhibitory effect on its biological activity. The linker was attached to this position. The coupled compound, colchitaxel (1), had some of the same effects on microtubules as the combination of starting compounds. It also caused shortening and fragmentation of the + end protein cap. Conclusion Since microtubule inhibitor combinations give results unlike those obtained with either inhibitor alone, it is important to determine how such combinations affect cell shape and growth. Colchitaxel shows a subset of the effects of the inhibitor combination. Thus, it may be able to bind the relevant cellular target of the combination. It will be useful to determine the basis of the shape reversal effect and possibly, the reasons for therapeutic efficacy of microtubule inhibitor combinations. PMID:16813651

Bombuwala, Karunananda; Kinstle, Thomas; Popik, Vladimir; Uppal, Sonal O; Olesen, James B; Vina, Jose; Heckman, Carol A

2006-01-01

239

An antimitotic and antivascular agent BPR0L075 overcomes multidrug resistance and induces mitotic catastrophe in paclitaxel-resistant ovarian cancer cells.  

PubMed

Paclitaxel plays a major role in the treatment of ovarian cancer; however, resistance to paclitaxel is frequently observed. Thus, new therapy that can overcome paclitaxel resistance will be of significant clinical importance. We evaluated antiproliferative effects of an antimitotic and antivascular agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50?=?2-7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III ?-tubulin or mutation of ?-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induces cell death by a dual mechanism in parental and paclitaxel-resistant ovarian cancer cells. In the parental cells (OVCAR-3 and SKOV-3), BPR0L075 induced apoptosis, evidenced by poly(ADP-ribose) polymerase (PARP) cleavage and DNA ladder formation. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage. Immunoblotting analysis shows that BPR0L075 treatment induced up-regulation of cyclin B1, BubR1, MPM-2, and survivin protein levels and Bcl-XL phosphorylation in parental cells; however, in resistant cells, the endogenous expressions of BubR1 and survivin were depleted, BPR0L075 treatment failed to induce MPM-2 expression and phosphorylation of Bcl-XL. BPR0L075 induced cell death in both parental and paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel resistance by bypassing efflux transporters and inducing mitotic catastrophe. BPR0L075 represents a novel microtubule therapeutic to overcome multidrug resistance and trigger alternative cell death by mitotic catastrophe in ovarian cancer cells that are apoptosis-resistant. PMID:23762410

Wang, Xiaolei; Wu, Erxi; Wu, Jun; Wang, Tian-Li; Hsieh, Hsing-Pang; Liu, Xinli

2013-01-01

240

An Antimitotic and Antivascular Agent BPR0L075 Overcomes Multidrug Resistance and Induces Mitotic Catastrophe in Paclitaxel-Resistant Ovarian Cancer Cells  

PubMed Central

Paclitaxel plays a major role in the treatment of ovarian cancer; however, resistance to paclitaxel is frequently observed. Thus, new therapy that can overcome paclitaxel resistance will be of significant clinical importance. We evaluated antiproliferative effects of an antimitotic and antivascular agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50?=?2–7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III ?-tubulin or mutation of ?-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induces cell death by a dual mechanism in parental and paclitaxel-resistant ovarian cancer cells. In the parental cells (OVCAR-3 and SKOV-3), BPR0L075 induced apoptosis, evidenced by poly(ADP-ribose) polymerase (PARP) cleavage and DNA ladder formation. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage. Immunoblotting analysis shows that BPR0L075 treatment induced up-regulation of cyclin B1, BubR1, MPM-2, and survivin protein levels and Bcl-XL phosphorylation in parental cells; however, in resistant cells, the endogenous expressions of BubR1 and survivin were depleted, BPR0L075 treatment failed to induce MPM-2 expression and phosphorylation of Bcl-XL. BPR0L075 induced cell death in both parental and paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel resistance by bypassing efflux transporters and inducing mitotic catastrophe. BPR0L075 represents a novel microtubule therapeutic to overcome multidrug resistance and trigger alternative cell death by mitotic catastrophe in ovarian cancer cells that are apoptosis-resistant. PMID:23762410

Wang, Xiaolei; Wu, Erxi; Wu, Jun; Wang, Tian-Li; Hsieh, Hsing-Pang; Liu, Xinli

2013-01-01

241

Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl- l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells  

Microsoft Academic Search

Prophylactic treatment with acetyl-l-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests

Hai Wei Jin; Sarah J. L. Flatters; Wen Hua Xiao; Howard L. Mulhern; Gary J. Bennett

2008-01-01

242

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer  

PubMed Central

Purpose The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. Materials and Methods Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2. Results A total of twenty-four patients were enrolled. Only one patient experienced a doselimiting toxicity—a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration- time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. Conclusion The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2. PMID:25038758

Lee, Hyun Jung; Heo, Dae-Seog; Cho, Joo-Youn; Han, Sae-Won; Chang, Hye-Jung; Yi, Hyeon-Gyu; Kim, Tae-Eun; Lee, Se-Hoon; Oh, Do-Youn; Im, Seock-Ah; Jang, In-Jin; Bang, Yung-Jue

2014-01-01

243

Fabrication, characterization and in vitro release of paclitaxel (Taxol ®) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid\\/cholesterol emulsifiers  

Microsoft Academic Search

Spray dry technique was applied to produce paclitaxel loaded microspheres of biodegradable poly (lactic-co-glycolic acid) (PLGA) as an alternative delivery system. Various emulsifiers such as l-?-dipalmitoyl-phosphatidylcholine (DPPC), cholesterol, polyvinyl alcohol (PVA), gelatin were incorporated in order to achieve high encapsulating efficiency of paclitaxel in the microspheres and desired properties for a sustained release. Atomic force microscopy (AFM) and scanning electron

L Mu; S. S Feng

2001-01-01

244

Paclitaxel alters the expression and specific activity of deoxycytidine kinase and cytidine deaminase in non-small cell lung cancer cell lines  

Microsoft Academic Search

BACKGROUND: We observed that paclitaxel altered the pharmacokinetic properties of gemcitabine in patients with non-small cell lung cancer (NSCLC) and limited the accumulation of gemcitabine and its metabolites in various primary and immortalized human cells. Therefore, we classified the drug-drug interaction and the effects of paclitaxel on deoxycytidine kinase (dCK) and cytidine deaminase (CDA) in three NSCLC cell lines. These

Stacy S Shord; Shitalben R Patel

2009-01-01

245

Preparation and in vitro anticancer activity of wheat germ agglutinin (WGA)-conjugated PLGA nanoparticles loaded with paclitaxel and isopropyl myristate  

Microsoft Academic Search

The purpose of this study was to develop a novel lectin-conjugated isopropyl myristate (IPM)-incorporated PLGA nanoparticle system (NP) for the local delivery of paclitaxel to the lungs. Wheat germ agglutinin (WGA) was conjugated onto preformed IPM- and paclitaxel-loaded PLGA NPs by a two-step carbodiimide method following comparative uptake studies of Concanavalin A, Ricinus communis-120 and WGA on A549, H1299 and

Yun Mo; Lee-Yong Lim

2005-01-01

246

A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors.  

PubMed

Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity. PMID:24894650

Vlahovic, Gordana; Karantza, Vassiliki; Wang, Ding; Cosgrove, David; Rudersdorf, Nikita; Yang, Jianning; Xiong, Hao; Busman, Todd; Mabry, Mack

2014-10-01

247

Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy  

PubMed Central

The use of paclitaxel (Taxol®), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy, CIPN) which predominantly results in sensory dysfunction including chronic pain. Here we show that paclitaxel CIPN was associated with an induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia (DRG). Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons while CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in DRG large and medium-sized but not small neurons mainly dissociated from paclitaxel- but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes but no CCR2 signal was detected in spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between DRG neurons plays a critical role in the development of paclitaxel CIPN and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach. PMID:23726937

Zhang, Haijun; Boyette-Davis, Jessica A.; Kosturakis, Alyssa K.; Li, Yan; Yoon, Seo-Yeon; Walters, Edgar T.; Dougherty, Patrick M.

2013-01-01

248

Piperlongumine Induces Apoptosis and Synergizes with Cisplatin or Paclitaxel in Human Ovarian Cancer Cells  

PubMed Central

Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer. PMID:24895529

Chen, Xiu-Xiu; Wang, Huan; Jiang, Qi-Wei; Pan, Shi-Shi; Qiu, Jian-Ge; Mei, Xiao-Long; Xue, You-Qiu; Qin, Wu-Ming; Zheng, Fei-Yun; Yan, Xiao-Jian

2014-01-01

249

Cyclosporin a aerosol improves the anticancer effect of Paclitaxel aerosol in mice.  

PubMed Central

Paclitaxel (PTX) is a lipophilic agent with broad anticancer activity. In the present study we examined the antitumor effect and toxicity of co-administration of cyclosporine A (CsA) and PTX in liposomal aerosol using the Renca lung metastases mouse model. The untreated and PTX-only groups exhibited cancer growth while CsA aerosol plus PTX had more favorable effects on tumor growth. Weight loss was seen in mice treated with CsA/PTX+CsA by day 9 to 22. Histopathological examination showed no toxicity following treatment. The findings offer evidence that a combination of CsA and PTX may be suitable for aerosol treatment of lung cancer if it is possible to control toxicity of the therapy. Images Fig. 1 PMID:17060982

Knight, Vernon; Koshkina, N. V.; Golunski, E.; Roberts, L. E.; Gilbert, B. E.

2004-01-01

250

Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 Paclitaxel groups and 8 PEG groups.  

PubMed

The synthesis and characterization of a generation three triazine dendrimer that displays a phenolic group at the core for labeling, up to eight 5 kDa PEG chains for solubility, and 16 paclitaxel groups is described. Three different diamine linkers--dipiperidine trismethylene, piperazine, and aminomethylpiperidine--were used within the dendrimer. To generate the desired stoichiometric ratio of 8 PEG chains to 16 paclitaxel groups, a monochlorotriazine was prepared with two paclitaxel groups attached through their 2'-hydroxyls using a linker containing a labile disulfide. This monochlorotriazine was linked to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could be reacted with the eight amines of the dendrimer. NMR and MALDI-TOF confirm successful reaction. The eight monochlorotriazines of the resulting material are used as the site for PEGylation affording the desired 2:1 stoichiometry. The target and intermediates were amenable to characterization by (1)H and (13)C NMR, and mass spectrometry. Analysis revealed that 16 paclitaxel groups were installed along with 5-8 PEG chains. The final construct is 63% PEG, 22% paclitaxel, and 15% triazine dendrimer. Consistent with previous efforts and computational models, 5 kDa PEG groups were essential for making the target water-soluble. Molecular dynamics simulations showed a high degree of hydration of the core, and a radius of gyration of 2.8 ± 0.2 nm. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation indicative of aggregation. Drug release studies performed in plasma showed slow and identical release in mouse and rat plasma (8%, respectively). SPECT/CT imaging was used to follow biodistribution and tumor uptake. Using a two component model, the elimination and distribution half-lives were 2.65 h and 38.2 h, respectively. Compared with previous constructs, this dendrimer persists in the vasculature longer (17.33 ± 0.88% ID/g at 48 h postinjection), and showed higher tumor uptake. Low levels of dendrimer were observed in lung, liver, and spleen (~6% ID/g). Tumor saturation studies of small prostate cancer tumors (PC3) suggest that saturation occurs at a dose between 23.2 mg/kg and 70.9 mg/kg. PMID:24134039

Lee, Changsuk; Lo, Su-Tang; Lim, Jongdoo; da Costa, Viviana C P; Ramezani, Saleh; Öz, Orhan K; Pavan, Giovanni M; Annunziata, Onofrio; Sun, Xiankai; Simanek, Eric E

2013-12-01

251

Combined Treatment of Murine Fibrosarcoma with Chemotherapy (Paclitaxel), Radiotherapy, and Intratumoral Injection of Dendritic Cells  

PubMed Central

Background New antitumor therapeutic strategies aim to combine different approaches that are able to induce tumor-specific effector and memory T cell responses that might control tumor growth. Dendritic cells (DCs) have the capacity to induce antigen-specific cytotoxic T lymphocytes. We have previously shown that the combined treatment of paclitaxel chemotherapy (Chemo) and injection of DCs led to complete tumor regression. Objective The goal of this study was to evaluate synergistic antitumor effect of a triple combination treatment comprising radiotherapy, paclitaxel Chemo and intratumoral injection of syngeneic bone marrow-derived DCs on murine fibrosarcoma, compared to other single or double combination treatments. Methods For the murine fibrosarcoma model, naïve C57BL/6 mice were inoculated intradermally with 2×103 MCA102 cells in the right upper flank. Mice were assigned to five groups (untreatedcontrol, RT alone, RT+Chemo, RT+DC, and RT+Chemo+DC), with eight mice in each group. In vitro cytotoxicity assays were performed to assess the immune activity. The persistence of tumor-specific immunity was determined by second tumor challenge in mice with complete tumor regression. Results The triple combination treatment showed a significantly enhanced therapeutic efficacy by decreasing tumor size and inducing complete tumor regression, resulting in a cure of 50% of mice. The results of in vitro cytotoxicity assays and the second tumor challenge experiment strongly indicated the induction of a tumor-specific cytotoxic T lymphocyte response and acquisition of prolonged tumor immunity. Conclusion These findings suggest that the triple combination treatment can be a promising strategy for the treatment of murine fibrosarcoma. PMID:24648686

Byun, Ji-Won; Lee, Hyeon-Sook; Song, Sun-Uk; Lee, Si-Won; Kim, Soon-Ki; Kim, Woo-Chul; Lee, Moon-Hee

2014-01-01

252

Delivery of paclitaxel from cobalt–chromium alloy surfaces without polymeric carriers  

PubMed Central

Polymer-based carriers are commonly used to deliver drugs from stents. However, adverse responses to polymer coatings have raised serious concerns. This research is focused on delivering drugs from stents without using polymers or any carriers. Paclitaxel (PAT), an anti-restenotic drug, has strong adhesion towards a variety of material surfaces. In this study, we have utilized such natural adhesion property of PAT to attach these molecules directly to cobalt–chromium (Co–Cr) alloy, an ultra-thin stent strut material. Four different groups of drug coated specimens were prepared by directly adding PAT to Co–Cr alloy surfaces: Group-A (PAT coated, unheated, and ethanol cleaned); Group-B (PAT coated, heat treated, and ethanol cleaned); Group-C (PAT coated, unheated, and not ethanol cleaned); and Group-D (PAT coated, heat treated and not ethanol cleaned). In vitro drug release of these specimens was investigated using high performance liquid chromatography. Groups A and B showed sustained PAT release for up to 56 days. A simple ethanol cleaning procedure after PAT deposition can remove the loosely bound drug crystals from the alloy surfaces and thereby allowing the remaining strongly bound drug molecules to be released at a sustained rate. The heat treatment after PAT coating further improved the stability of PAT on Co–Cr alloy and allowed the drug to be delivered at a much slower rate, especially during the initial 7 days. The specimens which were not cleaned in ethanol, Groups C and D, showed burst release. PAT coated Co–Cr alloy specimens were thoroughly characterized using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. These techniques were collectively useful in studying the morphology, distribution, and attachment of PAT molecules on Co–Cr alloy surfaces. Thus, this study suggests the potential for delivering paclitaxel from Co–Cr alloy surfaces without using any carriers. PMID:20398928

Mani, Gopinath; Macias, Celia E.; Feldman, Marc D.; Marton, Denes; Oh, Sunho; Agrawal, C. Mauli

2014-01-01

253

In vivo pharmacokinetic and tissue distribution studies in mice of alternative formulations for local and systemic delivery of Paclitaxel: gel, film, prodrug, liposomes and micelles.  

PubMed

The aim of this study was to increase the understanding on the pharmacokinetic and tissue distribution of paclitaxel as influenced by formulation approach. For this purpose, various formulations investigated in Swiss mice included liposomes, poloxamer 407 gel and chitosan film for subcutaneous route; and water-soluble methacrylate prodrug, liposomes and poloxamer micelles for systemic administration. During this study, the currently marketed formulation of Cremophor EL of paclitaxel was used as the reference. A highest plasma concentration following intravenous administration of paclitaxel was observed for rigid and 'Stealth((R))' liposomes containing the prodrug while, least was for covalently incorporated paclitaxel micelles. Further, poloxamer micelles demonstrated both the highest mean residence time of 7.34 h and volume of distribution (VSS=4.82 and VZ=5.87 L/kg) for paclitaxel. This was followed by prodrug loaded 'Stealth' liposomes, which showed a mean residence time of 4.96 h but were least distributed into apparent physiological volume (VSS=2.12 and VZ=3.16 L/kg). These results clearly signify the role of formulation/excipient in drug disposition and possible interactions. Importantly, due to decrease in the clearance rate of drug, the area under curve values of paclitaxel increased by 1.64- and 2.5-fold for micellar and prodrug loaded 'Stealth' liposomal formulations, respectively over reference formulation. While thermoreversible gels served to decrease plasma concentration of paclitaxel (8-fold) after subcutaneous administration, systemic levels were totally absent after implantation of films. In tissue distribution studies, maximum percent of paclitaxel was observed in liver for reference formulation, conventional liposomes and micelles whereas highest levels of prodrug and 'Stealth((R))' liposomes were in kidney and spleen, respectively. The novel formulations significantly altered tissue accumulation profiles of paclitaxel relative to the reference formulation, for example, reduction in uptake by heart from liposomes and micelles, as well as the major recognition mechanism for elimination. It is proposed that a combination therapy with liposomes and micelles of paclitaxel for systemic delivery along with implantation of chitosan film for local delivery, may serve not only to improve patient compliance by obliterating the need to administer Cremophor EL, but also increase patient survival. PMID:16305406

Dhanikula, Anand Babu; Singh, D Renu; Panchagnula, Ramesh

2005-01-01

254

A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers  

PubMed Central

Introduction The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Material and methods In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m2 or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m2 (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. Results The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. Conclusions Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable. PMID:25276156

Liu, Ke-Jun; Guan, Zhong-Zhen; Liang, Ying; Yang, Xu-Qing; Peng, Jin; Huang, He; Shao, Qing-Xiang; Wang, Meng-Zhao; Zhu, Yun-Zhong; Wu, Chang-Ping; Wang, Shao-Bin; Xiong, Jian-Ping; Bai, Yu-Xian; Yu, Shi-Ying; Zhang, Yang; Hu, Xiao-Hua; Feng, Ji-Feng; Wu, Shi-Xiu; Jiao, Shun-Chang; Zhou, Cai-Cun; Wang, Jie

2014-01-01

255

Effective Drug Delivery, in vitro and in vivo, By Carbon-Based Nanovectors Non-Covalently Loaded With Unmodified Paclitaxel  

PubMed Central

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least twenty weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when non-covalently loaded with an unmodified drug. PMID:20681596

Berlin, Jacob M.; Leonard, Ashley D.; Pham, Tam T.; Sano, Daisuke; Marcano, Daniela C.; Yan, Shayou; Fiorentino, Stefania; Milas, Zvonimir L.; Kosynkin, Dmitry V.; Katherine Price, B.; Lucente-Schultz, Rebecca M.; Wen, XiaoXia; Gabriela Raso, M.; Craig, Suzanne L.; Tran, Hai T.; Myers, Jeffrey N.; Tour, James M.

2010-01-01

256

Comparative study of the antitumor activity of Nab-paclitaxel and intraperitoneal solvent-based paclitaxel regarding peritoneal metastasis in gastric cancer.  

PubMed

Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has been shown to be a promising treatment strategy for peritoneal metastasis. The present study focused on the comparative evaluation of the therapeutic efficacy of nanoparticle albumin-bound PTX (Nab-PTX) and i.p. administration of the conventional solvent-based PTX (Sb-PTX). We also investigated the difference in antitumor activity depending on the route of administration in the Nab-PTX treatment. Nab-PTX was administered i.p. or intravenously (i.v.) and Sb-PTX was administered i.p. at equitoxic and equal doses to nude mice bearing gastric cancer OCUM-2MD3 cell subcutaneous and peritoneal xenografts. Therapeutic efficacy of Sb-PTX and Nab-PTX was evaluated as inhibition of tumor growth using a peritoneal metastatic model with subcutaneous xenografts. The survival rate was also investigated using mouse peritoneal models. For assessment of subcutaneous tumors, the change in tumor volume was measured, and for assessment of peritoneal tumors, the weight of ascitic fluid and the total peritoneal tumor burden were measured for each individual mouse. At equitoxic doses, treatment with Nab-PTX resulted in a greater reduction in the size of subcutaneous tumors and the weight of ascites and peritoneal burden as compared with i.p. Sb-PTX (p<0.05). Treatment with i.p. and i.v. Nab-PTX also achieved greater survival benefit than i.p. Sb-PTX (p<0.05). In contrast, there was no significant difference in the degree of tumor reduction and the survival time between both drugs at equal doses. With regard to the route of administration, the antitumor efficacy of Nab-PTX after i.v. administration was equivalent to the efficacy after i.p. administration. These results suggest that i.v. Nab-PTX may be another encouraging treatment option that can target peritoneal dissemination in gastric cancer. PMID:24859429

Kinoshita, Jun; Fushida, Sachio; Tsukada, Tomoya; Oyama, Katsunobu; Watanabe, Toshihumi; Shoji, Masatoshi; Okamoto, Koichi; Nakanuma, Shinichi; Sakai, Seisho; Makino, Isamu; Furukawa, Hiroyuki; Hayashi, Hironori; Nakamura, Keishi; Inokuchi, Masahumi; Nakagawara, Hisatoshi; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Ninomiya, Itasu; Fujimura, Takashi; Masakazu, Yashiro; Hirakawa, Kosei; Ohta, Tetsuo

2014-07-01

257

+TIP EB1 downregulates paclitaxel?induced proliferation inhibition and apoptosis in breast cancer cells through inhibition of paclitaxel binding on microtubules.  

PubMed

Microtubule plus?end?binding protein (+TIP) EB1 has been shown to be upregulated in breast cancer cells and promote breast tumor growth in vivo. However, its effect on the cellular actions of microtubule?targeted drugs in breast cancer cells has remained poorly understood. By using cellular and biochemical assays, we demonstrate that EB1 plays a critical role in regulating the sensitivity of breast cancer cells to anti?microtubule drug, paclitaxel (PTX). Cell viability assays revealed that EB1 expression in the breast cancer cell lines correlated with the reduction of their sensitivity to PTX. Knockdown of EB1 by enzymatically?prepared siRNA pools (esiRNAs) increased PTX?induced cytotoxicity and sensitized cells to PTX?induced apoptosis in three breast cancer cell lines, MCF?7, MDA MB?231 and T47D. Apoptosis was associated with activation of caspase?9 and an increase in the cleavage of poly(ADP?ribose) polymerase (PARP). p53 and Bax were upregulated and Bcl2 was downregulated in the EB1?depleted PTX?treated MCF?7 cells, indicating that the apoptosis occurs via a p53?dependent pathway. Following its upregulation, the nuclear accumulation of p53 and its association with cellular microtubules were increased. EB1 depletion increased PTX?induced microtubule bundling in the interphase cells and induced formation of multiple spindle foci with abnormally elongated spindles in the mitotic MCF?7 cells, indicating that loss of EB1 promotes PTX?induced stabilization of microtubules. EB1 inhibited PTX?induced microtubule polymerization and diminished PTX binding to microtubules in vitro, suggesting that it modulates the binding sites of PTX at the growing microtubule ends. Results demonstrate that EB1 downregulates inhibition of PTX?induced proliferation and apoptosis in breast cancer cells through a mechanism in which it impairs PTX?mediated stabilization of microtubule polymerization and inhibits PTX binding on microtubules. PMID:25310526

Thomas, Geethu Emily; Sreeja, Jamuna S; Gireesh, K K; Gupta, Hindol; Manna, Tapas K

2015-01-01

258

Phase I study of combination therapy with weekly paclitaxel and cyclophosphamide for advanced or recurrent breast cancer  

Microsoft Academic Search

Purpose  Although anthracycline is a key agent in breast cancer treatment, its use is associated with the risk of cardiotoxicity. Recently,\\u000a the value of combination therapy with docetaxel and cyclophosphamide was reported. Because the characteristics of paclitaxel\\u000a differ on weekly versus tri-weekly administration, such as in the induction of apoptosis and anti-angiogenic activity, establishment\\u000a of a treatment regimen with a combination

Norikazu Masuda; Takahiro Nakayama; Jun Yamamura; Shunji Kamigaki; Tetsuya Taguchi; Mai Hatta; Junichi Sakamoto

2010-01-01

259

A phase I clinical and pharmacokinetic study of paclitaxel and docetaxel given in combination in patients with solid tumours  

Microsoft Academic Search

The aim of this study was to determine the safety and feasibility profile of paclitaxel (PTX) and docetaxel (DTX) in combination and the pharmacokinetic and pharmacodynamic interaction between these two drugs in two different alternated sequences of administration. The starting dose was PTX (100mg\\/m2) as a 3-h IV infusion followed by DTX (50mg\\/m2) as 1-h IV infusion or the alternative

Miguel Angel Izquierdo; Margarita García; José Luis Pontón; Marisa Martínez; Vicente Valentí; Matilde Navarro; Miguel Gil; Felipe Cardenal; Ricard Mesía; Xavier Pérez; Ramón Salazar; Josep Ramón Germà-Lluch

2006-01-01

260

Gold nanoparticles surface-functionalized with paclitaxel drug and biotin receptor as theranostic agents for cancer therapy  

Microsoft Academic Search

We describe in this study whether the gold nanoparticle (AuNP) surface-functionalized with PEG, biotin, paclitaxel (PTX) and rhodamine B linked beta-cyclodextrin (?-CD) (AuNP-5?) can be useful as a theranostic agent for cancer therapy without the cytotoxic effect on normal cells. Prior to surface-functionalizing AuNPs, the cytotoxicity of the nanoparticles was evaluated, followed by their cytocompatibility. PTX, an anti-cancer agent, formed

Dong Nyoung Heo; Dae Hyeok Yang; Ho-Jin Moon; Jung Bok Lee; Min Soo Bae; Sang Cheon Lee; Won Jun Lee; In-Cheol Sun; Il Keun Kwon

261

Neoadjuvant intraperitoneal chemotherapy with paclitaxel for the radical surgical treatment of peritoneal carcinomatosis in ovarian cancer: a prospective pilot study  

Microsoft Academic Search

Purpose  The admitted benefits of intraperitoneal chemotherapy during postoperative administration for the treatment of peritoneal\\u000a carcinomatosis from ovarian origin are limited by their associated morbidity and restricted diffusion by the presence of multiple\\u000a intra-abdominal adherences. The purpose of the study was to evaluate the security, effectiveness, and cytoreduction optimization\\u000a of intraperitoneal paclitaxel administration previously to radical surgery\\/peritonectomy\\/HIPEC (hyperthermic intraoperative\\u000a intraperitoneal chemotherapy)

Francisco C. Muñoz-Casares; Sebastián Rufián; Álvaro Arjona-Sánchez; María J. Rubio; Rafael Díaz; Ángela Casado; Álvaro Naranjo; Carlos J. Díaz-Iglesias; Rosa Ortega; María C. Muñoz-Villanueva; Jordi Muntané; Enrique Aranda

2011-01-01

262

Phase II study with paclitaxel for the treatment of advanced inoperable non-small cell lung cancer.  

PubMed

Paclitaxel is a plant product isolated from the bark of the Western yew (Taxus brevifolia) that promotes the formation and stabilization of microtubules. This leads to growth arrest in the G2/M phase of the cell cycle. Paclitaxel has demonstrated significant antineoplastic activity in different tumor types, most notably in ovarian and breast carcinoma. In two Phase II trials (Eastern Cooperative Oncology Group [ECOG]/M.D. Anderson) in patients with previously untreated Stage IIIB-IV non-small cell lung cancer (NSCLC), response rates of 21% and 24% were reported. We are performing a Phase II trial investigating the efficacy of paclitaxel in patients with inoperable Stage IIIB-IV NSCLC. Forty-three patients were treated, 31 males and 12 females, with a median age of 59 years (range, 29-75), ECOG performance status 0-2, Stage IIIB 30%, Stage IV 70%. Patients were treated every 3 weeks with 225 mg/m2 as a 3-h infusion with standard premedication. Preliminary efficacy results from 37 patients include partial remissions in eight (21.6%) patients, no change in 22 (59.5%) and disease progression in seven (19%) patients. Eight patients are still receiving therapy. The hematologic toxicities (n = 43) were mild, and no World Health Organization (WHO) Grade 4 neutropenia was observed. Nonhematologic toxicities were Grade 1/2 polyneuropathy in 97.6%, Grade 1-3 myalgia/arthralgia in 76%, and Grade 1-3 nausea/vomiting in 18.6% of the patients. In conclusion, paclitaxel is an active single agent in this patient population. Mild hematologic toxicities were observed in the 3-h infusion setting (compared with 24-h infusion) and therapy was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7551941

Gatzemeier, U; Heckmayr, M; Neuhauss, R; Schlüter, I; Pawel, J V; Wagner, H; Dreps, A

1995-06-01

263

Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials.  

PubMed

Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K(i) values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K(I) of 0.93 ?M and k(inact) of 0.0137 min(-1), and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients. PMID:24476576

Wang, Yedong; Wang, Meiyu; Qi, Huixin; Pan, Peichen; Hou, Tingjun; Li, Jiajun; He, Guangzhao; Zhang, Hongjian

2014-04-01

264

A Novel Intraarterial Chemotherapy Using Paclitaxel in Albumin Nanoparticles to Treat Advanced Squamous Cell Carcinoma of the Tongue  

Microsoft Academic Search

OBJECTIVE. The purpose of our study was to evaluate the effectiveness of intraarterial in- fusion of paclitaxel incorporated into human albumin nanoparticles for use as induction che- motherapy before definitive treatment of advanced squamous cell carcinoma of the tongue. SUBJECTS AND METHODS. Twenty-three previously untreated patients (age range, 27-75 years) who had carcinoma of the tongue (stage T3-T4, any N)

Bruno Damascelli; Gian Luigi Patelli; Rodolfo Lanocita; Giuseppe Di Tolla; Laura Francesca Frigerio; Alfonso Marchianò; Francesco Garbagnati; Carlo Spreafico; Vladimira Tichà; Caroline Regna Gladin; Mauro Palazzi; Flavio Crippa; Cesare Oldini; Stefano Calò; Alberto Bonaccorsi; Franco Mattavelli; Luigi Costa; Luigi Mariani; Giulio Cantù

265

Effects of 19 herbal extracts on the sensitivity to paclitaxel or 5-fluorouracil in HeLa cells.  

PubMed

The popularity of traditional herbal medicine (THM) being used as complementary medicines or alternative medicines is increasing. On the other hand, the development of multidrug resistance (MDR) remains a major hurdle to successful cancer chemotherapy. Some THMs capable of reversing MDR may contribute to the improvement of clinical outcomes in cancer chemotherapy. Herein, 19 kinds of herb were chosen from the ingredients of major THMs, and their effects on the sensitivity to anticancer drugs of tumor cells were investigated using the human cervical carcinoma HeLa cells. Focusing on the major mechanism for MDR, i.e., MDR1/P-glycoprotein, the effects of herbal extracts on its transport function were also examined using a MDR1 substrate Rhodamine123. Glycyrrhizae Radix, Rhei Rhizoma, Scutellariae Radix, Poria, Zizyphi Fructus, Zingiberis Rhizoma (dry), Coptidis Rhizoma, Ephedrae Herba and Asiasari Radix significantly enhanced the sensitivity to a MDR1 substrate paclitaxel, whereas none of the herbal extracts used had any effect on the sensitivity to 5-fluorouracil, which is not a substrate for MDR1. Rhodamine123 uptake was significantly increased by Rhei Rhizoma, Poria or Ephedrae Herba among nine herbal extracts sensitized to paclitaxel. This suggests that the increase in paclitaxel sensitivity by Glycyrrhizae Radix, Rhei Rhizoma, Poria or Ephedrae Herba was caused, in part, by the inhibition of MDR1 function, and the change in paclitaxel sensitivity by the other herbal extracts was not always dependent on this. Collectively, these findings indicate that the combination of anticancer drugs with some herbal extracts contributes to the enhancement of clinical outcomes in cancer chemotherapy. PMID:15635178

Takara, Kohji; Horibe, Sayo; Obata, Yukihisa; Yoshikawa, Eri; Ohnishi, Noriaki; Yokoyama, Teruyoshi

2005-01-01

266

Efficient Drug Delivery of Paclitaxel Glycoside: A Novel Solubility Gradient Encapsulation into Liposomes Coupled with Immunoliposomes Preparation  

PubMed Central

Although the encapsulation of paclitaxel into liposomes has been extensively studied, its significant hydrophobic and uncharged character has generated substantial difficulties concerning its efficient encapsulation into the inner water core of liposomes. We found that a more hydrophilic paclitaxel molecule, 7-glucosyloxyacetylpaclitaxel, retained tubulin polymerization stabilization activity. The hydrophilic nature of 7-glucosyloxyacetylpaclitaxel allowed its efficient encapsulation into the inner water core of liposomes, which was successfully accomplished using a remote loading method with a solubility gradient between 40% ethylene glycol and Cremophor EL/ethanol in PBS. Trastuzumab was then conjugated onto the surface of liposomes as immunoliposomes to selectively target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells. In vitro cytotoxicity assays revealed that the immunoliposomes enhanced the toxicity of 7-glucosyloxyacetylpaclitaxel in HER2-overexpressing cancer cells and showed more rapid suppression of cell growth. The immunoliposomes strongly inhibited the tumor growth of HT-29 cells xenografted in nude mice. Notably, mice survived when treated with the immunoliposomes formulation, even when administered at a lethal dose of 7-glucosyloxyacetylpaclitaxel in vivo. This data successfully demonstrates immunoliposomes as a promising candidate for the efficient delivery of paclitaxel glycoside. PMID:25264848

Murakami, Masaharu; Sekhar, Sreeja C.; Tominaga, Yuki; Okada, Masashi; Kudoh, Takayuki; Mizutani, Akifumi; Murakami, Hiroshi; Salomon, David S.; Mikuni, Katsuhiko; Mandai, Tadakatsu; Hamada, Hiroki; Seno, Masaharu

2014-01-01

267

Stable phosphatidylcholine-bile salt mixed micelles enhance oral absorption of paclitaxel: preparation and mechanism in rats.  

PubMed

Abstract The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-?-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC0??) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel. PMID:25077358

Zhao, Yanli; Cui, Yanan; Li, Yimu; Li, Lingbing

2014-12-01

268

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer  

PubMed Central

Background: This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients. Patients and Methods: Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6?mg?ml?1?min?1, day 1)/paclitaxel (200?mg?m?2, day 1) every 3 weeks. The initial dose of lenvatinib was 6?mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated. Results: Twenty-eight patients were treated. At 6?mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4?mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4?mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1?, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity. Conclusion: The MTD for lenvatinib with carboplatin/paclitaxel is 4?mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity. PMID:23860537

Nishio, M; Horai, T; Horiike, A; Nokihara, H; Yamamoto, N; Takahashi, T; Murakami, H; Yamamoto, N; Koizumi, F; Nishio, K; Yusa, W; Koyama, N; Tamura, T

2013-01-01

269

Phase I study of escalating doses of paclitaxel (Taxol) with fixed doses of ifosfamide, carboplatin, and etoposide.  

PubMed

The combination of ifosfamide (with mesna uroprotection), carboplatin, and etoposide (ICE) has demonstrated activity in a variety of cancers. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a dipertene compound extracted from the Pacific yew Taxus brevifolia, appeared a good candidate for study as an addition to the ICE regimen (ICE-T) because of its broad antitumor activity, its unique mechanism of action, and its toxicity profile, which was not expected to impact the ICE regimen adversely. In a phase I study, we evaluated the impact of adding escalating doses of paclitaxel (120 mg/m2, 135 mg/m2, 150 mg/m2, and 175 mg/m2) to the ICE regimen in 13 previously untreated (with two exceptions) patients with breast cancer, sarcoma, lung cancer, and adenoid cystic carcinoma. In general, ICE-T was well tolerated with some myelosuppression observed. Responses were seen at all dose levels. To date, the maximal tolerated dose of paclitaxel has not been reached; we are currently administering 175 mg/m2. PMID:7610396

Boros, L; Garrow, G C; Asbury, R F; Chang, A Y

1995-06-01

270

Bioprocessing of plant in vitro systems for the mass production of pharmaceutically important metabolites: paclitaxel and its derivatives.  

PubMed

Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non-small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of tumor. Taxanes stabilize microtubules by enhancing their polymerization and inhibiting depolymerization. Microtubule dynamics are crucial to mitotic spindle formation and function; therefore, cells exposed to taxanes are unable to undergo chromosomal separation during mitosis, become arrested in the G2/M phases of the cell cycle, and are subsequently targeted for apoptosis. Plant cell cultures are used for industrial-scale biotechnological production of important bioactive plant secondary metabolites, including the anticancer agent paclitaxel. In the last two decades, there have been numerous empirical approaches to improve the biotechnological production of taxanes, leading to the conclusion that treatment of Taxus sp. cells with methyl jasmonate or other elicitors is the most effective strategy. However, little insight has been gained into how the elicitors increase taxane biosynthesis or how this process is regulated. In recent years, with the help of "omics" tools, a rational approach has provided new information about taxane metabolism and its control. Once pathway bottlenecks have been identified, it will be possible to engineer Taxus sp. cell lines with overexpression of genes that control the flux-limiting steps, thus boosting taxane productivity. This review describes the chemical and biological characterization of paclitaxel and its derivatives and discusses future prospects for their biotechnological production. PMID:23210777

Onrubia, M; Cusidó, R M; Ramirez, K; Hernández-Vázquez, L; Moyano, E; Bonfill, M; Palazon, J

2013-01-01

271

Biological assessment of triazine dendrimer: toxicological profiles, solution behavior, biodistribution, drug release and efficacy in a PEGylated, paclitaxel construct.  

PubMed

The physicochemical characteristics, in vitro properties, and in vivo toxicity and efficacy of a third generation triazine dendrimer bearing approximately nine 2 kDa polyethylene glycol chains and twelve ester linked paclitaxel groups are reported. The hydrodynamic diameter of the neutral construct varies slightly with aqueous solvent ranging from 15.6 to 19.4 nm. Mass spectrometry and light scattering suggest radically different molecular weights with the former approximately 40 kDa mass consistent with expectation, and the latter 400 kDa mass consistent with a decameric structure and the observed hydrodynamic radii. HPLC can be used to assess purity as well as paclitaxel release, which is insignificant in organic solvents or aqueous solutions at neutral and low pH. Paclitaxel release occurs in vitro in human, rat, and mouse plasma and is nonlinear, ranging from 7 to 20% cumulative release over a 48 h incubation period. The construct is 2-3 orders of magnitude less toxic than Taxol by weight in human hepatocarcinoma (Hep G2), porcine renal proximal tubule (LLC-PK1), and human colon carcinoma (LS174T) cells, but shows similar cytotoxicity to Abraxane in LS174T cells. Both Taxol and the construct appear to induce caspase 3-dependent apoptosis. The construct shows a low level of endotoxin, is not hemolytic and does not induce platelet aggregation in vitro, but does appear to reduce collagen-induced platelet aggregation in vitro. Furthermore, the dendrimer formulation slightly activates the complement system in vitro due most likely to the presence of trace amounts (<1%) of free paclitaxel. An animal study provided insight into the maximum tolerated dose (MTD) wherein 10, 25, 50, and 100 mg of paclitaxel/kg of construct or Abraxane were administered once per week for three consecutive weeks to non tumor bearing athymic nude mice. The construct showed in vivo toxicity comparable to that of Abraxane. Both formulations were found to be nontoxic at the administered doses, and the dendrimer had an acute MTD greater than the highest dose administered. In a prostate tumor model (PC-3-h-luc), efficacy was observed over 70 days with an arrest of tumor growth and lack of luciferase activity observed in the twice treated cohort. PMID:20481608

Lo, Su-Tang; Stern, Stephan; Clogston, Jeffrey D; Zheng, Jiwen; Adiseshaiah, Pavan P; Dobrovolskaia, Marina; Lim, Jongdoo; Patri, Anil K; Sun, Xiankai; Simanek, Eric E

2010-08-01

272

Co-delivery of TRAIL gene enhances the anti-glioblastoma effect of paclitaxel in vitro and in vivo.  

PubMed

Co-delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and paclitaxel (PTX) is an attractive strategy to enhance their anti-tumor efficacy. As the most aggressive brain tumor, glioblastoma is sensitive to TRAIL and PTX. However, their therapeutic efficacy for intracranial glioblastoma is significantly impaired by blood-brain barrier (BBB) and blood-tumor barrier (BTB). Previously, we have prepared c(RGDyK)-poly(ethylene glycol)-polyethyleneimine (RGD-PEG-PEI) as a non-viral gene carrier for glioblastoma targeted therapy by employing a cyclic RGD peptide (c(RGDyK), cyclic arginine-glycine-aspartic acid-d-tyrosine-lysine), which binds to integrin ?(v)?(3) over-expressed neovasculature and U87 glioblastoma cells with high affinities. In the present work, it was found that low concentration of paclitaxel (10nM) significantly enhanced the gene transfection of RGD-PEG-PEI/pDNA nanoparticle, which, in turn, dramatically elevated the anti-glioblastoma effect of paclitaxel in vitro. The gene transfection was also elevated in vivo. Co-delivery of brain-targeted CDX-PEG-PLA-PTX micelle dramatically enhanced gene transfection efficiency in the intracranial brain tumor. Due to the change of BBB integrity and the formation of BTB, we subsequently investigated the anti-glioblastoma effects of RGD-PEG-PEI/pORF-hTRAIL nanoparticle combined with CDX-PEG-PLA-PTX micelle (paclitaxel loaded CDX-poly(ethylene glycol)-block-poly(lactic acid) micelle). While at the same dosages, the median survival of the intracranial glioblastoma-bearing model mice treated with co-delivery (33.5 days) is significantly longer than those of solely treated mice with CDX-PEG-PLA-PTX (25.5 days), RGD-PEG-PEI/pORF-hTRAIL (24.5 days) or physiological saline (21.5 days). Herein, we verify the high potency of co-delivery of TRAIL gene and paclitaxel in the intervention of intracranial glioblastoma by employing tumor-targeted gene carrier RGD-PEG-PEI and brain-targeted micelle CDX-PEG-PLA, respectively. PMID:22410115

Zhan, Changyou; Wei, Xiaoli; Qian, Jun; Feng, Linglin; Zhu, Jianhua; Lu, Weiyue

2012-06-28

273

Effect of Antioxidants and Carbohydrates in Callus Cultures of Taxus brevifolia: Evaluation of Browning, Callus Growth, Total Phenolics and Paclitaxel Production  

PubMed Central

Introduction To control the tissue browning phenomenon, callus growth, total phenolics and paclitaxel production, in the current investigation, we evaluated the effects of citric acid and ascorbic acid (as antioxidants) and glucose, fructose and sucrose in callus cultures of Taxus brevifolia. Methods To obtain healthy callus/cell lines of Taxus brevifolia, the effects of two antioxidants ascorbic acid (100-1000 mg/L) and citric acid (50-500 mg/L), and three carbohydrates (glucose, fructose and sucrose (5-10 g/L)) were studied evaluating activities of polyphenol oxidase (PPO) and peroxidase (PO) enzymes, callus growth/browning, total phenolics and paclitaxel production. Results These antioxidants (ascorbic acid and citric acid) failed to show significant effects on callus growth, browning intensity or paclitaxel production. However, the carbohydrates imposed significant effects on the parameters studied. High concentrations of both glucose and sucrose increased the browning intensity, thus decreased callus growth. Glucose increased paclitaxel production, but sucrose decreased it. Conclusion These results revealed that the browning phenomenon can be controlled through supplementation of the growth media with glucose, sucrose (5 g/L) and fructose (10 g/L), while increased paclitaxel production can be obtain by the optimized media supplemented with glucose (10 g/L), sucrose and fructose (5 g/L). PMID:23678406

Yari Khosroushahi, Ahmad; Naderi-Manesh, Hossein; Toft Simonsen, Henrik

2011-01-01

274

Identification of the First Inhibitor of the GBP1:PIM1 Interaction. Implications for the Development of a New Class of Anticancer Agents against Paclitaxel Resistant Cancer Cells.  

PubMed

Class III ?-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitaxel-resistant cells. Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling, and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site, the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1. PMID:25211704

Andreoli, Mirko; Persico, Marco; Kumar, Ajay; Orteca, Nausicaa; Kumar, Vineet; Pepe, Antonella; Mahalingam, Sakkarapalayam; Alegria, Antonio E; Petrella, Lella; Sevciunaite, Laima; Camperchioli, Alessia; Mariani, Marisa; Di Dato, Antonio; Novellino, Ettore; Scambia, Giovanni; Malhotra, Sanjay V; Ferlini, Cristiano; Fattorusso, Caterina

2014-10-01

275

A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial  

Microsoft Academic Search

This phase II trial describes the use of TIP chemotherapy (paclitaxel, ifosfamide and cisplatin) as salvage for patients with metastatic germ cell cancer (GCC) who have failed initial BEP (bleomycin, etoposide and cisplatin) chemotherapy. Patients with first relapse following BEP for metastatic GCC, confirmed by biopsy or sequentially rising markers, received four courses of TIP (paclitaxel 175 mg m?2 day

G M Mead; M H Cullen; R Huddart; P Harper; G J S Rustin; P A Cook; S P Stenning; M Mason

2005-01-01

276

Engineering erythrocytes as a novel carrier for the targeted delivery of the anticancer drug paclitaxel.  

PubMed

Paclitaxel (PTX) is formulated in a mixture of Cremophor EL and dehydrated alcohol. The intravenous administration of this formula is associated with a risk of infection and hypersensitivity reactions. The presence of Cremophor EL as a pharmaceutical vehicle contributes to these effects. Therefore, in this study, we used human erythrocytes, instead of Cremophor, as a pharmaceutical vehicle. PTX was loaded into erythrocytes using the preswelling method. Analysis of the obtained data indicates that 148.8 ?g of PTX was loaded/mL erythrocytes, with an entrapment efficiency of 46.36% and a cell recovery of 75.94%. Furthermore, we observed a significant increase in the mean cell volume values of the erythrocytes, whereas both the mean cell hemoglobin and the mean cell hemoglobin concentration decreased following the loading of PTX. The turbulence fragility index values for unloaded, sham-loaded and PTX-loaded erythrocytes were 3, 2, and 1 h, respectively. Additionally, the erythrocyte glutathione level decreased after PTX loading, whereas lipid peroxidation and protein oxidation increased. The release of PTX from loaded erythrocytes followed first-order kinetics, and about 81% of the loaded drug was released into the plasma after 48 h. The results of the present study revealed that PTX was loaded successfully into human erythrocytes with acceptable loading parameters and with some oxidative modification to the erythrocytes. PMID:25061408

Harisa, Gamaleldin I; Ibrahim, Mohamed F; Alanazi, Fars; Shazly, Gamal A

2014-07-01

277

Phenethyl isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells  

PubMed Central

Combination of phenethyl isothiocyanate (PEITC) and paclitaxel (taxol) has been shown to work synergistically to increase apoptosis and cell cycle arrest in breast cancer cells. In this report, we further explored the mechanisms for the synergistic activity of PEITC and taxol in MCF7 and MDA-MB-231 (MB) breast cancer cell lines. By Western blotting analysis, treatment of MCF7 cells with both PEITC and taxol led to a 10.4-fold and 5.96-fold increase in specific acetylation of alpha-tubulin over single agent PEITC and taxol, respectively. This synergistic effect on acetylation of alpha-tubulin was also seen in MB cells. The combination of PEITC and taxol also reduced expressions of cell cycle regulator Cdk1, and anti-apoptotic protein bcl-2, enhanced expression of Bax and cleavage of PARP proteins. In conclusion, this study provided biochemical evidence for the mechanism of synergistic effect between the epigenetic agent PEITC and the chemotherapeutic agent taxol. PMID:24495785

2014-01-01

278

Phenethyl isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells.  

PubMed

Combination of phenethyl isothiocyanate (PEITC) and paclitaxel (taxol) has been shown to work synergistically to increase apoptosis and cell cycle arrest in breast cancer cells. In this report, we further explored the mechanisms for the synergistic activity of PEITC and taxol in MCF7 and MDA-MB-231 (MB) breast cancer cell lines. By Western blotting analysis, treatment of MCF7 cells with both PEITC and taxol led to a 10.4-fold and 5.96-fold increase in specific acetylation of alpha-tubulin over single agent PEITC and taxol, respectively. This synergistic effect on acetylation of alpha-tubulin was also seen in MB cells. The combination of PEITC and taxol also reduced expressions of cell cycle regulator Cdk1, and anti-apoptotic protein bcl-2, enhanced expression of Bax and cleavage of PARP proteins. In conclusion, this study provided biochemical evidence for the mechanism of synergistic effect between the epigenetic agent PEITC and the chemotherapeutic agent taxol. PMID:24495785

Cang, Shundong; Ma, Yuehua; Chiao, Jen-Wei; Liu, Delong

2014-01-01

279

Paclitaxel loaded nano-aggregates based on pH sensitive polyaspartamide amphiphilic graft copolymers.  

PubMed

Polyaspartamide (PASPAM) derivatives grafted with 1-(3-aminopropyl)imidazole (API), O-(2-aminoethyl)-O'-methylpolyethylene glycol (MPEG), and octadecylamine (C18) groups were synthesized and their pH-sensitive structure and Paclitaxel (PTX) load/release properties were investigated. C18/MPEG/API-g-PASPAMs systems synthesized showed a strong pH-dependent phase transition behavior near pH 6.7. Large amount of PTX up to 60-75%, depending on polymer composition, was possibly loaded into the C18/MPEG/API-g-PASPAMs nano-aggregates using a solvent-free protocol. Its pH dependent release pattern was affected correspondingly by the phase transition behavior associated with the composition of graft substituents. The pure C18/MPEG/API-g-PASPAMs systems did not show cell toxicity but the PTX-loaded copolymer systems showed a similar cell toxicity to a Taxol-type PTX. From the in vivo animal study, PTX-loaded nano-aggregates showed the much improved inhibition effect on tumor growth compared to the conventional PTX formulation. PMID:22226879

Seo, Kwangwon; Chung, Seung Woo; Byun, Youngro; Kim, Dukjoon

2012-03-15

280

Paclitaxel and iron oxide loaded multifunctional nanoparticles for chemotherapy, fluorescence properties, and magnetic resonance imaging.  

PubMed

The multifunctional nanoparticles constructed from triphenylamine-poly(lactide-co-glycolide)-poly(ethyleneglycol)-poly(lactide-co-glycolide) (TPA-PEP) and folate-poly(2-ethyl-2oxazoline)-poly(D,L-lactide) (folate-PEOz-PLA) were developed in this study. Iron oxide nanoparticles (IOP) and paclitaxel (PTX) were coencapsulated in the nanoparticles with diameter less than 200 nm. The drug-loaded nanoparticles emit fluorescence peak at 460 nm when excited with wavelength of 350 nm. The in vitro antitumor activity of the drug-loaded nanoparticles was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays against HeLa cells. When the cells were exposed to the nanoparticles with different levels of folate but the same drug loading, cell viability decreases as the level of folate increases. Confocal laser scanning microscopy (CLSM) analysis shows that cellular uptake is lower for the non-folate-nanoparticles than that for the folate-nanoparticles. The in vitro and in vivo magnetic resonance imaging (MRI) studies indicate the better T2-Weighted images can be obtained for the folate-nanoparticles. In the anticancer effect evaluation, tumor-bearing mice administered with the 30%-folate-nanoparticles showed ~50% reduction in tumor volume after 23 days. The multifunctional nanoparticles as drug carrier with capabilities of both tumor-targeting and MRI present a new direction in drug delivery system development. PMID:22374619

Chen, Yung-Chu; Lee, Wen-Fu; Tsai, Han-Hsueh; Hsieh, Wen-Yuan

2012-05-01

281

Management of peripheral neuropathy induced by nab-paclitaxel treatment for breast cancer.  

PubMed

Nanoparticle albumin-bound paclitaxel (nab-PTX) is a key drug used in breast cancer treatment which often causes chemotherapy-induced peripheral neuropathy (CIPN). No effective approach for CIPN control has been established to date. This study assessed a new approach to CIPN integrating two concepts: compression therapy using stockings and sleeves, and medication therapy using selected prophylactic drugs, including goshajinkigan, which we named the "3S" approach. Fourteen breast cancer patients were divided into a 3S group (n=7) and a control group (n=7), and were treated with 260 mg/m(2) of nab-PTX once every three weeks. CIPN initially developed in five control-group patients and one 3S-group patient (p=0.03). Across all cycles, the CIPN grades, as determined by the Common Terminology Criteria for Adverse Events (CTCAE), were significantly lower in the 3S group than in the control group (p<0.001). The mean nab-PTX dose in the 3S group was 77.1 mg/m(2)/week versus 64.7 mg/m(2)/week in the control group (p<0.01). By controlling the development and severity of CIPN, 3S treatment appears to support the use of the recommended nab-PTX dosing for breast cancer patients. PMID:25075049

Ohno, Tsuyoshi; Mine, Takashi; Yoshioka, Hiroki; Kosaka, Mikiko; Matsuda, Sadayuki; De Kerckhove, Maiko; De Kerckhove, Charles; Irie, Junji; Inoue, Keiji; Haraguchi, Masashi; Kitajima, Masachika; Shinichiro, Ito; Tokai, Hirotaka; Tanaka, Takayuki; Izumida, Ryoko

2014-08-01

282

Intraperitoneal Paclitaxel Is Useful as Adjuvant Chemotherapy for Advanced Gastric Cancer with Serosal Exposure  

PubMed Central

Background Intraperitoneal administration of paclitaxel (PTX) can elicit a marked clinical response in peritoneal metastases of gastric cancer. Methods In this study, we retrospectively analyzed the clinical outcome of 17 patients who underwent R0 resection with D2 dissection for advanced gastric cancer with macroscopic serosal exposure and received intraperitoneal PTX as adjuvant therapy. Results A pathological study revealed that the depth of invasion of the primary tumor was pT4a or pT4b in 10 cases, and that the pN stage was more than pN2 in 8 cases. Genetic analysis of peritoneal lavage fluid was performed in 14 cases, all of which were positive for carcinoembryonic antigen mRNA. In these patients, PTX was intraperitoneally administered at 20–60 mg/m2 with oral S-1 for 3–36 months after surgery. In a median follow-up period of 66 months, recurrence occurred in the liver and peritoneum in 2 (11.7%) and 1 (5.9%) patients, respectively, and no nodal recurrence was observed. Five-year overall survival and disease-free survival were 88.2 and 82.3%, respectively. Conclusion Since these patients are considered to be a high-risk group for peritoneal recurrence, this result strongly suggests that adjuvant chemotherapy including intraperitoneal PTX is a promising protocol to improve the outcome of patients with advanced gastric cancer with serosal exposure. PMID:24575018

Kitayama, Joji; Ishigami, Hironori; Yamaguchi, Hironori; Emoto, Shigenobu; Watanabe, Toshiaki

2014-01-01

283

Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors.  

PubMed

Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100 ?m) and release the drug over 10 days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14 days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability. PMID:22178261

Bajaj, Gaurav; Kim, Mi Ran; Mohammed, Sulma I; Yeo, Yoon

2012-03-28

284

The Formulation of Aptamer-Coated Paclitaxel-Polylactide Nanoconjugates and Their Targeting to Cancer Cells  

PubMed Central

Paclitaxel-polylactide (Ptxl-PLA) conjugate nanoparticles, termed as nanoconjugates (NCs), were prepared through Ptxl/(BDI)ZnN(TMS)2 (BDI = 2-((2,6-diisopropylphenyl)-amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene)-mediated controlled polymerization of lactide (LA) followed by nanoprecipitation. Nanoprecipitation of Ptxl-PLA resulted in sub-100 nm NCs with monomodal particle distributions and low polydispersities. The sizes of Ptxl-PLA NCs could be precisely controlled by using appropriate water-miscible solvents and by controlling the concentration of Ptxl-PLA during nanoprecipitation. Co-precipitation of a mixture of PLA-PEG-PLA (PLA = 14 kDa; PEG = 5kDa) and Ptxl-PLA in PBS resulted in NCs that could stay non-aggregated in PBS for an extended period of time. To develop solid formulations of NCs, we evaluated a series of lyoprotectants, aiming to identify candidates that could effectively reduce or eliminate NC aggregation during lyophilization. Albumin was found to be an excellent lyoprotectant for the preparation of NCs in solid form, allowing lyophilized NCs to be readily dispersed in PBS without noticeable aggregates. Aptamer-NCs bioconjugates were prepared and found to be able to effectively target prostate-specific membrane antigen in a cell-specific manner. PMID:20122727

Tong, Rong; Yala, Linda; Fan, Timothy M.; Cheng, Jianjun

2011-01-01

285

A Targeting Drug Delivery System for Ovarian Carcinoma: Transferrin Modified Lipid Coated Paclitaxel-loaded Nanoparticles.  

PubMed

The transferring modified lipid coated PLGA nanoparticles, as a targetable vector, were developed for the targeting delivery of anticancer drugs with paclitaxel (PTX) as a model drug to the ovarian carcinoma, which combines the advantages and avoids disadvantages of polymeric nanoparticles and liposomes in drug delivery. A transmission electron microscopy (TEM) confirmed the lipid coating on the polymeric core. Physicochemical characterizations of TFLPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. In the cellular uptake study, the TFLPs were more efficiently endocytosed by the A2780 cells with high expression of transferrin receptors than HUVEC cells without the transferrin receptors. Furthermore, the anticancer efficacy of TFLPs on the tumor spheroids was stronger than that of lipid coated PLGA nanoparticles (LPs) and PLGA nanoparticles. In the in vivo study, the TFLPs showed the best inhibition effect of the tumor growth for the ovarian carcinoma-bearing mice. In brief, the TFLPs were proved to be an efficient targeting drug delivery system for ovarian carcinoma. PMID:24443309

Li, R; Zhang, Q; Wang, X-Y; Chen, X-G; He, Y-X; Yang, W-Y; Yang, X

2014-10-01

286

Well-defined degradable brush polymer-drug conjugates for sustained delivery of Paclitaxel.  

PubMed

To achieve a conjugated drug delivery system with high drug loading but minimal long-term side effects, a degradable brush polymer-drug conjugate (BPDC) was synthesized through azide-alkyne click reaction of acetylene-functionalized polylactide (PLA) with azide-functionalized paclitaxel (PTXL) and poly(ethylene glycol) (PEG). Well-controlled structures of the resulting BPDC and its precursors were verified by (1)H NMR and gel permeation chromatography (GPC) characterizations. With nearly quantitative click efficiency, drug loading amount of the BPDC reached 23.2 wt %. Both dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) imaging indicated that the BPDC had a nanoscopic size around 10-30 nm. The significant hydrolytic degradability of the PLA backbone of the BPDC was confirmed by GPC analysis of its incubated solution. Drug release study showed that PTXL moieties can be released through the cleavage of the hydrolyzable conjugation linkage in pH 7.4 at 37 °C, with 50% release in about 22 h. As illustrated by cytotoxicity study, while the polymeric scaffold of the BPDC is nontoxic, the BPDC exhibited higher therapeutic efficacy toward MCF-7 cancer cells than free PTXL at 0.1 and 1 ?g/mL. Using Nile red as encapsulated fluorescence probe, cell uptake study showed effective internalization of the BPDC into the cells. PMID:23181264

Yu, Yun; Chen, Chih-Kuang; Law, Wing-Cheung; Mok, Jorge; Zou, Jiong; Prasad, Paras N; Cheng, Chong

2013-03-01

287

In vivo evaluation of novel chitosan graft polymeric micelles for delivery of paclitaxel.  

PubMed

A water-insoluble anti-tumor agent, Paclitaxel (PTX) was successfully incorporated into polymeric micelles formed from new graft copolymers, N-octyl-N-(2-carboxyl-cyclohexamethenyl) chitosan derivatives(OCCC). The objective of this study was to optimize and characterize the novel PTX micelle (PTX-M). Furthermore, the pharmacokinetics, NIR-imaging, biodistribution, and anti-tumor effects of PTX-M were evaluated. The results showed that the PTX-M had high drug loading (43.25%). The Vd and t1/2? of PTX-M were increased by 11.4- and 2.83-fold, respectively, but the plasma AUC of PTX-M was 3.8-fold lower than that of Taxol. Biodistribution study indicated that PTX-M was widely distributed into most tissues, most of them found in liver, spleen, lung, and kidney. This result was similar with NIR(near-infrared)-imaging. Tumor growth was significantly inhibited after intravenous injection of PTX-M. PTX-M showed the enhanced anti-tumor effect and non-toxic effects compared with Taxol, the commercial product of PTX. Therefore, the chitosan-derived micelle system offered a stable and effective platform for cancer chemotherapy with PTX. PMID:20942638

Liu, Jia; Li, Hongxia; Chen, Daquan; Jin, Xiang; Zhao, Xiaoliang; Zhang, Can; Ping, Qineng

2011-04-01

288

Self-assembled polymeric nanoparticle of PEGylated chitosan-ceramide conjugate for systemic delivery of paclitaxel.  

PubMed

Abstract Chitosan has been widely explored as one of the most favorable biomaterials for various pharmaceutical applications due to its biodegradability and biocompatibility. Here, we report novel PEGylated-chitosan-ceramide (PEG-CS-CE) that forms stable polymeric nanoparticles capable of functioning as efficient carriers of hydrophobic drug molecules. The chitosan-ceramide conjugate (CS-CE) was linked with amine-polyethyleneglycol (NH2-PEG2000) by using dicyclohexylcarbodiimide/N-hydroxysuccinimide (DCC-NHS) to obtain PEG-CS-CE that could exhibit steric stabilization in biological environments. The structure of the conjugate was determined by proton ((1)H) NMR and FT-IR spectrometry. Under suitable conditions, the PEG-CS-CE self-assembled to form colloidally stable nanoparticles with a mean diameter of ?200?nm. Further, hydrophobic anti-tumor agent paclitaxel (PTX) was incorporated into the polymeric nanoparticle with 90% loading efficiency and 11.3% loading capacity via an emulsion-solvent evaporation method. The PTX-loaded PEG-CS-CE nanoparticle showed sustained release and exhibited higher cellular uptake and a comparable cytotoxic efficacy to that of free PTX on B16F10 melanoma and MCF-7 human breast adenocarcinoma cell lines. The empty nanoparticle showed no toxicity, indicating that the co-polymer is safe to use in drug delivery. The polymeric nanoparticle PEG-CS-CE developed by us represent promising nanocarriers of hydrophobic drug molecules. PMID:24964055

Battogtokh, Gantumur; Ko, Young Tag

2014-11-01

289

Carcinoma of Unknown Primary Site Treated with Carboplatin + Paclitaxel + Bevacizumab + Erlotinib and Its Maintenance Chemotherapy  

PubMed Central

About 3% of all cancer patients suffer from carcinoma of unknown primary site (CUP). In spite of its rarity, we will encounter them. While CUPs manifest a wide variety of clinical presentations, they have often resulted in poor prognosis. Although platinum/taxane combination chemotherapy, e.g. carboplatin (CBDCA) + paclitaxel (PTX) is widely used for patients suffering from CUP, the response rate is only about 30–40% and the median overall survival (OS) is only 9 months, which means that improvement is needed. Among the new regimens, the combination of CBDCA, PTX, bevacizumab (BEV) and erlotinib is thought to be highly promising. Herein, we report a case with CUP treated with this regimen and his maintenance therapy. Our patient was a 75-year-old man who was admitted with a left neck lump. CT revealed systemic massive lymphadenopathy. In spite of various investigations for primary origin, he was diagnosed with CUP and treated with CBDCA + PTX + BEV + erlotinib (AUC 6 + 175 mg/m2 + 15 mg/kg + 150 mg). Since the evaluation of the efficacy indicated partial response, maintenance chemotherapy (BEV and erlotinib) was performed. Chemotherapy was continued for 9 months until the patient was in a progressive disease state with meningeal dissemination. He died 12 months after the initiation of chemotherapy, which is a longer period than the previously reported OS. Of note, according to our case, CBDCA + PTX + BEV + erlotinib and its maintenance chemotherapy are feasible and well tolerated for CUP. PMID:25298764

Yasui, Hirotoshi; Sato, Kazuhide; Takeyama, Yoshihiro; Kato, Toshio; Hashimoto, Hiroyuki; Fukui, Yasutaka; Yoshihisa, Nagashima; Maeda, Matsuyoshi; Gonda, Hideo; Suzuki, Ryujiro

2014-01-01

290

PEG-Derivatized Embelin as a Dual Functional Carrier for the Delivery of Paclitaxel  

PubMed Central

Embelin, identified primarily from the Embelia ribes plant, has been shown to be a natural small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP). It is also a potent inhibitor of NF-?B activation, which makes it a potentially effective suppressor of tumor cell survival, proliferation, invasion, angiogenesis, and inflammation. However, embelin itself is insoluble in water, which makes it unsuitable for in vivo applications. In this work, we developed a novel micelle system through conjugating embelin to a hydrophilic polymer, polyethylene glycol 3,500 (PEG3.5K) through an aspartic acid bridge. The PEG3.5k-embelin2 (PEG3.5k-EB2) conjugate readily forms micelles in aqueous solutions with a CMC of 0.0205mg/mL. Furthermore, PEG3.5k-EB2 micelles effectively solubilize paclitaxel (PTX), a model hydrophobic drug used in this study. Both drug-free and drug-loaded micelles were small in sizes (20 ~ 30 nm) with low polydispersity indexes. In vitro cytotoxicity studies with several tumor cell lines showed that PEG3.5k-EB2 is comparable to embelin in antitumor activity and synergizes with PTX at much lower doses. Our results suggest that PEG-derivatized embelin may represent a novel and dual-functional carrier to facilitate the in vivo applications of poorly water-soluble anticancer drugs such as PTX. PMID:22681537

Huang, Yixian; Lu, Jianqin; Gao, Xiang; Li, Jiang; Zhao, Wenchen; Sun, Ming; Stolz, Donna Beer; Venkataramanan, Raman; Rohan, Lisa Cencia; Li, Song

2012-01-01

291

Diversity of endophytic fungi and screening of fungal paclitaxel producer from Anglojap yew, Taxus x media  

PubMed Central

Background Endophytic fungi represent underexplored resource of novel lead compounds and have a capacity to produce diverse class of plant secondary metabolites. Here we investigated endophytic fungi diversity and screening of paclitaxel-producing fungi from Taxus x media. Results Eighty-one endophytic fungi isolated from T. media were grouped into 8 genera based on the morphological and molecular identification. Guignardia and Colletotrichum were the dominant genera, whereas the remaining genera were infrequent groups. The genera Glomerella and Gibberella were first reported in Taxus. Three representative species of the distinct genera gave positive hits by molecular marker screening and were capable of producing taxol which were validated by HPLC-MS. Among these 3 taxol-producing fungi, the highest yield of taxol was 720 ng/l by Guignardia mangiferae HAA11 compared with those of Fusarium proliferatum HBA29 (240 ng/l) and Colletotrichum gloeosporioides TA67 (120 ng/l). This is the first report of taxol producer from Guignardia. Moreover, the lower similarities of ts and bapt between microbial and plant origin suggested that fungal taxol biosynthetic cluster might be repeatedly invented during evolution, nor horizontal gene transfer from Taxus species. Conclusions Taxol-producing endophytic fungi could be a fascinating reservoir to generate taxol-related drug lead and to elucidate the remained 5 unknown genes or the potential regulation mechanism in the taxol biosynthesis pathway. PMID:23537181

2013-01-01

292

Covalent Functionalization of Graphene Oxide with Biocompatible Poly(ethylene glycol) for Delivery of Paclitaxel.  

PubMed

Graphene oxide (GO), a novel 2D nanomaterial prepared by the oxidation of natural graphite, has been paid much attention in the area of drug delivery due to good biocompatibility and low toxicity. In the present work, 6-armed poly(ethylene glycol) was covalently introduced into the surface of GO sheets via a facile amidation process under mild conditions, making the modified GO, GO-PEG (PEG: 65 wt %, size: 50-200 nm), stable and biocompatible in physiological solution. This nanosized GO-PEG was found to be nontoxic to human lung cancer A549 and human breast cancer MCF-7 cells via cell viability assay. Furthermore, paclitaxel (PTX), a widely used cancer chemotherapy drug, was conjugated onto GO-PEG via ?-? stacking and hydrophobic interactions to afford a nanocomplex of GO-PEG/PTX with a relatively high loading capacity for PTX (11.2 wt %). This complex could quickly enter into A549 and MCF-7 cells evidenced by inverted fluorescence microscopy using Fluorescein isothiocyanate as a probe, and it also showed remarkably high cytotoxicity to A549 and MCF-7 cells in a broad range of concentration of PTX and time compared to free PTX. This kind of nanoscale drug delivery system on the basis of PEGylated GO may find potential application in biomedicine. PMID:25216036

Xu, Zhiyuan; Wang, Song; Li, Yongjun; Wang, Mingwei; Shi, Ping; Huang, Xiaoyu

2014-10-01

293

Injectable poly(organophosphazene) hydrogel system for effective paclitaxel and doxorubicin combination therapy.  

PubMed

Combination therapy is an important option for gastric cancer which is the second leading cause of cancer-related death worldwide. The administration schedule of cell cycle-specific drugs, such as doxorubicin (DOX) and paclitaxel (PTX), is important for therapeutic efficacy. However, to control the schedule is clinically inconvenient. Additionally, in vitro cytotoxicity tests against human gastric cancer cells (SNU-601) showed that the combination indices (CIs) of DOX and PTX were 1.43 (?=0) and 1.90 (?=1), respectively, indicating that the DOX and PTX interaction was antagonistic. Thus, based on the finding that the release rate of drugs from poly(organophosphazene) (PPZ) hydrogel is dependent on the hydrophobicity of the drugs, we used injectable PPZ hydrogel in combination therapy. In vivo anticancer activity test in human gastric cancer cell-xenografted mice showed that intratumoral injection with aqueous PPZ solution, containing DOX (15?mg/kg) and PTX (30?mg/kg), resulted in the highest tumor inhibition and safety (no mortality for approximately 3 months) in the experimental groups. Consequently, PPZ hydrogel is expected to be a promising drug delivery system for cell cycle-specific drugs, facilitating the control of their administration schedule for effective combination therapy. PMID:24937548

Cho, Jung-Kyo; Kuh, Hyo-Jeong; Song, Soo-Chang

2014-09-01

294

Src inhibition potentiates antitumoral effect of paclitaxel by blocking tumor-induced angiogenesis.  

PubMed

The protein kinase Src is frequently over-activated in advanced cancers where it modulates the signaling transduction cascade of several growth factors. The feasibility of combination treatment of Src inhibitors with chemotherapy is currently under investigation. We evaluated the anti-tumoral effect of paclitaxel (PTX) in combination with S13, a tyrosine kinase inhibitor with a prevalent specificity for Src, in a hormone-insensible prostate cancer (PCa) cell model. In vivo, combination treatment with PTX and S13 reduced dramatically PCa tumor growth with a relevant difference in the density of new blood vessels with respect to control and single treatments. This reduction was determined by a concomitant impairment of endothelial cell migration and of VEGF release by cancer cells. In fact, S13, when used alone, was sufficient to reduce tubule formation in vivo, and to inhibit VEGFR2 activation and FAK expression in endothelial cells. In addition, the combination treatment determined a significant reduction in ROS production and HIF-1 stabilization in PCa cells respect to single treatments with S13 or PTX. In conclusion, Src-inhibition could be an effective therapeutic strategy aimed at supporting the anti-angiogenic action of PTX in aggressive PCa. PMID:25128812

Delle Monache, Simona; Sanità, Patrizia; Calgani, Alessia; Schenone, Silvia; Botta, Lorenzo; Angelucci, Adriano

2014-10-15

295

The Effect of Short-term Intra-arterial Delivery of Paclitaxel on Neointimal Hyperplasia and the Local Thrombotic Environment after Angioplasty  

SciTech Connect

PurposeTo evaluate the effects of short-term intra-arterial delivery of paclitaxel on neointimal hyperplasia and the local thrombotic environment after angioplasty.MethodsAn experimental common carotid artery injury model was established in 60 rats, which were divided into experimental groups (40 rats) and controls (20 rats). Local intra-arterial administration of paclitaxel was applied at 2 doses (90 and 180 {mu}g/30 {mu}l), and the effects of short-term delivery of paclitaxel on neointimal hyperplasia and the expression of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated at days 15 and 30 by hematoxylin and eosin staining and immunohistochemistry.ResultsAt 15 and 30 days after injury, neointimal thickness and area, the ratio of intimal area to medial area and the stenotic rate were all significantly decreased in the group provided the high concentrations (180 {mu}g/30 {mu}l) of paclitaxel for 2 min or 10 min and in the group provided the low concentration (90 {mu}g/30 {mu}l) of paclitaxel for 10 min (p < 0.05). At 30 days after injury, there were no significant changes in TF expression among all experimental groups. PAI-1 expression increased in the neointima of the high concentration 10 min group (p < 0.05), while t-PA expression decreased in the neointima of the high concentration 2 min group (p < 0.05).ConclusionIn the rat common carotid artery injury model, the short-term delivery of paclitaxel could effectively inhibit neointimal hyperplasia in the long term, with very little influence on the local expression of TF and PAI-1.

Yajun, E, E-mail: eyj7681@yahoo.com.cn [Affiliated Hospital of Hebei University, Department of Interventional Radiology (China); He Nengshu, E-mail: eyajun@hotmail.com; Fan Hailun, E-mail: mydream510@yahoo.com.cn [Tianjin Institute of Radiology, General Hospital of Tianjin Medical University, Department of Radiology (China)

2013-08-01

296

Poly(ethylene glycol)-block-poly(?-caprolactone) micelles for combination drug delivery: evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer.  

PubMed

Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(?-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET imaging, and overall survival. (18)F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles. PMID:23246471

Cho, Hyunah; Lai, Tsz Chung; Kwon, Glen S

2013-02-28

297

Structural significance of the benzoyl group at the C-3'-N position of paclitaxel for nitric oxide and tumor necrosis factor production by murine macrophages.  

PubMed

The antitumor agent paclitaxel (Taxol) mimics the actions of lipopolysaccharide (LPS) on murine macrophages (M phi). Recently, we have shown that the benzoyl group at the C-3' position of paclitaxel is the most important site to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by C3H/HeN M phi (Biochem. Biophys. Res. Commun. 210, 678-686, 1996). In the present study, synthetic analogs of paclitaxel with replacement of the C-3'-N position were examined for their potencies to induce NO and TNF production by peritoneal M phi of LPS-responsive C3H/HeN mice and LPS-hyporesponsive C3H/HeJ mice, by human blood cells and human M phi. In this structure-activity relationship study, we found that (i) the p-substitution of the benzoyl group definitely affects the activity to activate C3H/HeN M phi, (ii) the analogs having a methyl or chloro group at the p-position exhibit stronger activity than that of paclitaxel, (iii) there is good correlation between NO and TNF production by the M phi in response to compounds, (iv) the compounds tested do not induce either NO or TNF production by C3H/HeJ M phi or TNF production by human cells, (v) a previous treatment of C3H/HeN M phi with the inactive compounds can hardly affect either paclitaxel- or LPS-induced TNF production by the M phi, (vi) paclitaxel and its analogs marginally affect LPS-induced TNF production by human blood cells, and (vii) there is no correlation between the NO/TNF inducibility to C3H/HeN M phi and growth inhibitory activity against M phi-like J774.1 and J7.DEF3 cells. PMID:9588177

Kirikae, T; Ojima, I; Ma, Z; Kirikae, F; Hirai, Y; Nakano, M

1998-04-28

298

High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection  

PubMed Central

Background The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy. Methods Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel. Results The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within ± 15%, except at the limit of quantitation where values within ± 20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m2 of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion. Conclusion We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase. PMID:16412237

Andersen, Anders; Warren, David J; Brunsvig, Paal F; Aamdal, Steinar; Kristensen, Gunnar B; Olsen, Harald

2006-01-01

299

Low-dose paclitaxel enhances the anti-tumor efficacy of GM-CSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer  

Microsoft Academic Search

Chemotherapy combined with a tumor vaccine is an attractive approach in cancer therapy. This study was designed to investigate\\u000a the optimal schedule and mechanisms of action of a novel GM-CSF (granulocyte–macrophage colony-stimulating factor) surface-modified\\u000a tumor-cell vaccine in combination with paclitaxel in the treatment of mouse RM-1 prostate cancer. First, the anti-tumor efficiencies\\u000a of various dosage of paclitaxel (4, 20, 40 mg\\/kg)

Qiushan HeJinlong; Jinlong Li; Weihua Yin; Zhichun Song; Zhen Zhang; Tienan Yi; Jia Tang; Demin Wu; Yue Lu; Zhen Wang; Dan Liu; Xiaoren Zhang; Zhiming Hu; Jimin Gao

2011-01-01

300

PLGA Nanoparticles Stabilized with Cationic Surfactant: Safety Studies and Application in Oral Delivery of Paclitaxel to Treat Chemical-Induced Breast Cancer in Rat  

Microsoft Academic Search

Purpose  This study was carried out to formulate poly(lactide-co-glycolide) (PLGA) nanoparticles using a quaternary ammonium salt didodecyl\\u000a dimethylammonium bromide (DMAB) and checking their utility to deliver paclitaxel by oral route.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Particles were prepared by emulsion solvent diffusion evaporation method. DMAB and particles stabilized with it were evaluated\\u000a by MTT and LDH cytotoxicity assays. Paclitaxel was encapsulated in these nanoparticles and evaluated

V. Bhardwaj; D. D. Ankola; S. C. Gupta; M. Schneider; C.-M. Lehr; M. N. V. Ravi Kumar

2009-01-01

301

Intensity-Modulated Radiation Therapy with Concurrent Carboplatin and Paclitaxel for Locally Advanced Head and Neck Cancer: Toxicities and Efficacy  

PubMed Central

Background. Intensity-modulated radiation therapy (IMRT) and alternative chemotherapy regimens strive to maintain efficacy while minimizing toxicity in locally advanced head and neck cancer (LAHNC) treatment. Our experience with concurrent IMRT and taxane-based chemotherapy is presented. Methods. A retrospective review of 150 consecutive patients with LAHNC treated with IMRT and concurrent taxane-based chemotherapy with curative intent was performed. The IMRT fractionation regimen consisted of 69.3 Gy to gross disease (2.1 Gy/fraction) and 56.1 Gy to prophylactic nodal sites (1.7 Gy/fraction). Weekly paclitaxel (30 mg/m2) and carboplatin (area under the concentration–time curve [AUC], 1) were given concurrently to all patients, and 69% received weekly induction with paclitaxel (60 mg/m2) and carboplatin (AUC, 2). Results. Over 90% of patients received the prescribed radiation dose. Ninety-six percent completed five or more cycles of concurrent chemotherapy, with similar tolerability for induction chemotherapy. A percutaneous endoscopic gastrostomy (PEG) tube was required in 80 patients, with 10 maintaining PEG use >18 months. Acute grade 4 mucositis and dermatitis developed in 2.0% and 4.0% of patients, respectively. No patient experienced nadir sepsis, grade ?3 late xerostomia, or significant nephropathy or gastrointestinal toxicity. Median follow-up was 30 months. The 3-year locoregional control rate was 83.2% with disease-free survival and overall survival rates of 78.8% and 76.5%, respectively. Conclusion. Rates of acute and late toxicities were low, with excellent radiation dose delivery and impressive tumor control at 3 years, suggesting that concurrent carboplatin and paclitaxel with IMRT is a reasonable therapeutic option for the curative treatment of LAHNC. PMID:22550060

Vlacich, Gregory; Diaz, Roberto; Thorpe, Steven W.; Murphy, Barbara A.; Kirby, Wyndee; Sinard, Robert J.; Shakhtour, Bashar; Shyr, Yu; Murphy, Patrick; Netterville, James L.; Yarbrough, Wendell G.

2012-01-01

302

Swainsonine inhibits growth and potentiates the cytotoxic effect of paclitaxel in hepatocellular carcinoma in vitro and in vivo.  

PubMed

Swainsonine, an extract from Astragalus membranaceus, exhibits broad inhibition of growth and pro-apoptotic activity in a number of tumor types. However, the underlying mechanism involved remains unclear. To investigate the effects and mechanisms of swainsonine on hepatocellular carcinoma (HCC), we performed experiments on HepG2, SMCC7721, Huh7 and MHCC97-H human hepatoma and HL-7702 human hepatocyte cells. We observed that swainsonine significantly inhibited the viability of human hepatoma cells in a dose- and time-dependent manner, but did not affect human hepatocytes. Due to their highly proliferative and tumorigenic nature, we selected MHCC97-H cells as a model system to examine. Swainsonine significantly inhibited MHCC97-H cell growth by causing cell cycle arrest at the G0/G1 phase and the induction of apoptosis. Blockage of G0/G1 phase was accompanied by a decrease in cyclins (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4) and an increase in the Cdk inhibitors p21 and p27. Furthermore, swainsonine enhanced the apoptosis of MHCC97-H cells with the induction of the upregulation of Bax and the downregulation of Bcl-2, whereas the expressionof Fas and Fas-L remained almost unchanged. These changes were accompanied by the enhanced cytoplasmic accumulation of nuclear factor ?B (NF-?B) with a concomitant decrease in the nuclear fraction. Importantly, swainsonine also potentiated the cytotoxic effects of paclitaxel in vitro and in vivo, in part, by restricting the paclitaxel-induced nuclear accumulation of NF-?B. Taken together, these results suggest that swainsonine may be an important agent against HCC via directly inhibiting HCC cell growth and enhancing the responsiveness of HCC cells to paclitaxel. PMID:22993037

You, Nan; Liu, Weihui; Wang, Tao; Ji, Ru; Wang, Xing; Gong, Zhenbing; Dou, Kefeng; Tao, Kaishan

2012-12-01

303

Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin  

PubMed Central

Background Resistance to current chemotherapeutic agents is a major cause of therapy failure in ovarian cancer patients, but the exact mechanisms leading to the development of drug resistance remain unclear. Methods To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified changes in gene expression patterns using Illumina whole-genome expression microarrays. Validation of selected genes was performed by RT-PCR and immunoblotting. Pathway enrichment analysis using the KEGG, GO, and Reactome databases was performed to identify pathways that may be important in each drug resistance phenotype. Results A total of 845 genes (p < 0.01) were found altered in at least one drug resistance phenotype when compared to the parental, drug sensitive cell line. Focusing on each resistance phenotype individually, we identified 460, 366, and 337 genes significantly altered in cells resistant to cisplatin, doxorubicin, and paclitaxel, respectively. Of the 845 genes found altered, only 62 genes were simultaneously altered in all three resistance phenotypes. Using pathway analysis, we found many pathways enriched for each resistance phenotype, but some dominant pathways emerged. The dominant pathways included signaling from the cell surface and cell movement for cisplatin resistance, proteasome regulation and steroid biosynthesis for doxorubicin resistance, and control of translation and oxidative stress for paclitaxel resistance. Conclusions Ovarian cancer cells develop drug resistance through different pathways depending on the drug used in the generation of chemoresistance. A better understanding of these mechanisms may lead to the development of novel strategies to circumvent the problem of drug resistance. PMID:22141344

2011-01-01

304

Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.  

PubMed

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ? 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ? 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy. PMID:22872523

De Boer, Richard H; Kotasek, Dusan; White, Shane; Koczwara, Bogda; Mainwaring, Paul; Chan, Arlene; Melara, Rebeca; Ye, Yining; Adewoye, Adeboye H; Sikorski, Robert; Kaufman, Peter A

2012-08-01

305

The In vitro Subcellular Localization and In vivo Efficacy of Novel Chitosan\\/GMO Nanostructures containing Paclitaxel  

Microsoft Academic Search

Purpose  To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan\\/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol®).\\u000a \\u000a \\u000a \\u000a Methods  The sub-cellular localization of coumarin-6 labeled chitosan\\/GMO nanostructures was determined by confocal microscopy in MDA-MB-231\\u000a cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph\\u000a model. Treatments consisted of

W. J. Trickler; A. A. Nagvekar; A. K. Dash

2009-01-01

306

Carboplatin and Paclitaxel with vs without Bevacizumab in Older Patients with Advanced Non-Small-Cell Lung Cancer  

PubMed Central

Context A randomized trial demonstrates that adding bevacizumab to carboplatin and paxlitaxel improves survival in advanced non-small-cell lung cancer (NSCLC). Objective To examine whether adding bevacizumab to carboplatin and paclitaxel chemotherapy is associated with improved survival in the NSCLC Medicare population. Design, Setting and Participants Retrospective cohort study of Medicare beneficiaries aged 65 and older with stage IIIB or IV non-squamous NSCLC diagnosed in 2002–2007 in a Surveillance, Epidemiology and End Results (SEER) region. Patients were categorized into three cohorts based on diagnosis year and the type of initial chemotherapy administered within 4 months of diagnosis: 1) bevacizumab-carboplatin-paclitaxel (BCP) diagnosed 2006–7; 2) carboplatin-paclitaxel diagnosed 2006–7 (CP 2006–7); and, 3) CP diagnosed 2002–5 (CP 2002–5). The effects of BCP and CP on overall survival were compared using Cox proportional hazards models and propensity score analyses including information about patient characteristics recorded in SEER-Medicare. Main Outcome Measure Overall survival measured from the first date of chemotherapy treatment until death or the censoring date of December 31, 2009. Results 4,168 patients had either BCP or CP chemotherapy. The median survival (interquartile range) estimates were 9.7 (4.4–18.6) months, 8.9 (3.5–19.3) months, and 8.0 (3.7–17.2) months for BCP, CP 2006–7, and CP 2002–5 recipients, respectively. One-year survival probabilities (95% confidence interval [CI]) were 39.6% (34.6%–45.4%) for BCP, versus 40.1% (37.4%–43.0%) for CP 2006–7 and 35.6% (33.8%–37.5%) for CP 2002–5. Neither multivariable nor propensity score-adjusted Cox models demonstrated a survival advantage for BCP compared to CP cohorts. In propensity score-stratified models, the hazard ratio (HR) for overall survival for BCP compared with CP 2006–7 was 1.01 (95% CI, 0.89–1.16; P=.85); and compared with CP 2002–5 was 0.93 (95% CI, 0.83–1.06; P=.28). The propensity score-weighted model and propensity score-matching model similarly failed to demonstrate a statistically significant superiority for BCP. Subgroup and sensitivity analyses for key variables did not change these findings. Conclusions Adding bevacizumab to carboplatin and paclitaxel was not associated with better survival among Medicare patients with advanced NSCLC. PMID:22511687

Zhu, Junya; Sharma, Dhruv B.; Gray, Stacy W.; Chen, Aileen B.; Weeks, Jane C.; Schrag, Deborah

2012-01-01

307

Dual targeting biomimetic liposomes for paclitaxel/DNA combination cancer treatment.  

PubMed

Combinations of chemotherapeutic drugs with nucleic acid has shown great promise in cancer therapy. In the present study, paclitaxel (PTX) and DNA were co-loaded in the hyaluronic acid (HA) and folate (FA)-modified liposomes (HA/FA/PPD), to obtain the dual targeting biomimetic nanovector. The prepared HA/FA/PPD exhibited nanosized structure and narrow size distributions (247.4 ± 4.2 nm) with appropriate negative charge of -25.40 ± 2.7 mV. HA/FA/PD (PTX free HA/FA/PPD) showed almost no toxicity on murine malignant melanoma cell line (B16) and human hepatocellular carcinoma cell line (HepG2) (higher than 80% cell viability), demonstrating the safety of the blank nanovector. In comparison with the FA-modified PTX/DNA co-loaded liposomes (FA/PPD), HA/FA/PPD showed significant superiority in protecting the nanoparticles from aggregation in the presence of plasma and degradation by DNase I. Moreover, HA/FA/PPD could also significantly improve the transfection efficiency and cellular internalization rates on B16 cells comparing to that of FA/PPD (p < 0.05) and PPD (p < 0.01), demonstrating the great advantages of dual targeting properties. Furthermore, fluorescence microscope and flow cytometry results showed that PTX and DNA could be effectively co-delivered into the same tumor cell via HA/FA/PPD, contributing to PTX/DNA combination cancer treatment. In conclusion, the obtained HA/FA/PPD in the study could effectively target tumor cells, enhance transfection efficiency and subsequently achieve the co-delivery of PTX and DNA, displaying great potential for optimal combination therapy. PMID:25177862

Liu, Guo-Xia; Fang, Gui-Qing; Xu, Wei

2014-01-01

308

Brain-penetrating nanoparticles improve Paclitaxel efficacy in malignant glioma following local administration.  

PubMed

Poor drug distribution and short drug half-life within tumors strongly limit efficacy of chemotherapies in most cancers, including primary brain tumors. Local or targeted drug delivery via controlled-release polymers is a promising strategy to treat infiltrative brain tumors, which cannot be completely removed surgically. However, drug penetration is limited with conventional local therapies since small-molecule drugs often enter the first cell they encounter and travel only short distances from the site of administration. Nanoparticles that avoid adhesive interactions with the tumor extracellular matrix may improve drug distribution and sustain drug release when applied to the tumor area. We have previously shown model polystyrene nanoparticles up to 114 nm in diameter were able to rapidly diffuse in normal brain tissue, but only if coated with an exceptionally dense layer of poly(ethylene glycol) (PEG) to reduce adhesive interactions. Here, we demonstrate that paclitaxel (PTX)-loaded, poly(lactic-co-glycolic acid) (PLGA)-co-PEG block copolymer nanoparticles with an average diameter of 70 nm were able to diffuse 100-fold faster than similarly sized PTX-loaded PLGA particles (without PEG coatings). Densely PEGylated PTX-loaded nanoparticles significantly delayed tumor growth following local administration to established brain tumors, as compared to PTX-loaded PLGA nanoparticles or unencapsulated PTX. Delayed tumor growth combined with enhanced distribution of drug-loaded PLGA-PEG nanoparticles to the tumor infiltrative front demonstrates that particle penetration within the brain tumor parenchyma improves therapeutic efficacy. The use of drug-loaded brain-penetrating nanoparticles is a promising approach to achieve sustained and more uniform drug delivery to treat aggressive gliomas and potentially other brain disorders. PMID:25259648

Nance, Elizabeth; Zhang, Clark; Shih, Ting-Yu; Xu, Qingguo; Schuster, Benjamin S; Hanes, Justin

2014-10-28

309

Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel  

PubMed Central

Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)-N,N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50 % (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 ?g/mL to 86 ?g/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH-sensitivity, which was clearly observed at relatively high AA contents and pH > 6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH=6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH=1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery. PMID:18672013

Kim, Sungwon; Kim, Ji Young; Huh, Kang Moo; Acharya, Ghanshyam; Park, Kinam

2008-01-01

310

Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel.  

PubMed

Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)-N,N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50% (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 microg/mL to 86 microg/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH sensitivity, which was clearly observed at relatively high AA contents and pH>6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH=6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH=1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery. PMID:18672013

Kim, Sungwon; Kim, Ji Young; Huh, Kang Moo; Acharya, Ghanashyam; Park, Kinam

2008-12-18

311

Dual Targeting Biomimetic Liposomes for Paclitaxel/DNA Combination Cancer Treatment  

PubMed Central

Combinations of chemotherapeutic drugs with nucleic acid has shown great promise in cancer therapy. In the present study, paclitaxel (PTX) and DNA were co-loaded in the hyaluronic acid (HA) and folate (FA)-modified liposomes (HA/FA/PPD), to obtain the dual targeting biomimetic nanovector. The prepared HA/FA/PPD exhibited nanosized structure and narrow size distributions (247.4 ± 4.2 nm) with appropriate negative charge of ?25.40 ± 2.7 mV. HA/FA/PD (PTX free HA/FA/PPD) showed almost no toxicity on murine malignant melanoma cell line (B16) and human hepatocellular carcinoma cell line (HepG2) (higher than 80% cell viability), demonstrating the safety of the blank nanovector. In comparison with the FA-modified PTX/DNA co-loaded liposomes (FA/PPD), HA/FA/PPD showed significant superiority in protecting the nanoparticles from aggregation in the presence of plasma and degradation by DNase I. Moreover, HA/FA/PPD could also significantly improve the transfection efficiency and cellular internalization rates on B16 cells comparing to that of FA/PPD (p < 0.05) and PPD (p < 0.01), demonstrating the great advantages of dual targeting properties. Furthermore, fluorescence microscope and flow cytometry results showed that PTX and DNA could be effectively co-delivered into the same tumor cell via HA/FA/PPD, contributing to PTX/DNA combination cancer treatment. In conclusion, the obtained HA/FA/PPD in the study could effectively target tumor cells, enhance transfection efficiency and subsequently achieve the co-delivery of PTX and DNA, displaying great potential for optimal combination therapy. PMID:25177862

Liu, Guo-Xia; Fang, Gui-Qing; Xu, Wei

2014-01-01

312

Paclitaxel delivery from cobalt-chromium alloy surfaces using self-assembled monolayers.  

PubMed

Polymer-based platforms in drug-eluting stents (DESs) can cause adverse reactions in patients. Hence, the development of a polymer-free drug delivery platform may reduce adverse reactions to DES. In this study, the use of a polymer-free platform, self-assembled monolayers (SAMs), is explored for delivering an antiproliferative drug [paclitaxel (PAT)] from a stent material [cobalt-chromium ((Co-Cr) alloy]. Initially, carboxylic acid terminated phosphonic acid SAMs were coated on Co-Cr alloy. Two different doses (25 and 100 ?g/cm²) of PAT were coated on SAM coated Co-Cr surfaces using a microdrop deposition method. Also, control experiments were carried out to coat PAT directly on Co-Cr surfaces with no SAM modification. The PAT coated specimens were characterized using the Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). FTIR spectra showed the successful deposition of PAT on SAM coated and control-Co-Cr surfaces. SEM images showed islands of high density PAT crystals on SAM coated surfaces, while low density PAT crystals were observed on control-Co-Cr alloy. AFM images showed molecular distribution of PAT on SAM coated as well as control-Co-Cr alloy surfaces. In vitro drug release studies showed that PAT was released from SAM coated Co-Cr surfaces in a biphasic manner (an initial burst release in first 7 days was followed by a slow release for up to 35 days), while the PAT was burst released from control-Co-Cr surfaces within 1-3 days. Thus, this study demonstrated the use of SAMs for delivering PAT from Co-Cr alloy surfaces for potential use in drug-eluting stents. PMID:21721838

Mani, Gopinath; Torres, Nelson; Oh, Sunho

2011-06-01

313

Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma  

SciTech Connect

Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

Safran, Howard [Brown University Oncology Group, Providence, RI (United States)]. E-mail: hsafran@lifespan.org; Di Petrillo, Thomas [Brown University Oncology Group, Providence, RI (United States); Akerman, Paul [Brown University Oncology Group, Providence, RI (United States); Ng, Thomas [Brown University Oncology Group, Providence, RI (United States); Evans, Devon [Brown University Oncology Group, Providence, RI (United States); Steinhoff, Margaret [Brown University Oncology Group, Providence, RI (United States); Benton, David [Brown University Oncology Group, Providence, RI (United States); Purviance, John [Brown University Oncology Group, Providence, RI (United States); Goldstein, Lisa [Brown University Oncology Group, Providence, RI (United States); Tantravahi, Umadevi [Brown University Oncology Group, Providence, RI (United States); Kennedy, Teresa R.N. [Brown University Oncology Group, Providence, RI (United States)

2007-02-01

314

The Multicenter, Phase II Prospective Study of Paclitaxel Plus Capecitabine as First-Line Chemotherapy in Advanced Gastric Carcinoma  

PubMed Central

Background. The efficacy and toxicity of paclitaxel plus capecitabine (PX) as first-line treatment in advanced gastric cancer (AGC) was evaluated. Methods. Patients with previously untreated AGC were included. PX was given every 3 weeks until a maximum of six cycles or progression. Capecitabine monotherapy was continued for patients without disease progression. The primary endpoint was progression-free survival, and secondary endpoints were objective response rate, overall survival (OS), and safety. Results. Overall, 194 patients were treated per protocol and one patient was excluded because of allergy to paclitaxel. Response was evaluated in 175 patients, with an objective response rate of 34.8%. After a median follow-up of 33.2 months, disease progression was observed in 141 patients, 137 died, and 16 were lost to follow-up, with progression-free survival of 188 days and OS of 354 days. In multivariate Cox regression analysis, no factor remained an independent predictor of OS. Forty-five patients who received capecitabine monotherapy after PX had longer OS (531 days). Adverse events were mild (Fig. 1), and the most common grade 3–4 toxicities were leucopenia and neutropenia. Conclusion. PX as a first-line treatment has promising efficacy in AGC. Based on these data, a phase III study has been launched for further investigation. PMID:24457378

Hu, Bing; Zhang, Xiaotian; Zhang, Fengchun; Zhang, Jun; Xu, Nong; Fan, Qingxia; Bai, Yuxian; Jiao, Shunchang; Wang, Jinwan; Bai, Chunmei; Zheng, Leizhen; Shi, Yingqiang; Liu, Yunpeng; Liang, Jun; Hu, Guoqing; Cheng, Ying; Xu, Ruihua; Bai, Yu; Shen, Lin

2014-01-01

315

Decreased hypersensitivity reactions with carboplatin-pegylated liposomal doxorubicin compared to carboplatin-paclitaxel combination: Analysis from the GCIG CALYPSO relapsing ovarian cancer trial  

Microsoft Academic Search

ObjectiveTo describe and analyze observed hypersensitivity reactions (HSR) from the randomized, multicenter phase III CALYPSO trial that evaluated the efficacy and safety of the combination of carboplatin and pegylated liposomal doxorubicin (CD) compared with standard carboplatin–paclitaxel (CP) in patients with platinum-sensitive relapsed ovarian cancer (ROC).

Florence Joly; Isabelle Ray-Coquard; Michel Fabbro; Mark Donoghoe; Karin Boman; Akira Sugimoto; Michelle Vaughan; Alexander Reinthaller; Ignace Vergote; Gabriella Ferrandina; Tiziana Dell'Anna; Jens Huober; Eric Pujade-Lauraine

2011-01-01

316

A phase I/II study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy of poor-prognosis advanced-stage epithelial ovarian cancer.  

PubMed

Epithelial ovarian cancer patients with bulky residual tumor have a poor response to therapy and limited survival. We investigated the addition of dose-intense paclitaxel to cisplatin and cyclophosphamide for patients with FIGO III/IV epithelial ovarian cancer. Paclitaxel dose was intensified from 135 to 250 mg/m2 and administered in combination with cisplatin at > or = 75 mg/m2 and cyclophosphamide at 750 mg/m2. Thirty-one of 36 patients (86%) and 25 (70%) had > or = 2 and > or = 3 cm residual disease after surgery, respectively. One-third had stage IV disease, and 80% had grade 3 tumors. The maximally tolerated doses (MTD) were paclitaxel at 250 mg/m2, cisplatin at 75 mg/m2, and cyclophosphamide at 750 mg/m2 on a 21-day cycle with G-CSF, 10 micrograms/kg/day. Administered dose intensity at the MTD was > or = 86%. Reversible grade 3 peripheral neuropathy occurred in 28% of patients and fever during neutropenia in 2/352 cycles (0.5%). The pathologic response rate is 36% with an additional 25% having minimal microscopic disease. Median progression-free and overall survivals for patients receiving paclitaxel at 250 mg/m2 at a median potential follow-up of 22 months have not been reached for the cohort nor for the > or = 3-cm subgroup. This regimen should be evaluated in a prospective, randomized clinical trial. PMID:8751547

Kohn, E C; Sarosy, G A; Davis, P; Christian, M; Link, C E; Ognibene, F P; Sindelar, W F; Jacob, J; Steinberg, S M; Premkumar, A; Reed, E

1996-08-01

317

Vibrational circular dichroism analysis reveals a conformational change of the baccatin III ring of paclitaxel: visualization of conformations using a new code for structure-activity relationships.  

PubMed

The comparison between measured and conformer-weighted calculated VCD spectra of the baccatin III ring of paclitaxel and visualization of the conformations using the new code for structure-activity relationships are reported for the first time. The VCD spectrum of paclitaxel closely resembles that of the baccatin III ring. The large characteristic nuCO VCD bands with bisignate signs (1732 cm-1, Deltaepsilon = -1.6 x 10(-1); 1715 cm(-1), Deltaepsilon = 2.4 x 10(-1)) strongly reflect the structural property of the family of conformations bacc-ABC32F defined using the new code. The comparison with the conformation of the baccatin III core in the electron micrograph of the crystal structure of tubulin-paclitaxel (1JFF) suggests a conformational change of paclitaxel corresponding to a switch through the binding with beta-tublin and the intermolecular interactions involving the hydroxyl group (D) and carbonyl of acetoxy group (E). The representation of conformational codes allows complicated conformations to be very easily compared and facilitates future computational analyses such as those for the large-molecule calculations as well as genome analysis. PMID:18275218

Izumi, Hiroshi; Ogata, Atsushi; Nafie, Laurence A; Dukor, Rina K

2008-03-21

318

Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III beta-tubulin.  

PubMed

Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III beta-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatin- and topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drug-resistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III beta-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III beta-tubulin. PMID:19423340

Pepe, Antonella; Sun, Liang; Zanardi, Ilaria; Wu, Xinyuan; Ferlini, Cristiano; Fontana, Gabriele; Bombardelli, Ezio; Ojima, Iwao

2009-06-15

319

Phase I Study of Paclitaxel and Uracil plus Tegafur Combination in Patients with Pretreated Metastatic Breast Cancer: Drug Sequencing Based on Preclinical Modelling Studies  

Microsoft Academic Search

Objective: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. Methods: Pacl was infused at a fixed dose

A. Passardi; R. Maltoni; C. Milandri; L. Cecconetto; I. Massa; W. Zoli; A. Tesei; F. Fabbri; O. Nanni; D. Amadori

2007-01-01

320

A Phase I Pharmacokinetic and Pharmacodynamic Correlative Study of the Antisense Bcl-2 Oligonucleotide G3139, in Combination with Carboplatin and Paclitaxel, in Patients with Advanced Solid Tumors  

PubMed Central

Purpose This phase I trial assessed the safety and tolerability of G3139 when administered in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined. Experimental Design Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1–7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (pre-chemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured. Results Forty-two patients were evaluable for safety analysis. Primary toxicities were hematological (myelosuppression and thrombocytopenia). Dose-escalation was stopped with G3139 at 7 mg/kg/day, carboplatin at AUC 6, and paclitaxel at 175 mg/m2 due to significant neutropenia seen in cycle 1, and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/day, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs. Conclusions Although the MTD was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs. PMID:18451239

Liu, Glenn; Kolesar, Jill; McNeel, Douglas G.; Leith, Catherine; Schell, Kathy; Eickhoff, Jens; Lee, Fred; Traynor, Anne; Marnocha, Rebecca; Alberti, Dona; Zwiebel, James; Wilding, George

2010-01-01

321

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small Cell Lung Cancer (NSCLC)  

PubMed Central

Purpose We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a phase I study for inoperable non-small cell lung cancer (NSCLC). Methods and Materials Paclitaxel at escalating doses of 15 mg/m2, 20 mg/m2, and 25 mg/m2 were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation (RT) was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by High Performance Liquid Chromatography (HPLC). Results Dose-limiting toxicities included 3/18 patients with grade 3 pneumonitis and 3/18 patients with grade 3 esophagitis. There was no grade 4 or 5 pneumonitis or esophagitis. There was no grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For dose levels I (15 mg/m2), II (20 mg/m2), and III (25 mg/m2), the mean peak plasma level was 0.23 ±0.06 ?M, 0.32±0.05 ?M, and 0.52±0.14 ?M, respectively; AUC was 0.44± 0.09 ?M, 0.61± 0.1 ?M, and 0.96± 0.23 ?M, respectively; and duration of drug concentration above 0.05 ?M (t >0.05 ?M) was 1.6± 0.3 hr, 1.9± 0.2 hr, and 3.0± 0.9 hr, respectively. Conclusion Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration above 0.05 ?M for a minimum of 1.6 hours was sufficient for effective radiosensitization. PMID:18164866

Pandya, Kishan J.; Feins, Richard; Johnstone, David W.; Watson, Thomas; Smudzin, Therese; Keng, Peter C.

2009-01-01

322

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of ?III-Tubulin Expression as a Predictive Marker  

PubMed Central

Background. This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of ?III-tubulin as a predictive marker was also evaluated. Patients and Methods. Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m2 (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m2 (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. ?III-Tubulin expression was assessed using immunohistochemistry. Results. There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6–30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4–31.7). ?III-Tubulin-positive patients obtained higher pCR rates compared with ?III-tubulin-negative patients in both treatment arms; however, ?III-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy. Conclusions. Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among ?III-tubulin-positive patients. PMID:23853246

Tseng, Ling-Ming; Chan, Stephen; Chacko, Raju T.; Campone, Mario; Manikhas, Alexy; Nag, Shona M.; Leichman, Cynthia G.; Dasappa, Lokanatha; Fasching, Peter A.; Hurtado de Mendoza, Fernando; Symmans, W. Fraser; Liu, David; Mukhopadhyay, Pralay; Horak, Christine; Xing, Guan; Pusztai, Lajos

2013-01-01

323

Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma.  

PubMed

We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR-1, sVEGFR-2 and sVEGFR-3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti-VEGF-antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus-mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti-VEGF-antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR-1, -2 and -3 (n = 21); combination of AdsVEGFR-1, -2, -3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer. PMID:22336998

Sopo, Minna; Anttila, Maarit; Sallinen, Hanna; Tuppurainen, Laura; Laurema, Anniina; Laidinen, Svetlana; Hamalainen, Kirsi; Tuunanen, Pasi; Koponen, Jonna K; Kosma, Veli-Matti; Heinonen, Seppo; Alitalo, Kari; Yla-Herttuala, Seppo

2012-11-15

324

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer  

PubMed Central

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80?mg?m?2?day?1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40?mg?m?2?day?1. The dose was increased in a stepwise manner to 70?mg?m?2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70?mg?m?2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60?mg?m?2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1–17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer. PMID:17133268

Mochiki, E; Ohno, T; Kamiyama, Y; Aihara, R; Haga, N; Ojima, H; Nakamura, J; Ohsawa, H; Nakabayashi, T; Takeuchi, K; Asao, T; Kuwano, H

2006-01-01

325

Feasibility of radiotherapy after high-dose dense chemotherapy with epirubicin, preceded by dexrazoxane, and paclitaxel for patients with high-risk Stage II-III breast cancer  

SciTech Connect

Purpose: To verify the feasibility of, and quantify the risk of, pneumonitis from locoregional radiotherapy (RT) after high-dose dense chemotherapy with epirubicin and paclitaxel with peripheral blood progenitor cell support in patients with high-risk Stage II-III breast cancer. Methods and Materials: Treatment consisted of a mobilizing course of epirubicin 150 mg/m{sup 2}, preceded by dexrazoxane (Day 1), paclitaxel 175 mg/m{sup 2} (Day 2), and filgrastim; followed by three courses of epirubicin 150 mg/m{sup 2}, preceded by dexrazoxane (Day 1), paclitaxel 400 mg/m{sup 2} (Day 2), and peripheral blood progenitor cell support and filgrastim, every 16-19 days. After chemotherapy, patients were treated with locoregional RT, which included the whole breast or the chest wall, axilla, and supraclavicular area. Results: Overall, 64 of 69 patients were evaluable. The interval between the end of chemotherapy and the initiation of RT was at least 1.5-2 months (mean 2). No treatment-related death was reported. After a median follow-up of 27 months from RT (range 5-77 months), neither clinically relevant radiation pneumonitis nor congestive heart failure had been reported. Minor and transitory lung and cardiac toxicities were observed. Conclusion: Sequential high doses of epirubicin, preceded by dexrazoxane, and paclitaxel did not adversely affect the tolerability of locoregional RT in breast cancer patients. The risk of pneumonitis was not affected by the use of sequential paclitaxel with an interval of at least 1.5-2 months between the end of chemotherapy and the initiation of RT. Long-term follow-up is needed to define the risk of cardiotoxicity in these patients.

De Giorgi, Ugo [Istituto Oncologico Romagnolo, Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna (Italy)]. E-mail: ugo_degiorgi@yahoo.com; Giannini, Massimo [Istituto Oncologico Romagnolo, Department of Radiotherapy, Santa Maria delle Croci Hospital, Ravenna (Italy); Department of Radiotherapy, Pierantoni Hospital, Forli (Italy); Frassineti, Luca [Department of Medical Oncology, Pierantoni Hospital, Forli (Italy); Kopf, Barbara [Istituto Oncologico Romagnolo, Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna (Italy); Palazzi, Silvia [Istituto Oncologico Romagnolo, Department of Radiotherapy, Santa Maria delle Croci Hospital, Ravenna (Italy); Giovannini, Noemi [Department of Medical Oncology, Pierantoni Hospital, Forli (Italy); Zumaglini, Federica [Istituto Oncologico Romagnolo, Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna (Italy); Rosti, Giovanni [Istituto Oncologico Romagnolo, Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna (Italy); Emiliani, Ermanno [Istituto Oncologico Romagnolo, Department of Radiotherapy, Santa Maria delle Croci Hospital, Ravenna (Italy); Marangolo, Maurizio [Istituto Oncologico Romagnolo, Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna (Italy)

2006-07-15

326

Phase I trial of biochemotherapy with cisplatin, temozolomide, and dose escalation of nab-paclitaxel combined with interleukin-2 and interferon-? in patients with metastatic melanoma.  

PubMed

The primary objective of this study was to determine the safety, toxicity, and maximum tolerated dose of nanoparticle albumin-bound (nab)-paclitaxel as part of biochemotherapy for metastatic melanoma and to determine whether substituting nab-paclitaxel for less potent agents could increase response rates and duration. Treatment consisted of intravenous cisplatin (20 mg/m) on days 1-4, oral temozolomide (250 mg/m) on days 1-3, subcutaneous interferon-? (5×10 IU/m) on days 1-5, and continuous intravenous interleukin-2 (9×10 IU/m) for 96 h on days 1-4. A standard 3+3 dose escalation method was used; the nab-paclitaxel starting dose was 100 mg/m on day 1 and 70 mg/m on day 5. The treatment cycle was repeated every 3 weeks and toxicity was assessed weekly. Ten patients were enrolled. Dose-limiting toxicities included diarrhea, transaminasemia, and neutropenia. The maximum tolerated dose was not identified because the nab-paclitaxel dose on day 1 at the lowest planned dose (80 mg/m) caused dose-limiting toxicity in two of five patients. Of the nine patients who were evaluable for response, five had a partial response. The median time to disease progression was 5.30 months and the median overall survival was 8.73 months. Six patients developed central nervous system metastasis at a median of 5.33 months after treatment initiation. Biochemotherapy including nab-paclitaxel according to the doses and schedule regimen used in the present study has significant toxicity. Substituting dacarbazine with temozolomide did not prevent central nervous system metastasis in patients with metastatic melanoma. PMID:24743052

Alrwas, Anas; Papadopoulos, Nicholas E; Cain, Suzanne; Patel, Sapna P; Kim, Kevin B; Deburr, Tawania L; Bassett, Roland; Hwu, Wen-Jen; Bedikian, Agop Y; Davies, Michael A; Woodman, Scott E; Hwu, Patrick

2014-08-01

327

Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy.  

PubMed

Endosomal pH-activatable paclitaxel (PTX) prodrug micellar nanoparticles were designed and prepared by conjugating PTX onto water-soluble poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acid-labile acetal bond to the PAA block and investigated for potent growth inhibition of human cancer cells in vitro. PTX was readily conjugated to PEG-PAA with high drug contents of 21.6, 27.0, and 42.8 wt % (denoted as PTX prodrugs 1, 2, and 3, respectively) using ethyl glycol vinyl ether (EGVE) as a linker. The resulting PTX conjugates had defined molecular weights and self-assembled in phosphate buffer (PB, pH 7.4, 10 mM) into monodisperse micellar nanoparticles with average sizes of 158.3-180.3 nm depending on PTX contents. The in vitro release studies showed that drug release from PTX prodrug nanoparticles was highly pH-dependent, in which ca. 86.9%, 66.4% and 29.0% of PTX was released from PTX prodrug 3 at 37 °C in 48 h at pH 5.0, 6.0, and pH 7.4, respectively. MTT assays showed that these pH-sensitive PTX prodrug nanoparticles exhibited high antitumor effect to KB and HeLa cells (IC(50) = 0.18 and 0.9 ?g PTX equiv/mL, respectively) as well as PTX-resistant A549 cells. Notably, folate-decorated PTX prodrug micellar nanoparticles based on PTX prodrug 3 and 20 wt % folate-poly(ethylene glycol)-b-poly(D,L-lactide) (FA-PEG-PLA) displayed apparent targetability to folate receptor-overexpressing KB cells with IC(50) over 12 times lower than nontargeting PTX prodrug 3 under otherwise the same conditions. Furthermore, PTX prodrug nanoparticles could also load doxorubicin (DOX) to simultaneously release PTX and DOX under mildly acidic pH. These acetal-linked PTX prodrug micellar nanoparticles have appeared as a highly versatile and potent platform for cancer therapy. PMID:23777504

Gu, Yudan; Zhong, Yinan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Zhong, Zhiyuan

2013-08-12

328

Specific tumor delivery of paclitaxel using glycolipid-like polymer micelles containing gold nanospheres.  

PubMed

It is difficult for most of the drug delivery systems to really display a temporal and spatial release of entrapped drug once the systems are iv administrated. We hypothesized that the photothermal effect, mediated by a near-infrared (NIR) laser and hollow gold nanospheres (HAuNS), can modulate paclitaxel (PTX) release from polymer micelles, and further result in the enhanced antitumor activity of the micelles. We loaded PTX and HAuNS, which display strong plasmon absorption in the NIR region, into glycolipid-like polymer micelles with an excellent cell internalization capability. The surface of the micelles was conjugated successfully with a peptide, which has the specific-binding with EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on cell membrane of numerous tumors, to increase the delivery of PTX into tumor cells. Rapid and repetitive drug release from our polymer (HP-TCS) micelles could be readily achieved upon NIR laser irradiation. Our data demonstrated the specific delivery of HP-TCS micelles into positive-EphB4 tumors using a duel-tumor model after iv administration during the whole experiment process (1-48 h). Interestingly, significantly higher uptake of the micelles by SKOV3 tumors (positive-EphB4) than A549 tumors (negtive-EphB4) was observed, with increased ratio on experiment time. However, the specific cell uptake was observed only during the short incubation time (1-4 h) in vitro. Our data also indicated the treatment of tumor cells with the micelles followed by NIR laser irradiation showed significantly greater toxicity activity than the treatment with the micelles alone, free PTX and the micelles (without PTX loading) plus NIR laser irradiation. The enhanced toxicity activity to tumor cells should be attributed to the enhanced drug cellular uptake mediated by the glycolipid-like micelles, chemical toxicity of the released drug from the micelles due to the trigger of NIR laser, and the photothermal ablation under NIR laser irradiation. PMID:23510855

You, Jian; Wang, Zuhua; Du, Yongzhong; Yuan, Hong; Zhang, Peizun; Zhou, Jialin; Liu, Fei; Li, Chun; Hu, Fuqiang

2013-06-01

329

Experimental design towards an optimal lipid nanosystem: a new opportunity for paclitaxel-based therapeutics.  

PubMed

Lipid based nanoparticles represent a class of nanocarriers that have caused great expectation, particularly due to their suitability to incorporate BCS class II and IV drugs. The use of solid lipid nanoparticles (SLNs) as a nanocarrier for antineoplastic agents has been underexplored when compared to the encapsulation of the same agents in polymeric particles. The preparation and efficacy assessment of a SLN platform as drug delivery carrier for anticancer agents, herein proposed as a strategy to find innovative formulations, could dramatically improve the outcome of cancer therapy. Considering these lipid nanoparticles, despite the great amount of insights described in the literature, it seems that improving their manufacturability could be the missing step to convert this system into a drug product. A way to circumvent that problem would be to select a preparation method that could take advantage of the pharmaceutical industry installed capabilities, thus speeding-up the scale-up translational steps while maintaining both regulatory compliance and flexibility. The High Pressure Homogenization (HPH) has proved to be a reliable process for SLN preparation. However, the use of the high-shear mixer, a well established process to manufacture coarse dispersions at industrial scale, has still not been fully explored to prepare SLN. In this study, we explore the possibility of using the hot emulsification/solidification method to prepare SLN's that complies with the current pharmaceutical quality requirements. Thus, a high-shear based process that consistently accomplishes performance requirements was optimized in order to standardize the nanocarrier production following the identification of some process and formulation critical parameters. A hydrophobic drug, Paclitaxel (Ptx) was successfully incorporated using the proposed developed method. The particles physicochemical characteristics changes caused by the drug entrapment as well as the particles stability were also evaluated. In addition the ability of SLN to travel across biological barriers due to its matrix lipid nature was explored upon comparing the efficacy of the drug loaded SLN with the conventional marketed drug product (Taxol®). The cellular uptake studies showed that the developed Ptx loaded SLN were in fact internalized and demonstrated higher efficacy in the cancer cells death process than Taxol. The experimental data demonstrated that the hot homogenization technique using a high-shear mechanical homogenizer allows the preparation of suitable size (around 150 nm) SLN. Overall, the results obtained can be particularly impactful in the forthcoming SLN research. PMID:23528739

Videira, Mafalda A; Arranja, Alexandra G; Gouveia, Luís F

2013-05-13

330

Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery  

PubMed Central

The bioavailability of paclitaxel (Ptx) has previously been improved via its encapsulation in lipid nanocapsules (LNCs). In this work, the interactions between LNCs and intestinal mucus are studied because they are viewed as an important barrier to successful oral delivery. The rheological properties of different batches of pig intestinal mucus were studied under different conditions (the effect of hydration and the presence of LNCs). Fluorescence resonance energy transfer (FRET) was used to study the stability of LNCs in mucus at 37°C for at least 3 hours. Diffusion through 223, 446, and 893 ?m mucus layers of 8.4, 16.8, and 42 ?g/mL Ptx formulated as Taxol® (Bristol-Myers Squibb, Rueil-Malmaison, France) or encapsulated in LNCs (Ptx-LNCs) were investigated. The effect of the size of the LNCs on their diffusion was also investigated (range, 25–110 nm in diameter). Mucus behaves as a non-Newtonian gel with rheofluidifying properties and a flow threshold. The viscous (G?) and elastic (G?) moduli and flow threshold of the two mucus batches varied with water content, but G? remained below G?. LNCs had no effect on mucus viscosity and flow threshold. The FRET efficiency remained at 78% after 3 hours. Because the destruction of the LNCs would lead to a FRET efficiency below 25%, these results suggest only a slight modification of LNCs after their contact with mucus. The diffusion of Taxol® and Ptx-LNCs in mucus decreases if the mucus layer is thicker. Interestingly, the apparent permeability across mucus is higher for Ptx-LNCs than for Taxol® for drug concentrations of 16.8 and 42 ?g/mL Ptx (P<0.05). The diffusion of Ptx-LNCs through mucus is not size-dependent. This study shows that LNCs are stable in mucus, do not change mucus rheological properties, and improve Ptx diffusion at low concentrations, thus making these systems good candidates for Ptx oral delivery. The study of the physicochemical interaction between the LNC surface and its diffusion in mucus is now envisioned. PMID:24235827

Groo, Anne-Claire; Saulnier, Patrick; Gimel, Jean-Christophe; Gravier, Julien; Ailhas, Caroline; Benoit, Jean-Pierre; Lagarce, Frederic

2013-01-01

331

Well-defined, Reversible Disulfide Cross-linked Micelles for On-demand Paclitaxel Delivery  

PubMed Central

To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross-linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti-tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N-acetylcysteine, after PTX-DCMs have reached the tumor site. PMID:21658763

Li, Yuanpei; Xiao, Kai; Luo, Juntao; Xiao, Wenwu; Lee, Joyce S.; Gonik, Abby M.; Kato, Jason; Dong, Tiffany; Lam, Kit S.

2011-01-01

332

Locally advanced breast cancer with bleeding - two cases effectively treated with bevacizumab plus weekly paclitaxel.  

PubMed

Bleeding is one of the serious adverse events of bevacizumab (BV). In our report, two patients had locally advanced breast cancer with bleeding. They received BV plus weekly paclitaxel (PTX), and good local control was observed. Case 1: The patient was a 50-year-old postmenopausal woman. She had left-sided breast cancer (T4cN2cM1 [bone]-stageIV) that was negative for estrogen receptor (ER), negative for progesterone receptor(PgR), and 1+for human epidermal growth factor receptor 2 (HER2). The patient began receiving different regimens of chemotherapy: 5-fluorouracil (5-FU), epirubicin (EPI), and cyclophosphamide(CPA), (FEC); PTX; docetaxel (DTX); and gemcitabine (GEM) plus PTX. Subsequently, she received BV plus PTX. The tumor was markedly reduced in size at the completion of 2 cycles. Bleeding and exudate were also reduced. The patient had a partial response until the sixth cycle, and good local control was obtained. However, the patient had progressive disease at the completion of 8 cycles. Therefore, therapy was changed to capecitabine(CAP)plus CPA, but the patient died one year after she began treatment with BV plus PTX. Case 2: The patient was a 76-year-old postmenopausal woman. She had right-sided breast cancer (T4bN3bM1[lung]-stageIV) that was negative for ER, negative for PgR, and 0 for HER2. The patient began receiving different regimens of chemotherapy: EPI and CPA (EC); and PTX. Subsequently, she received BV plus PTX. The tumor was markedly reduced in size at the completion of 2 cycles. Bleeding and exudate were also reduced. The patient had a partial response until the third cycle, and good local control was obtained. However, the patient had progressive disease at the completion of 4 cycles. Therefore, therapy was changed to CAP and DTX, but the patient died six months after she began treatment with BV plus PTX. PMID:24917012

Ishizuna, Kazuo; Ninomiya, Jun; Ogawa, Toshihisa; Kojima, Makoto; Kawashima, Miho; Nozaki, Miwako; Yamagishi, Hidetsugu; Ueda, Yoshihiko

2014-05-01

333

Structural significance of the acyl group at the C-10 position and the A ring of the taxane core of paclitaxel for inducing nitric oxide and tumor necrosis factor production by murine macrophages.  

PubMed

The antitumor agent, paclitaxel (Taxol), mimics the actions of lipopolysaccharide (LPS) on murine macrophages (Mphi). Various synthetic analogs of paclitaxel were examined for their potencies to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by murine peritoneal Mphi, and by human peripheral blood cells. The benzoyl group at C-2, the hydroxy group at C-7 and the acetyl group at C-10 were found to be critically important sites to activate murine Mphi. Nor-seco-taxoid analogs lacking the A ring of the taxane core of paclitaxel were inactive, but inhibit paclitaxel- or LPS-induced NO production. All the compounds tested did not induce TNF production by human blood cells. PMID:10930572

Kirikae, T; Ojima, I; Fuero-Oderda, C; Lin, S; Kirikae, F; Hashimoto, M; Nakanoc, M

2000-08-01

334

Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study  

Microsoft Academic Search

BACKGROUND: Carboplatin\\/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin\\/paclitaxel for

Sandro Pignata; Sabino De Placido; Rosalbino Biamonte; Giovanni Scambia; Giovanni Di Vagno; Giuseppe Colucci; Antonio Febbraro; Marco Marinaccio; Alessandra Vernaglia Lombardi; Luigi Manzione; Giacomo Cartenì; Mario Nardi; Saverio Danese; Maria Rosaria Valerio; Andrea de Matteis; Bruno Massidda; Giampietro Gasparini; Massimo Di Maio; Carmela Pisano; Francesco Perrone

2006-01-01

335

Effects of paclitaxel in combination with radiation on human head and neck cancer cells (ZMK-1), cervical squamous cell carcinoma (CaSki), and breast adenocarcinoma cells (MCF7)  

Microsoft Academic Search

Background and purpose  : The anticancer drug paclitaxel, a natural product from Taxus brevifolia, is a microtubule-stabilising agent, which has been shown to block different cells in the G2\\/M phase of the cell cycle and\\u000a so modulate their radioresponsiveness. We investigated the radiosensitizing potential of paclitaxel in human head and neck\\u000a cancer cells (ZMK-1), in cervical squamous cell carcinoma cells (CaSki)

Olivier Pradier; Margaret Rave-Fränk; Heinz Schmidberger; Michael Bömecke; Jörg Lehmann; Harald Meden; Clemens-F. Hess

1999-01-01

336

Advanced papillary serous carcinoma of the uterine cervix: a case with a remarkable response to paclitaxel and carboplatin combination chemotherapy  

PubMed Central

Papillary serous carcinoma of the uterine cervix (PSCC) is a very rare, recently described variant of cervical adenocarcinoma. This review, describes a case of stage IV PSCC whose main tumor existed in the uterine cervix and invaded one third of the inferior part of the anterior and posterior vaginal walls. Furthermore, it had metastasized from the para-aortic lymph nodes to bilateral neck lymph nodes. Immnoreactivity for CA125 was positive, whereas the staining for p53 and WT-1 were negative in both the original tumor and the metastatic lymph nodes. Six cycles of paclitaxel and carboplatin combination chemotherapy were administered and the PSCC dramatically decreased in size. The main tumor of the uterine cervix showed a complete response by magnetic resonance imaging (MRI), and on rebiopsy, more than 95% of the tumor cells in the cervix had microscopically disapperared. This is the first report of PSCC in which combination chemotherapy was used and showed a remarkable response. PMID:22532907

Ueda, Masashi; Koshiyama, Masafumi; Yamaguchi, Ayaka; Ukita, Shingo; Ukita, Masayo; Hishikawa, Kenji; Kakui, Kazuyo; Kim, Tomoko; Shirase, Tomoyuki

2011-01-01

337

A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel  

PubMed Central

microRNAs (miRNAs) are small RNAs endogenously expressed in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs (mRNAs). Over the past few years, numerous studies have demonstrated critical roles for miRNAs in the pathogenesis of many cancers, including lung cancer. Cellular miRNA levels can be easily manipulated, showing the promise of developing miRNA-targeted oligos as next-generation therapeutic agents. In a comprehensive effort to identify novel miRNA-based therapeutic agents for lung cancer treatment, we combined a high-throughput screening platform with a library of chemically synthesized miRNA inhibitors to systematically identify miRNA inhibitors that reduce lung cancer cell survival and those that sensitize cells to paclitaxel. By screening three lung cancer cell lines with different genetic backgrounds, we identified miRNA inhibitors that potentially have a universal cytotoxic effect on lung cancer cells and miRNA inhibitors that sensitize cells to paclitaxel treatment, suggesting the potential of developing these miRNA inhibitors as therapeutic agents for lung cancer. We then focused on characterizing the inhibitors of three miRNAs (miR-133a/b, miR-361-3p, and miR-346) that have the most potent effect on cell survival. We demonstrated that two of the miRNA inhibitors (miR-133a/b and miR-361-3p) decrease cell survival by activating caspase-3/7-dependent apoptotic pathways and inducing cell cycle arrest in S phase. Future studies are certainly needed to define the mechanisms by which the identified miRNA inhibitors regulate cell survival and drug response, and to explore the potential of translating the current findings into clinical applications. PMID:24157646

Du, Liqin; Borkowski, Robert; Zhao, Zhenze; Ma, Xiuye; Yu, Xiaojie; Xie, Xian-Jin; Pertsemlidis, Alexander

2013-01-01

338

Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity  

PubMed Central

Introduction Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis. We examined the effects of the 'pure' prolactin receptor antagonist ?1–9-G129R-hPrl (?1–9) on the breast cancer cell number and clonogenicity, alone and in combination with chemotherapy. Methods The effects of doxorubicin, paclitaxel and ?1–9 on the growth of breast cancer cell lines (MCF-7, T47D, MDA-MB-453, MDA-MB-468 and SK-BR-3) in monolayer culture were assessed by the sulphorhodamine B assay. Effects on clonogenicity were assessed by soft agar assay for the cell lines and by the mammosphere assay for disaggregated primary ductal carcinoma in situ samples. Dual-fluorescence immunocytochemistry was used to identify subpopulations of cells expressing the prolactin receptor and autocrine prolactin. Results ?1–9 as a single agent had no effect on the cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel. Doxorubicin accordingly induced expression of prolactin mRNA and protein in all five breast cancer cell lines tested. ?1–9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and the mammosphere forming efficiency of six disaggregated primary ductal carcinoma in situ samples by a median of 56% (range 32% to 88%). Subpopulations of cells could be identified in the cell lines based on the prolactin receptor and prolactin expression. Conclusion Autocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells. The rational combination of cytotoxics and ?1–9 may therefore improve outcomes in breast cancer therapy by targeting this cell population. PMID:18681966

Howell, Sacha J; Anderson, Elizabeth; Hunter, Tom; Farnie, Gillian; Clarke, Robert B

2008-01-01

339

Targeted Disruption of the JAK2/STAT3 Pathway in Combination with Systemic Administration of Paclitaxel Inhibits the Priming of Ovarian Cancer Stem Cells Leading to a Reduced Tumor Burden.  

PubMed

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo, we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7?days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4?weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients. PMID:24782986

Abubaker, Khalid; Luwor, Rodney B; Escalona, Ruth; McNally, Orla; Quinn, Michael A; Thompson, Erik W; Findlay, Jock K; Ahmed, Nuzhat

2014-01-01

340

Prophylactic cannabinoid administration blocks the development of paclitaxel-induced neuropathic nociception during analgesic treatment and following cessation of drug delivery  

PubMed Central

Background Chemotherapeutic treatment results in chronic pain in an estimated 30-40 percent of patients. Limited and often ineffective treatments make the need for new therapeutics an urgent one. We compared the effects of prophylactic cannabinoids as a preventative strategy for suppressing development of paclitaxel-induced nociception. The mixed CB1/CB2 agonist WIN55,212-2 was compared with the cannabilactone CB2-selective agonist AM1710, administered subcutaneously (s.c.), via osmotic mini pumps before, during, and after paclitaxel treatment. Pharmacological specificity was assessed using CB1 (AM251) and CB2 (AM630) antagonists. The impact of chronic drug infusion on transcriptional regulation of mRNA markers of astrocytes (GFAP), microglia (CD11b) and cannabinoid receptors (CB1, CB2) was assessed in lumbar spinal cords of paclitaxel and vehicle-treated rats. Results Both WIN55,212-2 and AM1710 blocked the development of paclitaxel-induced mechanical and cold allodynia; anti-allodynic efficacy persisted for approximately two to three weeks following cessation of drug delivery. WIN55,212-2 (0.1 and 0.5 mg/kg/day s.c.) suppressed the development of both paclitaxel-induced mechanical and cold allodynia. WIN55,212-2-mediated suppression of mechanical hypersensitivity was dominated by CB1 activation whereas suppression of cold allodynia was relatively insensitive to blockade by either CB1 (AM251; 3 mg/kg/day s.c.) or CB2 (AM630; 3 mg/kg/day s.c.) antagonists. AM1710 (0.032 and 3.2 mg/kg /day) suppressed development of mechanical allodynia whereas only the highest dose (3.2 mg/kg/day s.c.) suppressed cold allodynia. Anti-allodynic effects of AM1710 (3.2 mg/kg/day s.c.) were mediated by CB2. Anti-allodynic efficacy of AM1710 outlasted that produced by chronic WIN55,212-2 infusion. mRNA expression levels of the astrocytic marker GFAP was marginally increased by paclitaxel treatment whereas expression of the microglial marker CD11b was unchanged. Both WIN55,212-2 (0.5 mg/kg/day s.c.) and AM1710 (3.2 mg/kg/day s.c.) increased CB1 and CB2 mRNA expression in lumbar spinal cord of paclitaxel-treated rats in a manner blocked by AM630. Conclusions and implications Cannabinoids block development of paclitaxel-induced neuropathy and protect against neuropathic allodynia following cessation of drug delivery. Chronic treatment with both mixed CB1/CB2 and CB2 selective cannabinoids increased mRNA expression of cannabinoid receptors (CB1, CB2) in a CB2-dependent fashion. Our results support the therapeutic potential of cannabinoids for suppressing chemotherapy-induced neuropathy in humans. PMID:24742127

2014-01-01

341

Five-Year Update of an Expanded Phase II Study of Dose-Dense and Intense Doxorubicin, Paclitaxel and Cyclophosphamide (ATC) in High-Risk Breast Cancer  

Microsoft Academic Search

Objectives: This study evaluated the safety and efficacy of dose-dense and -intense sequential doxorubicin (A), paclitaxel (T) and cyclophosphamide (C) as adjuvant therapy for breast cancer (BC) with ?4 ipsilateral axillary lymph nodes.Methods: Patients were recruited after BC surgery if ?4 axillary nodes were involved by metastatic cancer. Planned treatment was A 90 mg\\/m2 three times every 14 days (q14d×3),

Maysa M. Abu-Khalaf; Stephen Windsor; Keita Ebisu; Saritha Salikooti; Gowri Ananthanarayanan; Gina G. Chung; Michael P. DiGiovanna; Bruce G. Haffty; Martin Abrams; Leonard R. Farber; Arlene D. Hsu; Michael Reiss; Daniel Zelterman; Barbara A. Burtness

2005-01-01

342

A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.  

PubMed

Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NF?B) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-?, IL-1?) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. PMID:25242567

Janes, Kali; Esposito, Emanuela; Doyle, Timothy; Cuzzocrea, Salvatore; Tosh, Dillip K; Jacobson, Kenneth A; Salvemini, Daniela

2014-12-01

343

Chemoradiation With Paclitaxel and Carboplatin in High-Risk Cervical Cancer Patients After Radical Hysterectomy: A Korean Gynecologic Oncology Group Study  

SciTech Connect

Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiation with paclitaxel and carboplatin in patients with high-risk cervical cancer. Methods and Materials: Patients after radical hysterectomy for cervical cancer, with at least 1 high-risk characteristic, were administered paclitaxel 135 mg/m{sup 2}, carboplatin area under the curve = 5 every 3 weeks for 3 cycles concomitant with radiation therapy as adjuvant treatment. Results: This prospective study enrolled 71 consecutive patients. Sixty-six patients (93%) completed the planned treatment. The majority of grade 3/4 neutropenia or nonhematologic toxicities were usually self-limited. Diarrhea grades 3/4 were observed in 4 patients (5.6%). One patient developed anaphylactic shock after infusion of paclitaxel. With a median follow-up of 57 months, recurrences occurred in 16 patients. Multivariable analysis indicated that common iliac lymph node involvement is an independent risk factor for disease recurrence (odds ratio 13.48; 95% confidence interval 2.93-62.03). In the intent-to-treat population (n=71), the estimated 5-year disease-free survival and overall survival rates were 77.3% and 80.3% respectively. In the per-protocol population (n=62), disease-free survival was 78.9% and overall survival was 83.9%. Conclusions: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and seems to be effective for patients who undergo radical hysterectomy. Therefore, a prospective, randomized controlled study should be designed to evaluate efficacy of this approach for patients with high-risk cervical cancer.

Lee, Taek Sang [Department of Obstetrics and Gynecology, SMG-SNU Boramae Medical Center, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, SMG-SNU Boramae Medical Center, Seoul (Korea, Republic of); Kang, Soon Beom, E-mail: tslee70@gmail.com [Department of Obstetrics and Gynecology, Konkuk University Medical Center, Seoul (Korea, Republic of); Kim, Young Tak [Department of Obstetrics and Gynecology, Asan Medical Center, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, Asan Medical Center, Seoul (Korea, Republic of); Park, Byung Joo [Department of Preventive Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of)] [Department of Preventive Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Yong Man [Department of Obstetrics and Gynecology, Asan Medical Center, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, Asan Medical Center, Seoul (Korea, Republic of); Lee, Jong Min [Department of Obstetrics and Gynecology, Kyung Hee University Hospital at Gangdong, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, Kyung Hee University Hospital at Gangdong, Seoul (Korea, Republic of); Kim, Seok Mo [Department of Obstetrics and Gynecology, Chonnam National University Medical School, Gwangju (Korea, Republic of)] [Department of Obstetrics and Gynecology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Young Tae [Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Jae Hoon [Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Seoul (Korea, Republic of); Kim, Kyung Tai [Department of Obstetrics and Gynecology, Hanyang University Medical Center, Seoul (Korea, Republic of)] [Department of Obstetrics and Gynecology, Hanyang University Medical Center, Seoul (Korea, Republic of)

2013-06-01

344

Combined downregulation of microRNA-133a and microRNA-133b predicts chemosensitivity of patients with esophageal squamous cell carcinoma undergoing paclitaxel-based chemotherapy.  

PubMed

microRNA-133a (miR-133a) and miR-133b, located on chromosome 18 in the same bicistronic unit, have been commonly identified as being downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the correlation of miR-133a/b expression with efficacy of paclitaxel-based chemotherapy and clinical outcome of ESCC patients. miR-133a expression and miR-133b expression were examined in 100 newly diagnosed ESCC patients prior to treatment by quantitative real-time PCR. Then, the patients received four cycles of paclitaxel-based chemotherapy, the short-term treatment efficacy was evaluated, and a 3-year follow-up was performed. Expression levels of miR-133a and miR-133b were both significantly lower in ESCC tissues compared to adjacent noncancerous tissues (both P < 0.001). In addition, combined miR-133a/b downregulation was found to be closely correlated with advanced tumor stage (P = 0.02) and poor differentiation (P = 0.01). Moreover, the response rate of ESCC patients to paclitaxel-based chemotherapy was significantly higher in combined miR-133a/b downregulation group compared with other groups (P = 0.02). Furthermore, univariate and multivariate Cox analyses revealed that tumor stage and combined expression of miR-133a/b were independent prognosis factors in ESCC patients. Our data offer the convincing evidence that combined expression of miR-133a and miR-133b may predict chemosensitivity of patients with ESCC undergoing paclitaxel-based chemotherapy, implying its importance in applying 'personalized cancer medicine' in the clinical treatment of ESCC. We also identified combined expression of miR-133a and miR-133b as an effective prognostic marker of this malignancy. PMID:25280517

Chen, Guiming; Peng, Jin; Zhu, Weiguo; Tao, Guangzhou; Song, Yaqi; Zhou, Xilei; Wang, Wanwei

2014-11-01

345

Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer  

Microsoft Academic Search

A mouse model of human ovarian cancer was used to investigate the effect of adenovirus-mediated thymidine kinase gene therapy (gt) in combination with chemotherapy. One hundred sixty female CD-1 nu\\/nu mice were injected intraperitoneally with Ov-ca-2774 cells. Onset of intraperitoneal treatment with either topotecan (6 or 12 mg\\/kg) or paclitaxel (18 or 36 mg\\/kg) was on day 4 or8 and

Dirk G Kieback; Dagmar-Christiane Fischer; Dirk G Engehausen; Willi Sauerbrei; Martin K Oehler; Xiao-Wen Tong; Estuardo Aguilar-Cordova

2002-01-01

346

Conservation of the Class I Tubulin Gene in Human Populations and Lack of Mutations in Lung Cancers and Paclitaxel-resistant Ovarian Cancers1  

Microsoft Academic Search

The goal of this study was to determine the prevalence of sequence variants in the class I -tubulin (clone m40) gene and their occurrence in human tumors and cancer cell lines. DNA was isolated from 93 control individuals representing a wide variety of ethnicities, 49 paclitaxel-naive specimens (16 ovarian cancers, 17 non-small cell lung cancers, and 16 ovarian cancer cell

Sanja Sale; Raphael Sung; Peidong Shen; Kristine Yu; Yan Wang; George E. Duran; Jong-Hyeok Kim; Tito Fojo; Peter J. Oefner; Branimir I. Sikic

2002-01-01

347

[Recurrence of skin and lymph nodes from asynchronous breast cancer successfully treated with paclitaxel and toremifene therapy--a case report].  

PubMed

We report a case of recurrence of skin and lymph nodes from asynchronous breast cancer achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 49-year-old woman who received both sides of muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) had a skin redness of her left breast. Aspiration biopsy cytology for the skin led to a diagnosis of Class V. Skin biopsy for the part of the redness was performed. The pathological diagnosis was an invasive ductal carcinoma, negative for estrogen receptor and positive for progesteron receptor, and negative for HER2/neu protein expression. Ultrasonography showed the subpectral and the inflaclavicular lymph nodes swelling and the skin metastasis. Enhancement CT showed no metastasis of brain, lung, liver, and other organs. Although she had already received 6 cycles of tri-weekly FEC (C: 500 mg, E 60 mg, F: 500 mg/m2) after previous operation, we performed 7 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The response for the lesion of lymph nodes metastasis after paclitaxel and toremifene therapy was evaluated as a complete response. The subpectoral and the inflaclavicular lymph nodes metastasis disappeared. However, the skin redness of her left breast was still remained. She had received a radiation therapy (30 Gy) for skin metastasis. After radiation therapy, we performed a skin biopsy for the part of the redness. The pathological diagnosis was no carcinoma of skin. She had no recurrence during the two years after the treatment. Paclitaxel and toremifene therapy was effective for a recurrent breast tumor and could improve patient's QOL and the clinical outcomes. PMID:19106577

Sakurai, Kenichi; Enomoto, Katsuhisa; Tani, Mayumi; Kitajima, Akira; Amano, Sadao; Shiono, Motomi

2008-11-01

348

Vitamin E TPGS used as emulsifier in the solvent evaporation\\/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol ®)  

Microsoft Academic Search

The d-?-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was applied in the present investigation as surfactant stabiliser to fabricate paclitaxel-loaded PLGA nanospheres in the solvent evaporation\\/extraction technique with successful achievement. Laser light scattering system (LLS), scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) were employed

L Mu; S. S Feng

2002-01-01

349

Reduction in Circulating Tumor Cell Count following Therapy with nab®-Paclitaxel plus Carboplatin in a Patient with Leptomeningeal Carcinomatosis from Breast Cancer  

PubMed Central

This case study reports on a 56-year-old woman with breast adenocarcinoma and leptomeningeal metastases. After initial chemotherapy with a dose-dense regimen of doxorubicin/cyclophosphamide followed by 3 cycles of docetaxel (100 mg/m2), a lumpectomy was performed that revealed invasive ductal carcinoma with lymph node involvement. Because of the extent of the disease, she underwent a mastectomy. Two months after the completion of initial chemotherapy, leptomeningeal metastases were detected on December 13, 2006. After completion of whole-brain radiation therapy, she received systemic chemotherapy with a novel albumin-bound 130-nm formulation of paclitaxel (nab®-paclitaxel) at 100 mg/m2 combined with carboplatin AUC = 6, both given weekly. Clinical response was prompt, with a reduction in the circulating tumor cell (CTC) count from 63 before treatment to 2 after the first treatment cycle. While undergoing treatment with nab-paclitaxel plus carboplatin, she reported an improvement in neurologic symptoms, including a decrease in headaches, improved cognition and balance, and an overall improved quality of life. Before the third treatment cycle, she had a CTC count of 2. Without treatment, the median survival of patients diagnosed with leptomeningeal metastases is 4–6 weeks. However, this patient survived for 4 months after the diagnosis of leptomeningeal carcinomatosis. Treatment was discontinued because of complications of urosepsis, and the patient died on April 7, 2007. Our case shows that additional treatment with weekly nab-paclitaxel combined with carboplatin (AUC6) can prolong life for some patients with leptomeningeal carcinomatosis from breast cancer. PMID:22423247

Stebel, Andrea

2012-01-01

350

Excellent Biochemical Response to Polychemotherapy with Nab-Paclitaxel/Gemcitabine in an 82-Year-Old Female with Metastatic Breast Cancer  

PubMed Central

We report the case of an 82-year-old female diagnosed with HER2-negative, hormone receptor (HR)-positive metastatic breast cancer. Upon biochemical disease progression of the initially HR-receptor positive disease under anti-hormonal treatment with tamoxifen and letrozole, she received combination chemotherapy with paclitaxel/gemcitabine. Due to her suffering from severe toxicity, therapy was switched to nab-paclitaxel/gemcitabine. From April 22, 2013, to July 15, 2013, the patient received 5 cycles of nab-paclitaxel/gemcitabine as a 30-min infusion every 3 weeks, with excellent biochemical responses to treatment. Tumor marker levels as well as bilirubin were reduced to baseline levels. Chemotherapy with nab-paclitaxel/gemcitabine was well tolerated. At a follow-up visit immediately after the end of chemotherapy, the patient reported well-being and presented with a Karnofsky performance status (KPS) of 100%. At the last follow-up in October 2013, she was alive with multiple metastatic sites in the liver and bone metastases in the spine without risk of fracture and a KPS of 90%. She has received palliative single agent chemotherapy with capecitabine (14/7 regimen, 1,500 mg b.i.d.) since August 2013 and continued to show a good biochemical treatment response at the last follow-up in October 2013. Since August 2013, the patient has also received denosumab (120 mg sc, q4w) for her metastatic bone disease. As of July 2014, treatment has not been changed and the patient reports her well-being.

Völkl, Siegfried J.

2014-01-01

351

Dairy milk fat augments paclitaxel therapy to suppress tumour metastasis in mice, and protects against the side-effects of chemotherapy  

Microsoft Academic Search

Milk fat is a natural product containing essential nutrients as well as fatty acids and other food factors with reported anti-cancer\\u000a potential. Here bovine milk fat was tested for its ability to inhibit the growth of breast and colon cancers and their metastasis\\u000a to the lung and liver; either alone or in combination with the chemotherapeutic agent paclitaxel. A diet

Xueying Sun; Jie Zhang; Rita Gupta; Alastair K. H. MacGibbon; Barbara Kuhn-Sherlock; Geoffrey W. Krissansen

352

Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy  

PubMed Central

Objective The purpose of this study was to assess changes in the tumor microvasculature induced by combination antiangiogenic therapy in MCF-7 breast tumor mouse models, using a noninvasive DCE-MRI method that minimizes the effect of water exchange. Materials and methods 3D quantitative DCE-MRI images were acquired with a heavily T1-weighted saturation recovery gradient echo sequence with a recovery delay of 20 ms. Tumor vascular volume (VV) and vascular permeability-surface area product (PS) were obtained through a linear regression of the albumin-Gd-DTPA-enhanced dynamic image intensity on MCF-7 breast tumor mouse models treated with combination bevacizumab/paclitaxel therapy. Results Measured tumor VV values were significantly higher than the values that have been reported previously using quantitative T1 mapping, and are in good agreement with micro-CT (computed tomography) results reported earlier from other tumor models. A trend of decreasing tumor PS was detected in the group of MCF-7 tumor bearing mice treated with the bevacizumab/paclitaxel combination regimen. Conclusion VV and PS maps obtained by a heavily T1-weighted acquisition protocol revealed the large peripheral blood vessels as well as the permeable areas within the tumor. A 12-day/three-dose combination treatment of bevacizumab and paclitaxel resulted in delayed tumor growth and a trend of decreasing tumor vascular permeability surface area product. PMID:23807596

Zhu, Wenlian; Kato, Yoshinori

2014-01-01

353

LC-MS/MS quantitative analysis of paclitaxel and its major metabolites in serum, plasma and tissue from women with ovarian cancer after intraperitoneal chemotherapy.  

PubMed

A method for determination of the antineoplastic drug paclitaxel and its main metabolites (viz. 6?-hydroxypaclitaxel and p-3'-hydroxypaclitaxel) at the sub-ng/ml level is here presented. Sample preparation consisted of a liquid-liquid extraction step for cleanup and preconcentration of the target analytes prior to chromatographic analysis by tandem mass spectrometry detection (LC-ESI-MS/MS). The determination step was optimized by selected reaction monitoring (SRM) mode for highly selective identification and sensitive quantitation of paclitaxel and its metabolites in human serum, plasma and tissue. The detection limits were in the range 0.03-0.15ng/ml for serum and 0.07-0.62ng/g for tissue, with intra-day variability range from 0.5 to 2.7%, expressed as relative standard deviation. The method was applied to determine paclitaxel and its metabolites in serum and tissue from 13 women suffering from ovarian peritoneal carcinomatosis, after hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) treatment. The method reported here can be considered a suited tool to monitor the concentration of this drug in patients subjected to HIPEC as strategy to evaluate the toxicity and efficiency of this treatment. PMID:24447964

Fernández-Peralbo, M A; Priego-Capote, F; Luque de Castro, M D; Casado-Adam, A; Arjona-Sánchez, A; Muñoz-Casares, F C

2014-03-01

354

Cytotoxic effects toward human hematopoietic progenitor cells and tumor cell lines of paclitaxel, docetaxel, and newly developed analogues IDN5109, IDN5111, and IDN5127.  

PubMed

The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained in liquid culture and on three human cancer cell lines (MDA-MB231, MCF-7 ADRr, CEM VBLr). Concomitantly, DNA analysis was also performed. For unfractionated peripheral blood progenitor cells (PBPC) toxicity was also assessed by clonogenic assay. The cytotoxic effects induced by taxanes toward PBPC as measured by clonogenic assay were correlated with those found for multidrug resistance (MDR)-positive cell lines (IDN5109 > IDN5111 > IDN5127 > docetaxel > paclitaxel). We established a therapeutic index (TI) between the antitumor activity in MDR-positive cells and the toxicity toward PBPC. Paclitaxel and IDN5109, as determined by TI, showed the best value in MDR-negative and MDR-positive cells, respectively. The ranking of the cytotoxic effects observed in PB CD34+ was not correlated with that obtained in clonogenic assay and in cancer cells (IDN5127 > IDN5109 > docetaxel > IDN5111). Remarkably, in DNA analysis docetaxel induced the maximal cell cycle blocking activity. Newly developed taxanes IDN5109 and IDN5111 are endowed of a profile of anticancer activity in MDR-bearing cells and toxicity toward hematopoietic progenitors better than that of docetaxel. However, mechanism(s) underlying toxicity toward hematopoietic progenitors could be, at least in part, different from that of docetaxel and likely dependent on the interaction with P-glycoprotein function in PB CD34+ cells. PMID:10850888

Ferlini, C; Distefano, M; Pierelli, L; Bonanno, G; Riva, A; Bombardelli, E; Ojima, I; Mancuso, S; Scambia, G

1999-01-01

355

A phase II study of paclitaxel and nedaplatin as front-line chemotherapy in Chinese patients with metastatic esophageal squamous cell carcinoma  

PubMed Central

AIM: To evaluate the efficacy and safety of paclitaxel-nedaplatin combination as a front-line regimen in Chinese patients with metastatic esophageal squamous cell carcinoma (ESCC). METHODS: A two-center, open-label, single-arm phase II study was designed. Thirty-nine patients were enrolled and included in the intention-to-treat analysis of efficacy and adverse events. Patients received 175 mg/m2 of paclitaxel over a 3 h infusion on 1 d, followed by nedaplatin 80 mg/m2 in a 1 h infusion on 2 d every 3 wk until the documented disease progression, unacceptable toxicity or patient’s refusal. RESULTS: Of the 36 patients assessable for efficacy, there were 2 patients (5.1%) with complete response and 16 patients (41.0%) with partial response, giving an overall response rate of 46.1%. The median progression-free survival and median overall survival for all patients were 7.1 mo (95%CI: 4.6-9.7) and 12.4 mo (95%CI: 9.5-15.3), respectively. Toxicities were moderate and manageable. Grade 3/4 toxicities included neutropenia (15.4%), nausea (10.3%), anemia (7.7%), thrombocytopenia (5.1%), vomiting (5.1%) and neutropenia fever (2.6%). CONCLUSION: The combination of paclitaxel and nedaplatin is active and well tolerated as a first-line therapy for patients with metastatic ESCC. PMID:24124338

He, Yi-Fu; Ji, Chu-Shu; Hu, Bing; Fan, Ping-Sheng; Hu, Chang-Lu; Jiang, Feng-Shou; Chen, Jian; Zhu, Lei; Yao, Yi-Wei; Wang, Wei

2013-01-01

356

A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer.  

PubMed

Matuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored in combination with paclitaxel. Dose was escalated from 100 mg to 1,600 mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity (DLT) over the first two cycles. DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles. Patients with non-progressive disease could then continue to receive study treatment for up to 6 months. The safety population comprised 44 patients, with DLT evaluable in 33. The maximum tolerated dose was not reached, with only one DLT reported at the 1,600 mg 3-weekly dose level. The most frequent grade 3/4 adverse events across all cycles were dyspnea (23 %) and neutropenia (11 %). Matuzumab exhibited non-linear PK, with accumulation after escalation and repeated dosing. Tumor growth control was seen in 15/44 (34 %) patients, including 5/9 (56 %) at the 800 mg weekly dose level. Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. There was some evidence of anticancer activity in relation to the matuzumab 800 mg weekly dose. PMID:22832803

Hartmann, J T; Kollmannsberger, C; Cascorbi, I; Mayer, F; Schittenhelm, M M; Heeger, S; Bokemeyer, C

2013-06-01

357

Activation of the mitochondria-driven pathway of apoptosis in human PC-3 prostate cancer cells by a novel hydrophilic paclitaxel derivative, 7-xylosyl-10-deacetylpaclitaxel.  

PubMed

Paclitaxel, a natural product originally isolated from Taxus brevifolia, belongs to the most successful anticancer drugs. Nevertheless, its poor water solubility represents a considerable disadvantage in clinical use, and novel derivatives with improved pharmacological features are required. We isolated 7-xylosyl-10-deacetylpaclitaxel from Taxus chinensis, which reveals higher water solubility than paclitaxel. This compound induced mitotic cell cycle arrest and apoptosis as measured by flow cytometry, DNA laddering, and transmission electron microscopy. Pro-apoptotic Bax and Bad protein expression was up-regulated and anti-apoptotic Bcl-2 and Bcl-XL expression down-regulated, which lead to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9. In turn, caspase-9 activated downstream caspases-3 and -6, but not caspase-8. Bid was also activated by caspase-3. Reversely, treatment with a caspase-10-specific inhibitor could not protect PC-3 cells from 7-xylosyl-10-deacetyl-paclitaxel-triggered apoptosis. Moreover, 7-xylosyl-10-deacetylpaclitaxel had no effect on the expression of CD95 and NF-kappaB proteins, indicating that apoptosis was induced through the mitochondrial-dependent pathway in PC-3 cells. PMID:18575755

Jiang, Shougang; Zu, Yuangang; Fu, Yuejie; Zhang, Yu; Efferth, Thomas

2008-07-01

358

Intensified Neoadjuvant Chemotherapy with Nab-Paclitaxel plus Gemcitabine Followed by FOLFIRINOX in a Patient with Locally Advanced Unresectable Pancreatic Cancer  

PubMed Central

The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose (18F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial.

Kunzmann, Volker; Herrmann, Ken; Bluemel, Christina; Kapp, Markus; Hartlapp, Ingo; Steger, Ulrich

2014-01-01

359

A Phase I Study of UFT/Leucovorin, Carboplatin, and Paclitaxel in Combination With External Beam Radiation Therapy for Advanced Esophageal Carcinoma  

SciTech Connect

Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is not well established. We evaluated the safety and preliminary efficacy of a combination of UFT/leucovorin, carboplatin, and paclitaxel with RT in a Phase I study of patients with advanced esophageal cancer. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received UFT/leucovorin, carboplatin, and paclitaxel with RT (1.8 Gy daily to 45 Gy). After completion, the disease was restaged and patients were evaluated for surgery. Primary end points included determination of dose-limiting toxicities (DLTs) and a recommended Phase II dose. Secondary objectives included determination of non-DLTs, as well as preliminary radiographic and pathologic response rates. Results: Twelve patients were enrolled (11 men, 1 woman). All were assessable for toxicity and efficacy. One of 6 patients at Dose Level 1 (UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, area under the curve [AUC] 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4) had a DLT (febrile neutropenia). Of these 6 patients, 4 underwent esophagectomy and none achieved a pathologic complete response. Six patients were then enrolled at Dose Level 2 (UFT/leucovorin, 300/30 mg in the morning and 200/30 mg in the evening on RT days; carboplatin, AUC 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4). Two of 6 patients at Dose Level 2 developed DLTs (febrile neutropenia in both). Esophagectomy was performed in 3 patients, with 2 achieving a pathologic complete response. Conclusions: Maximum tolerated doses in this study were UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, AUC 5, Weeks 1 and 4; and paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4 when delivered with external RT. In this small study, this regimen appears active, but toxic.

Czito, Brian G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)], E-mail: czito@radonc.duke.edu; Cohen, Darrel P. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); Kelsey, Chris R. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Lockhart, A. Craig; Bendell, Johanna C. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States); Willett, Christopher G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Petros, William P. [Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV (United States); D'Amico, Thomas A. [Department of General Surgery, Duke University Medical Center, Durham, NC (United States); Truax, Roxanne R.N.; Hurwitz, Herbert I. [Department of Internal Medicine, Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC (United States)

2008-03-15

360

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer  

SciTech Connect

Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m{sup 2}, 20 mg/m{sup 2}, and 25 mg/m{sup 2} were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m{sup 2}), II (20 mg/m{sup 2}), and III (25 mg/m{sup 2}), the mean peak plasma level was 0.23 {+-} 0.06 {mu}mol/l, 0.32 {+-} 0.05 {mu}mol/l, and 0.52 {+-} 0.14 {mu}mol/l, respectively; AUC was 0.44 {+-} 0.09 {mu}mol/l, 0.61 {+-} 0.1 {mu}mol/l, and 0.96 {+-} 0.23 {mu}mol/l, respectively; and duration of drug concentration >0.05 {mu}mol/l (t > 0.05 {mu}mol/l) was 1.6 {+-} 0.3 h, 1.9 {+-} 0.2 h, and 3.0 {+-} 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 {mu}mol/l for a minimum of 1.6 h was sufficient for effective radiosensitization.

Chen, Yuhchyau [Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY (United States)], E-mail: yuhchyau_chen@urmc.rochester.edu; Pandya, Kishan J. [Department of Medical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY (United States); Feins, Richard [Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC (United States); Johnstone, David W. [Division of Cardiothoracic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Lebanon); Watson, Thomas [Division of Cardiothoracic Surgery, University of Rochester School of Medicine and Dentistry, Rochester, NY (United States); Smudzin, Therese; Keng, Peter C. [Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY (United States)

2008-06-01

361

Paclitaxel-loaded poly(glycolide-co-?-caprolactone)-b-D-?-tocopheryl polyethylene glycol 2000 succinate nanoparticles for lung cancer therapy  

PubMed Central

In order to improve the therapeutic efficacy and minimize the side effects of lung cancer chemotherapy, the formulation of paclitaxel-loaded poly(glycolide-co-?-caprolactone)-b-D-?-tocopheryl polyethylene glycol 2000 succinate nanoparticles (PTX-loaded [PGA-co-PCL]-b-TPGS2k NPs) was prepared. The novel amphiphilic copolymer (PGA-co-PCL)-b-TPGS2k was synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance spectroscopy and gel permeation chromatography. The PTX-loaded (PGA-co-PCL)-b-TPGS2k NPs were characterized in terms of size, size distribution, zeta potential, drug encapsulation, surface morphology, and drug release. In vitro cellular uptakes of NPs were investigated with confocal laser scanning microscopy, indicating the coumarin 6-loaded (PGA-co-PCL)-b-TPGS2k NPs could be internalized by human lung cancer A-549 cells. The antitumor effect of PTX-loaded NPs was evaluated, both in vitro and in vivo, on an A-549 cell tumor-bearing mouse model via intratumoral injection. The commercial PTX formulation Taxol was chosen as the reference. Experimental results showed that the PTX-loaded NPs possessed higher cytotoxicity and could effectively inhibit the growth of tumor. All the results suggested that amphiphilic copolymer (PGA-co-PCL)-b-TPGS2k could act as a potential biological material for nanoformulation in the treatment of lung cancer. PMID:23696703

Zhao, Tiejun; Chen, Hezhong; Dong, Yuchao; Zhang, Jiajun; Huang, Haidong; Zhu, Ji; Zhang, Wei

2013-01-01

362

Characteristics of the combination paclitaxel plus doxorubicin in breast cancer cell lines analyzed with the ATP-cell viability assay.  

PubMed

Preliminary clinical data show promising activity regarding the combination of paclitaxel (Taxol) (TAX) and doxorubicin (Adriamycin) (ADR) in the treatment of breast cancer. This combination needs both further preclinical and clinical investigations to better understand the drug interaction, and to optimize the dose and schedule of these drugs. This study was done to evaluate the combination effect of TAX and ADR in three human breast cancer cell lines. The ATP-Cell-Viability Assay was used to evaluate the chemosensitivity profiles and to obtain dose response curves. For quantitation of synergism and antagonism the median-effect principle was applied and the corresponding combination index values were calculated. Drug synergism/antagonism was shown to be dose-related; synergism was enhanced at higher fractions affected. From this preclinical data, we have concluded that TAX-ADR is highly effective and partly synergistic in vitro. In spite of severe initial toxicities in early clinical trials in metastatic breast cancer patients, further clinical studies appear to be justified in order to define a tolerable dosage. PMID:7907234

Koechli, O R; Sevin, B U; Perras, J P; Chou, T C; Angioli, R; Steren, A; Untch, M; Averette, H E

1993-10-01

363

Delivery of paclitaxel by physically loading onto poly(ethylene glycol) (PEG)-graftcarbon nanotubes for potent cancer therapeutics  

NASA Astrophysics Data System (ADS)

Physically loading of paclitaxel (PTX) onto carbon nanotubes (CNTs) is achieved through immersion of poly(ethylene glycol) (PEG)-graft-single walled CNTs (PEG-g-SWNTs) or PEG-graft-multi-walled CNTs (PEG-g-MWNTs) in a saturated solution of PTX in methanol. After loading once the loading capacity (LD%) is 26% (w/w) and 36% (w/w) for PEG-g-SWNTs or PEG-g-MWNTs, respectively. With these PTX contents, PTX loaded PEG-g-SWNTs and PTX loaded PEG-g-MWNTs still have good dispersity in aqueous solution and individual CNTs can be observed in TEM images. PTX can be released from PEG-g-CNTs several times faster than from free PTX but still in a sustained profile with less than 40% of PTX being released in 40 days at pH 7 or 5. In vitro cytotoxicity of samples is evaluated in HeLa cells and MCF-7 cells. PEG-g-SWNTs and PEG-g-MWNTs show low cytotoxicity in both cells with insignificant effects on the cell proliferation rates. However, both PTX loaded PEG-g-SWNTs and PTX loaded PEG-g-MWNTs show high efficacy to kill HeLa cells and MCF-7 cells, as reflected by IC50 lower than free PTX. Therefore, PTX loaded PEG-g-CNTs are promising for cancer therapeutics. Keywords: carbon nanotubes, poly(ethylene glycol), drug delivery, cancer therapy, nanomedicine.

Leng Lay, Chee; Liu, Hui Qi; Tan, Hui Ru; Liu, Ye

2010-02-01

364

d-?-Tocopherol Polyethylene Glycol Succinate-Based Redox-Sensitive Paclitaxel Prodrug for Overcoming Multidrug Resistance in Cancer Cells.  

PubMed

To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-?-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ?140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors. PMID:25102234

Bao, Yuling; Guo, Yuanyuan; Zhuang, Xiangting; Li, Dan; Cheng, Bolin; Tan, Songwei; Zhang, Zhiping

2014-09-01

365

Tubulins in the primate retina: evidence that xanthophylls may be endogenous ligands for the paclitaxel-binding site.  

PubMed

The xanthophylls-lutein, zeaxanthin, and meso-zeaxanthin (L&Z)-are found in the central region of the primate retina, which is called the macula lutea (yellow spot). How they are anchored there and what their function is has been debated for over 50 years. Here, we present evidence that they may be bound to the paclitaxel (Taxol) binding site of the beta-tubulin subunit of microtubules and that a major function may be to modulate the dynamic instability of microtubules in the macula. Also, we compare nucleic acid and amino acid sequences of tubulins that are in human brain with those we have isolated from human-retina and monkey-macula cDNA libraries. In so doing, we suggest that in primates, class I beta-tubulin consists of at least two subtypes (beta(Ia) and beta(Ib)). Alignment analysis of the sequences of the genes for beta(Ia) and beta(Ib) indicates that the corresponding mRNAs may have other functions in addition to that of coding for proteins. Furthermore, we show that there are at least five different types of beta-tubulin in the macula lutea of rhesus monkey. PMID:11504633

Crabtree, D V; Ojima, I; Geng, X; Adler, A J

2001-08-01

366

Paclitaxel is an Inhibitor and its Boron Dipyrromethene Derivative is a Fluorescent Recognition Agent for Botulinum Neurotoxin Subtype A  

PubMed Central

We have successfully identified one new inhibitor and one new fluorescent recognition agent for the botulinum neurotoxin subtype A (BoNT/A) using the virtual screening protocol Protein Scanning with Virtual Ligand Screening (PSVLS). Hit selection used an in-house developed Holistic Binding scoring method. Selected hits were tested experimentally for inhibitory activity using Fluorescence Resonance Energy Transfer (FRET) assays against the light chain (catalytic domain) of BoNT/A. Ligand binding was determined against the light and heavy chain BoNT/A complex either through radiolabeled ligand binding assays (non-fluorescent ligands) or fluorescence intensity assays (fluorescent ligands). These experimental assays have confirmed one compound (paclitaxel) to inhibit BoNT/A’s proteolytic activity experimentally with an IC50 of 5.2 ?M. A fluorescent derivative was also confirmed to bind to the toxin, and therefore is a suitable candidate for the rational design of new detection agents and for the development of fluorescence-based multi-probe detection assays. PMID:23484537

Dadgar, Saedeh; Ramjan, Zack; Floriano, Wely B.

2013-01-01

367

Safety and efficacy of a non-polymeric paclitaxel-eluting microporous stent in real-world percutaneous coronary intervention  

PubMed Central

At present, there is an increasing focus on stents that have a biodegradable polymer coating, rather than a permanent polymer coating. This is due to the fact that following the implantation of a drug-eluting stent (DES) with a permanent polymer coating, the continued existence of the coating may result in a foreign body reaction and delayed re-endothelialization. The aim of the present study was to evaluate the safety and efficacy of a non-polymeric paclitaxel-eluting microporous (YINYI™) stent in real-life percutaneous coronary intervention (PCI) for patients with coronary artery disease (CAD). A total of 686 YINYI™ stents were implanted in 404 patients with CAD in a PCI procedure and outpatient follow-ups were performed 1, 6, 12 and 15 months subsequent to the PCI, respectively. The observation endpoints were major adverse cardiac events (MACEs), including cardiac death, non-fatal myocardial infarction (MI), restenosis, target lesion revascularization, stent thrombosis and recurrence of angina pectoris. The average follow-up time was 15 months. The results revealed that the cumulative incidences of MACEs were as follows: mortality, 0.99%; non-fatal MI, 0.74%; restenosis, 4.0%; and target lesion revascularization, 2.7%. The results at the short- and long-term clinical follow-ups indicated that YINYI™ stents are effective and safe for use in PCI for patients with CAD. PMID:24137271

WANG, SHAO-PENG; HUANG, RONG-CHONG; ZHU, HAO; ZHANG, BO; ZHENG, ZHEN-GUO; YIN, DA; WANG, JUN-JIE; ZHOU, XU-CHEN

2013-01-01

368

Comparison of bare metal stent and paclitaxel-eluting stent using a novel rat aorta stent model  

PubMed Central

The purpose of our study was to create a novel rat aorta stent implantation model. Stainless steel bare metal stents (BMS) or paclitaxel-eluting stents (PES) were implanted in male Sprague-Dawley rats (BW 400 ± 20 g). Two and four weeks after stent implantation, the aorta were collected, fixed with 2% glutaraldehyde, and cut into two segments. One segment was used for scanning electron microscopy analysis to evaluate re-endothelialization, and the other segment was used to calculate the neointimal area. At 2 weeks after stenting, the appearance of neointimal hyperplasia was less in the PES group than in the BMS group. At 4 weeks after stenting, no significant difference in neointimal hyperplasia was observed between two groups. On the other hand, the PES group showed more thrombus formation and less re-endothelialization compared to the BMS group. This study demonstrated the ability of a novel rat model of aorta stenting via a common carotid artery to measure the efficacy and safety of commercially available drug-eluting stents. PMID:21586873

Kwon, Jin Sook; Park, Rho Kwan; Shim, Tae Jin; Jeong, Myung Ho; Cho, Myeong Chan

2011-01-01

369

Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer  

SciTech Connect

Purpose: A key research objective in radiation oncology is to identify agents that can improve chemoradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC) as a model disease. Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM's efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared with that after Taxol administration. Results: Genexol-PM has a size of 23.91 ± 0.41 nm and surface charge of ?8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule counterpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postadministration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC.

Werner, Michael E.; Cummings, Natalie D.; Sethi, Manish; Wang, Edina C.; Sukumar, Rohit [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States) [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Moore, Dominic T. [Division of Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States)] [Division of Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Wang, Andrew Z., E-mail: zawang@med.unc.edu [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States)

2013-07-01

370

A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.  

PubMed

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo. PMID:24903226

Tu, Yifan; Hershman, Dawn L; Bhalla, Kapil; Fiskus, Warren; Pellegrino, Christine M; Andreopoulou, Eleni; Makower, Della; Kalinsky, Kevin; Fehn, Karen; Fineberg, Susan; Negassa, Abdissa; Montgomery, Leslie L; Wiechmann, Lisa S; Alpaugh, R Katherine; Huang, Min; Sparano, Joseph A

2014-07-01

371

Concurrent Chemoradiotherapy With Paclitaxel and Nedaplatin Followed by Consolidation Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix: Preliminary Results of a Phase II Study  

SciTech Connect

Purpose: To evaluate the efficacy and toxicities of concurrent chemoradiotherapy (CCRT) and consolidation chemotherapy in patients with locally advanced squamous cell cervical carcinoma. Methods and Materials: Patients with LASCC (FIGO Stage IIB-IIIB) were treated with pelvic external beam radiotherapy (45 Gy for Stage IIB and 50 Gy for Stage III) and high-dose-rate intracavitary brachytherapy (50 Gy for Stage IIB and 35 Gy for Stage III). The cumulative dose at point A was 50 Gy for Stage IIB and 65 Gy for Stage III. Concurrent chemotherapy with paclitaxel (35 mg/m{sup 2}) and nedaplatin (20 mg/m{sup 2}) was given every week for 6 weeks. Consolidation chemotherapy with paclitaxel (135 mg/m{sup 2}) and nedaplatin (60 mg/m{sup 2}) was administered every 3 weeks for 4 cycles. Results: All patients completed CCRT, and 28 of 34 patients completed consolidation chemotherapy. The complete response rate was 88% (95% CI, 73-96%). The most common Grade 3 or higher toxicities were leukopenia/neutropenia (10.9% of the cycles). During a median follow up of 23 months (range, 14-30 months), 5 patients had locoregional failure and 1 patient had distant metastasis. The estimated 2-year progression-free survival and overall survival were 82% (95% CI, 68-95%) and 93% (95% CI, 83-100%), respectively. Grade 3 late complications occurred in 3 patients (9%). Conclusions: CCRT with paclitaxel and nedaplatin followed by consolidation chemotherapy is well tolerated and effective in patients with locally advanced squamous cell cervical carcinoma. Further randomized trials of comparing this regimen with the standard treatment are worth while.

Zhang Meiqin, E-mail: pianozmq@hotmail.co [Department of Gynecologic Oncology, Cancer Hospital, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Liu Suping; Wang, Xiang-E. [Department of Gynecologic Oncology, Cancer Hospital, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

2010-11-01

372

Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy.  

PubMed

An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ? 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined. PMID:21584666

Lalisang, R I; Erdkamp, F L G; Rodenburg, C J; Knibbeler-van Rossum, C T A M; Nortier, J W R; van Bochove, A; Slee, P H Th J; Voest, E E; Wils, J A; Wals, J; Loosveld, O J L; Smals, A E M; Blijham, G H; Tjan-Heijnen, V C G; Schouten, H C

2011-07-01

373

Neoadjuvant Chemoradiation With Paclitaxel/Carboplatin for Selected Stage III Non-Small-Cell Lung Cancer: Long-Term Results of a Trimodality Phase II Protocol  

SciTech Connect

Purpose: To evaluate, in a Phase II trial conducted August 1998 through January 2001, the efficacy of neoadjuvant chemotherapy followed by chemoradiotherapy and definitive surgery in patients with locally advanced non-small-cell lung cancer (LA-NSCLC), Stages IIIA bulky and selected Stage IIIB. Patients and Methods: Staging of LA-NSCLC included computed tomography of cranium, thorax, and abdomen, whole-body positron emission tomography, and video mediastinoscopy. Induction chemotherapy with weekly paclitaxel and carboplatin was followed by hyperfractionated accelerated thoracic radiotherapy (45 Gy) with simultaneous weekly paclitaxel and carboplatin. Four to six weeks after completion of induction therapy, restaging and resection of primary tumor and lymph nodes was intended. Results: A total of 59 consecutive patients were enrolled, 25% with Stage IIIA bulky disease, 65% with Stage IIIB, and 10% with Stage IV (excluded from further analysis). Forty-one patients completed induction therapy; in 52.4% a functional (positron emission tomography) downstaging was proven. Thirty-two patients (59.3%) underwent complete tumor resection, and 5 patients had an exploratory thoracotomy only. Histopathologic downstaging was proven in 59.4% and complete response in 21.9%. Hospital mortality was 5.4%. Median duration of follow-up for living patients was 62.1 months. Overall median survival was 22.6 months, 58.2 months for completely resected patients. During induction chemotherapy, Grade 3/4 granulocytopenia occurred in 8% of patients; the most common Grade 3/4 toxicity of chemoradiation was esophagitis, in 26.4% of patients. Conclusions: Indu