These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

Paclitaxel Injection  

MedlinePLUS

... other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to treat ovarian cancer (cancer that ... and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also used to treat Kaposi's sarcoma (a ...

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

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

4

Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer  

Microsoft Academic Search

vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P = 0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P = 0.02) were more frequent in patients receiving paclitaxel plus bevacizumab. Infection was more common in patients receiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P<0.001), but febrile neutropenia was uncommon (<1% overall). Conclusions Initial therapy of metastatic breast

Kathy Miller; Molin Wang; Julie Gralow; Maura Dickler; Melody Cobleigh; Edith A. Perez; Tamara Shenkier; David Cella; Nancy E. Davidson

2007-01-01

5

Comparative pharmacokinetics of paclitaxel after oral administration of Taxus yunnanensis extract and pure paclitaxel to rats.  

PubMed

Taxus yunnanensis (T. yunnanensis) is endemic to China and has been used in traditional medicine for the treatment of cancer, diabetic ailments and others. Paclitaxel is a representative antitumor compound in the Taxus species. The pharmacokinetic behavior of paclitaxel after oral administration of the crude extract of T. yunnanensis has not been investigated. This study attempts to compare the pharmacokinetics of paclitaxel after an oral administration of the crude extract of the twigs and leaves of T. yunnanensis and pure paclitaxel. A UPLC and a UPLC/MS/MS analysis method were developed for the determination of paclitaxel in T. yunnanensis extract and in the comparative pharmacokinetic study. Caco-2 cells were used to investigate the transport profile of paclitaxel in vitro. In the pharmacokinetic study, rats were randomly grouped and administered with T. yunnanensis extract or pure paclitaxel. The results showed that the AUC and C(max) of paclitaxel in rats receiving the T. yunnanensis extract were significantly increased than those receiving the pure paclitaxel, and the in vitro Caco-2 cell monolayer transport study found that the coexisting constituents in the extract of T. yunnanensis could inhibit the efflux of paclitaxel. These findings suggested that the oral absorption and bioavailability of paclitaxel in T. yunnanensis extract were remarkably higher when compared with the pure paclitaxel, and the coexisting constituents in the T. yunnanensis extract might play an important role for the enhancement of the oral absorption and bioavailability of paclitaxel. PMID:23811429

Jin, Jing; Cai, Dake; Bi, Huichang; Zhong, Guoping; Zeng, Hang; Gu, Lianquan; Huang, Zhiying; Huang, Min

2013-10-01

6

Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules  

Microsoft Academic Search

\\u000a Purpose  The aim of this study was to evaluate the pharmacokinetics of paclitaxel-loaded lipid nanocapsules (LNC) in rats to assess\\u000a the intrinsic effect of the dosage form on the improvement of paclitaxel oral exposure.\\u000a \\u000a \\u000a \\u000a Methods  Paclitaxel-loaded LNC were prepared and characterized in terms of size distribution, drug payload, and the kinetics of paclitaxel\\u000a crystallization. Taxol, Taxol with verapamil, or paclitaxel-loaded LNC were

Sandra Peltier; Jean-Michel Oger; Frédéric Lagarce; William Couet; Jean-Pierre Benoît

2006-01-01

7

Paclitaxel (Taxol)--a guide to administration.  

PubMed

The introduction of a new chemotherapeutic agent has implications for nursing care. Paclitaxel (Taxol) chemotherapy is now being used throughout Europe for treatment of patients with ovarian cancer who have previously failed a platinum-containing chemotherapy regimen, and in many countries to treat metastatic breast cancer. Nurses need to be equipped to care for these patients receiving Paclitaxel. This paper introduces nurses to Paclitaxel, the history of its development, its mechanism of action, potential side-effects and administration. Paclitaxel's side-effects include hypersensitivity reactions, neutropaenia, peripheral neuropathy, asymptomatic bradycardia, alopecia, malaise, myalgias and arthralgias. Administration guidelines will be discussed because Paclitaxel leaches plasticizer from polyvinyl chloride (PVC) intravenous-giving sets normally used to administer chemotherapy, hence an alternative delivery system is required. PMID:9117048

Preston, N J

1996-09-01

8

Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.  

PubMed

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007. PMID:16489089

Desai, Neil; Trieu, Vuong; Yao, Zhiwen; Louie, Leslie; Ci, Sherry; Yang, Andrew; Tao, Chunlin; De, Tapas; Beals, Bridget; Dykes, Donald; Noker, Patricia; Yao, Rosie; Labao, Elizabeth; Hawkins, Michael; Soon-Shiong, Patrick

2006-02-15

9

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

10

21 CFR 516.1684 - Paclitaxel.  

...CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Conditionally Approved New Animal Drugs For Minor Use and Minor Species § 516.1684 Paclitaxel. (a) Specifications....

2014-04-01

11

Management of paclitaxel-induced neurotoxicity  

Microsoft Academic Search

Paclitaxel exerts its antitumor activity by promoting microtubule assembly and stabilizing microtubules. Microtubules are\\u000a important for the development and maintenance of neurons. As a consequence, neurotoxicity is one of the drug’s major side\\u000a effects. The risk of neurotoxicity depends on dose, duration and schedule of paclitaxel. Risk increases for patients with\\u000a pre-existing conditions that may cause neuropathy (such as alcohol

Manisha Bhutani; Philomena M. Colucci; Heather Laird-Fick; Barbara A. Conley

2010-01-01

12

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

13

Conformationally Constrained and Nanoparticle Targeted Paclitaxels*  

PubMed Central

Paclitaxel (Taxol®) is one of the most important anticancer agents developed over the last 30 years. Its primary mechanism of action is by interaction with the cellular protein tubulin, causing irreversible polymerization to microtubules. A detailed knowledge of this crucial interaction is thus of paramount importance in the design and development of highly potent analogs and also for the potential development of “non-taxane” tubulin polymerization agents. This review briefly describes the discovery and development of taxol, and then describes our work on delineating the tubulin-binding conformation of paclitaxel by a combination of REDOR NMR and molecular modeling. The resulting “T-taxol” conformation was validated by the synthesis of conformationally constrained paclitaxel analogs, which had bioactivities up to twenty-fold higher than those of paclitaxel. The review concludes with recent work on the development of a gold nanoparticle derivative of paclitaxel. This delivery method has the potential to lower the dosage of paclitaxel needed while maintaining or increasing its effectiveness, thus significantly improving the benefits of this important chemotherapeutic agent.

Tamarkin, Lawrence; Paciotti, Giulio F.

2014-01-01

14

Continuous-flow fluoro-immunosensor for paclitaxel measurement  

Microsoft Academic Search

A fluorescence-based continuous-flow immunosensor for sensitive, precise, accurate and fast determination of paclitaxel was developed. The sensor utilizes anti-paclitaxel antibody immobilized through its Fc region and crosslinked by dimethylpimelimidate to protein A attached covalently onto the silanized inner walls of a glass capillary column followed by saturation of the paclitaxel-binding sites with rhodamine-labeled paclitaxel. The assay is based on the

Sohail H. Sheikh; Ashok Mulchandani

2001-01-01

15

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

16

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

17

Peripheral Neuropathy Induced by Paclitaxel: Recent Insights and Future Perspectives  

PubMed Central

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

2006-01-01

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

Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes  

NASA Astrophysics Data System (ADS)

A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual-targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems.

Meng, Shuyan; Su, Bo; Li, Wei; Ding, Yongmei; Tang, Liang; Zhou, Wei; Song, Yin; Li, Heyan; Zhou, Caicun

2010-10-01

20

Kinetics of paclitaxel 2?-N-methylpyridinium mesylate decomposition  

Microsoft Academic Search

This study was designed to examine the kinetics of decomposition of paclitaxel 2?-N-methylpyridinium mesylate (PNMM), a derivative\\u000a of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies\\u000a of PNMM were conducted over a pH range of 4.0 to 8.0 at 25°C. The critical micelle concentration (CMC) of PNMM was determined

Jaber G. Qasem; Paul M. Bummer; George A. Digenis

2003-01-01

21

Cremophor reduces paclitaxel penetration into bladder wall during intravesical treatment  

Microsoft Academic Search

Purpose: We have previously shown that paclitaxel, when dissolved in water and instilled into the bladder, readily penetrates the\\u000a urothelium. The FDA-approved formulation uses Cremophor and ethanol to dissolve paclitaxel. In the present study, the effects\\u000a of this solvent system on the urine, bladder tissue, and plasma pharmacokinetics of intravesical paclitaxel were evaluated.\\u000a Methods: Plasma, urine, and tissue pharmacokinetics were

Ian Knemeyer; M. Guillaume Wientjes; Jessie L.-S. Au

1999-01-01

22

Neurological monitoring of neurotoxicity induced by paclitaxel\\/cisplatin chemotherapy  

Microsoft Academic Search

To evaluate the neurotoxicity of paclitaxel\\/cisplatin chemotherapy, we studied neurological and electrophysiological functions in 14 patients who had been treated with 1–7 courses of paclitaxel\\/cisplatin. The cumulative paclitaxel and cisplatin doses ranged from 175 to 1225 mg\\/m2 and 100–700 mg\\/m2, respectively. Neurological examinations as well as motor nerve conduction studies of the peroneal nerve were performed and summarised by means

T. Berger; R. Malayer; A. Doppelbauer; G. Krajnik; E. Auff; R. Pirker

1997-01-01

23

Evaluation of neurotoxicity induced by paclitaxel second-line chemotherapy  

Microsoft Academic Search

The most important cytotoxic drugs for the treatment of ovarian cancer, platinum compounds and paclitaxel, are known to induce\\u000a neurotoxicity, which is dose limiting when higher paclitaxel doses are used or platinum-pretreated patients are treated. The\\u000a absolute dose of paclitaxel per course has been demonstrated to be an important risk factor for the development of neurotoxicity.\\u000a The role of cumulative

Andreas du Bois; Markus Schlaich; Hans-Joachim Lück; Anne Mollenkopf; Ulrike Wechsel; Matthea Rauchholz; Thomas Bauknecht; Hans-Gerd Meerpohl

1999-01-01

24

Motor neuropathy due to docetaxel and paclitaxel.  

PubMed

Paclitaxel and docetaxel are novel chemotherapeutic agents that promote the polymerization and inhibit the depolymerization of microtubules. Sensory neuropathy is common with these agents, particularly paclitaxel. We evaluated 64 patients treated with these drugs; 54 were followed prospectively. Eleven (17%, including six of the 54 prospectively followed patients) developed muscle weakness that was predominantly proximal. The weakness was idiosyncratic, occurring at any stage of treatment, had a variable course, and was reversible upon cessation of drug. All patients developed symptoms or signs of taxane-induced sensory neuropathy. Weakness was likely neuropathic in origin; electrodiagnostic studies suggested a distal axonopathy in some patients and proximal denervation (anterior horn cell or nerve root) in other. PMID:8710063

Freilich, R J; Balmaceda, C; Seidman, A D; Rubin, M; DeAngelis, L M

1996-07-01

25

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,

26

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

Cancer.gov

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

27

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,

28

Management of Paclitaxel-Induced Hand-Foot Syndrome  

PubMed Central

Summary Background Hand-foot syndrome (HFS), also known as acral erythema or palmoplantar dysesthesia, is a manifestation of painful erythema and dysesthesia mostly occurring in the palms and soles. Although many chemotherapeutic agents have been shown to cause HFS, it remains an uncommon adverse cutaneous manifestation of paclitaxel. Case Report We report a case of paclitaxel-induced grade 3 HFS in a patient with breast cancer. HFS developed after 6 weeks of paclitaxel weekly infusions. The patient was managed by avoidance of sun exposure and extensive use of sunscreen and moisturizers. The skin lesions stabilized and improved gradually. This allowed us to continue the planned necessary course of 12 weeks of paclitaxel under close surveillance. Conclusion Paclitaxel-induced HFS can be managed with topical creams and avoidance of sun exposure without the need to discontinue chemotherapy. However, close monitoring for any increase or change in symptoms is warranted. PMID:24415973

Assi, Hussein A.; Ayoub, Zeina A.; Jaber, Sara M.; Sibai, Hassan A.; El Saghir, Nagi S.

2013-01-01

29

Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants  

Microsoft Academic Search

Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome P450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to

Radka Václavíková; Stanislav Horský; Petr Šimek; Ivan Gut

2003-01-01

30

Paclitaxel Nano-Delivery Systems: A Comprehensive Review  

PubMed Central

Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

Ma, Ping; Mumper, Russell J.

2013-01-01

31

Paclitaxel Nano-Delivery Systems: A Comprehensive Review.  

PubMed

Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

Ma, Ping; Mumper, Russell J

2013-02-18

32

Dose-dense Paclitaxel in Advanced Ovarian Cancer.  

PubMed

Carboplatin and paclitaxel, delivered on a 3-weekly basis, is the historical standard for the management of advanced epithelial ovarian cancers (EOC). Increased dose intensity, the inclusion of additional active cytotoxic agents and lengthening treatment duration have failed to improve the outcomes seen with standard doses of carboplatin and paclitaxel in the treatment of EOC. Dose-dense (i.e. weekly) delivery of paclitaxel may exploit anticancer mechanisms such as anti-angiogenesis and the induction of apoptosis. Tumour regrowth may be more effectively impaired by the dose-dense delivery of paclitaxel. Non-randomised studies of dose-dense chemotherapy in EOC have been promising, particularly in heavily pretreated and platinum-resistant disease, with reported response rates as high as 60%. Dose-dense paclitaxel also seems to be well tolerated. These observations led to a number of comparative trials of dose-dense paclitaxel chemotherapy, three have been reported and four are ongoing. This review explores the rationale behind dose-dense delivery of paclitaxel and evaluates the results of completed phase III trials. PMID:25455846

Kumar, A; Hoskins, P J; Tinker, A V

2015-01-01

33

Isolation of microtubules and microtubule-associated proteins using Paclitaxel.  

PubMed

Paclitaxel binds to tubulin, strongly promotes microtubule assembly from subunits, and stabilizes the assembled polymer against disassembly. Because of its ability to drive the assembly reaction almost completely toward microtubules, the paclitaxel-dependent procedure outlined here is particularly useful for the isolation of microtubules from tissues in which the intracellular concentration of tubulin is low (e.g., nonneuronal sources, cultured cells, and invertebrate tissues). The microtubule-associated proteins (MAPs) remain bound to the paclitaxel-stabilized microtubules. The isolation of these MAPs by salt extraction is also described here. PMID:25561621

Sloboda, Roger D

2015-01-01

34

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

35

Preparation and evaluation of paclitaxel-loaded PEGylated immunoliposome  

Microsoft Academic Search

A sterically stabilized paclitaxel-loaded liposome tailored to target human breast cancer cells was developed, thereby promoting the efficiency of intracellular delivery of paclitaxel through receptor-mediated endocytosis. Results indicated that the targeting moiety (thiolated Herceptin) was successfully coupled to the distal reactive maleimide terminus of the poly (ethylene glycol)-phospholipid conjugate as well as being incorporated in the liposomal bilayers. The particle

Tao Yang; Min-Koo Choi; Fu-De Cui; Jung Sun Kim; Suk-Jae Chung; Chang-Koo Shim; Dae-Duk Kim

2007-01-01

36

Effect of several compounds on biliary excretion of paclitaxel and its metabolites in guinea-pigs.  

PubMed

The objective of this study was to evaluate the in vivo metabolic profile of paclitaxel and to examine the effect of potential co-administered drugs on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. We first investigated in vitro paclitaxel metabolism using liver microsomes obtained from various species to identify the most suitable animal model with a similar metabolism to humans. Then, in vivo paclitaxel metabolism was investigated in male guinea-pigs. The levels of paclitaxel and its metabolites were measured by high-performance liquid chromatography in bile samples from guinea-pigs after paclitaxel i.v. injection (6 mg/kg). We further evaluated the effects of various drugs (quercetin, ketoconazole, dexamethasone, cotrimoxazole) on the biliary secretion of paclitaxel and its metabolites in guinea-pigs. This work demonstrated significant in vitro interspecies differences in paclitaxel metabolism. Our findings showed both in vitro and in vivo similarities between human and guinea-pig biotransformation of paclitaxel. 6alpha-Hydroxypaclitaxel, the main human metabolite of paclitaxel, was found in guinea-pig bile. After paclitaxel combination with ketoconazole or quercetin in guinea-pigs, the cumulative biliary excretion of paclitaxel and its metabolites up to 6 h was significantly decreased by 62 and 76%, respectively. The co-administration of cotrimoxazole or pretreatment with dexamethasone did not alter significantly cumulative biliary excretion. The guinea-pig is a suitable model to study metabolism and biliary excretion of paclitaxel, and to investigate in vivo drug interactions. PMID:15930897

Bun, Sok-Siya; Giacometti, Sarah; Fanciullino, Raphaëlle; Ciccolini, Joseph; Bun, Hot; Aubert, Claude

2005-07-01

37

Acetyl l-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy  

Microsoft Academic Search

This study examines the potential efficacy of acetyl-l-carnitine (ALC) to prevent and treat paclitaxel-induced pain. Rats received four intraperitoneal (i.p.) injections of 2mg\\/kg paclitaxel on alternate days which, following a short delay induced marked mechanical hypersensitivity. Daily administration of ALC (50mg\\/kg and 100mg\\/kg; p.o.; concurrently with paclitaxel and for 14 days afterwards) prevented the development of paclitaxel-induced pain. This effect

Sarah J. L. Flatters; Wen-Hua Xiao; Gary J. Bennett

2006-01-01

38

The distribution of systemically administered [ 3 H]-paclitaxel in rats: a quantitative autoradiographic study  

Microsoft Academic Search

Paclitaxel is an important agent in the treatment of many common malignancies. Although the symptomatic peripheral neuropathy caused by this drug is its principal nonhematologic toxicity, little is known about the distribution of paclitaxel within the peripheral or central nervous system following systemic administration. In order to study paclitaxel's distribution in neural and extraneural tissues, adult Sprague-Dawley rats were sacrificed

Glenn J. Lesser; Stuart A. Grossman; Susan Eller; Eric K. Rowinsky

1995-01-01

39

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

40

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

41

Scleroderma-like cutaneous lesions induced by paclitaxel: A case study  

Microsoft Academic Search

Paclitaxel is a recent antineoplastic agent that belongs to the taxane family. Its activity has been demonstrated in advanced and refractory ovarian, breast, lung, and head and neck cancer. Adverse cutaneous reactions to paclitaxel have been reported, namely bullous fixed drug eruption, onycholysis, acral erythema, erythema multiforme, and pustular eruption. We report the first case of scleroderma-like changes after paclitaxel

I. Kupfer; X. Balguerie; P. Courville; P. Chinet; P. Joly

2003-01-01

42

Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell.  

PubMed

Paclitaxel has been proved to be active in treatment and larynx preservation of HNSCC, however, the fact that about 20-40% patients do not respond to paclitaxel makes it urgent to figure out the biomarkers for paclitaxel-based treatment in Hypopharynx cancer (HPC) patients to improve the therapy effect. In this work, Fadu cells, treated or untreated with low dose of paclitaxel for 24 h, were applied to DNA microarray chips. The differential expression in mRNAs and miRs was analyzed and the network between expression-altered mRNAs and miRs was constructed. Differentially expressed genes were mainly enriched in superpathway of cholesterol biosynthesis (ACAT2, MSMO1, LSS, FDFT1 and FDPS etc.), complement system (C3, C1R, C1S, CFR and CFB etc.), interferon signaling (IFIT1, IFIT3, IFITM1 and MX1 etc.), mTOR signaling (MRAS, PRKAA2, PLD1, RND3 and EIF4A1 etc.) and IGF1 signaling (MRAS, IGFBP7, JUN and FOS etc.), most of these pathways are implicated in tumorigenesis or chemotherapy resistance. The first three pathways were predicted to be suppressed, while the last two pathways were predicted to be induced by paclitaxel, suggesting the combination therapy with mTOR inhibition and paclitaxel might be better than single one. The dramatically expression-altered miRs were miR-112, miR-7, miR-1304, miR-222*, miR-29b-1* (these five miRs were upregulated) and miR-210 (downregulated). The 26 putative target genes mediated by the 6 miRs were figured out and the miR-gene network was constructed. Furthermore, immunoblotting assay showed that ERK signaling in Fadu cells was active by low dose of paclitaxel but repressed by high dose of paclitaxel. Collectively, our data would provide potential biomarkers and therapeutic targets for paclitaxel-based therapy in HPC patients. PMID:24294361

Xu, Cheng-Zhi; Shi, Run-Jie; Chen, Dong; Sun, Yi-Yuan; Wu, Qing-Wei; Wang, Tao; Wang, Pei-Hua

2013-01-01

43

Chemotherapy with paclitaxel plus carboplatin for relapsed advanced thymic carcinoma  

PubMed Central

Objective For rarity of thymic carcinoma, no definitive chemotherapeutic regimen has been established in second- or further-line settings. The aim of this study was to evaluate the feasibility and safety of paclitaxel plus carboplatin in advanced thymic carcinoma as second- or further-line treatment in our institute. Methods We evaluated the efficacy and toxicity of paclitaxel plus carboplatin as salvage therapy in 12 patients with previously treated advanced thymic carcinoma from 2005 to 2012 in Zhejiang Cancer Hospital. Survival analysis was evaluated by Kaplan-Meier method. Results Twelve patients were included in current study. Four patients achieved stable disease (SD), and three achieved partial response (PR), representing a response rate of 25.0% and disease control rate (DCR) of 58.3%. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 24.0 months, respectively. The toxicities associated with the paclitaxel plus carboplatin was generally acceptable. Conclusions Paclitaxel plus carboplatin appears to have some activity against thymic carcinoma as second-line or later chemotherapy in advanced thymic carcinoma.

2014-01-01

44

Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres  

PubMed Central

Object The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. Methods The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. Results Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6–12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6–12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). Conclusions These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy. PMID:24605841

Gabikian, Patrik; Tyler, Betty M.; Zhang, Irma; Li, Khan W.; Brem, Henry; Walter, Kevin A.

2015-01-01

45

A preliminary risk-benefit assessment of paclitaxel.  

PubMed

Paclitaxel is an antineoplastic agent, first isolated and described in 1971. Despite its novel structure and apparent activity in vitro, little interest was shown in developing the compound because of its scarcity, problems with its formulation and the mistaken assumption that its mechanism of action was similar to that of the vinca alkaloids. Approximately 10 years later, the unique mechanism of action of paclitaxel, its ability to stabilise microtubules, was discovered, and its activity against human tumour xenografts was demonstrated. Interest in the drug was reignited and clinical testing began. Severe hypersensitivity reactions were controlled in the phase II programme with a premedication regimen consisting of dexamethasone, histamine H1-antagonists and H2-antagonists. Neutropenia was dose limiting in all studies conducted in patients with solid tumours. This toxicity was schedule-dependent, and less severe when paclitaxel was administered as a 3-hour infusion regimen. Peripheral neuropathy was mild to moderate in the initial experience, and dose-dependent. However, when bone marrow support with haemopoietic growth factors was used to allow paclitaxel dose intensification, neurotoxicity became dose limiting. To date, substantial clinical efficacy has been demonstrated in ovarian, breast, non-small-cell lung, and head and neck cancers. Response rates were low in initial studies in melanoma, prostate, colon, cervix and renal cancer. In December 1992, US Food and Drug Administration approval was granted for the use of paclitaxel as second-line therapy in ovarian cancer patients. More recently, similar approval was granted for use in recurrent breast cancer. Nevertheless, important questions remain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7619331

Bitton, R J; Figg, W D; Reed, E

1995-03-01

46

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

47

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

48

Development of new lipid-based paclitaxel nanoparticles using sequential simplex optimization  

Microsoft Academic Search

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

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

2009-01-01

49

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

E-print Network

polytetrafluoroethylene grafts might prevent myofibroblast proliferation, which might cause hematomas, seromas, infections insertion. Therefore, paclitaxel inner-coated expanded polytetrafluoroethylene grafts can reduce the coated

Park, Jong-Sang

50

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

51

A TPGS-incorporating nanoemulsion of paclitaxel circumvents drug resistance in breast cancer.  

PubMed

Paclitaxel resistance is usually developed in clinical chemotherapy, which remains a major obstacle for successful cancer treatment. Herein, we attempted to develop a TPGS incorporating nanoemulsion of paclitaxel (NE-PTX) to circumvent the drug resistance in breast cancer. NE-PTX was prepared by a self-assembly technique and the physicochemical properties were characterized. The efficacy of NE-PTX on overcoming paclitaxel resistance was measured by in vitro and in vivo evaluation. The measured results indicated that NE-PTX was nanometer-sized droplets with the mean diameter of 24.93±3.45 nm. The IC50 value of paclitaxel in resistant MCF-7/ADR cells was greatly reduced from 101.45 ?g/mL to 5.39 ?g/mL, which indicated that the paclitaxel resistance was effectively reduced by NE-PTX. The reversal of paclitaxel resistance could mainly ascribe to the significant inhibition of P-gp activity and enhancement of anti-cancer activity. Moreover, the tumor volume in resistant tumor xenograft model treated with NE-PTX was only 10.06% of that of paclitaxel solution group, and the tumor inhibitory rate of NE-PTX reached 93.84%, which effectively verified the efficacy of NE-PTX on treating paclitaxel resistance. Thereby, NE-PTX could provide an effective strategy for circumventing paclitaxel resistance in breast cancer. PMID:24866272

Bu, Huihui; He, Xinyu; Zhang, Zhiwen; Yin, Qi; Yu, Haijun; Li, Yaping

2014-08-25

52

Identification of P-Glycoprotein and Transport Mechanism of Paclitaxel in Syncytiotrophoblast Cells  

PubMed Central

When chemotherapy is administered during pregnancy, it is important to consider the fetus chemotherapy exposure, because it may lead to fetal consequences. Paclitaxel has become widely used in the metastatic and adjuvant settings for woman with cancer including breast and ovarian cancer. Therefore, we attempted to clarify the transport mechanisms of paclitaxel through blood-placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of paclitaxel was time- and temperature-dependent. Paclitaxel was eliminated about 50% from the cells within 30 min. The uptake of paclitaxel was saturable with Km of 168 ?M and 371 ?M in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. [3H]Paclitaxel uptake was markedly inhibited by cyclosporine and verapamil, well-known substrates of P-glycoprotein (P-gp) transporter. However, several MRP substrates and organic anions had no effect on [3H]paclitaxel uptake in TR-TBT cells. These results suggest that P-gp may be involved in paclitaxel transport at the placenta. TR-TBT cells expressed mRNA of P-gp. These findings are important for therapy of breast and ovarian cancer of pregnant women, and should be useful data in elucidating teratogenicity of paclitaxel during pregnancy. PMID:24596624

Lee, Na-Young; Lee, Ha-Eun; Kang, Young-Sook

2014-01-01

53

A unique paclitaxel-mediated modulation of the catalytic activity of topoisomerase IIalpha.  

PubMed

Paclitaxel (Taxol) is known to act by polymerizing and stabilizing microtubules. In spite of a known target, the existence of additional targets is suggested by a poor understanding of the mechanism(s) underlying eventual cell death by paclitaxel and by the drug's high efficacy, as compared to other spindle poisons. Based on the enhanced sensitivity of a mutant DNA double-strand break repair-deficient Chinese hamster ovary cell line to paclitaxel as well as to various topoisomerase (Topo) II poisons, it was hypothesized that paclitaxel, in addition to having an effect on microtubules, may also alter the activity of Topo II. This study demonstrates the unique, in vitro effects of paclitaxel on Topo II activity as investigated by monitoring the decatenation of kinetoplast DNA and relaxation of supercoiled plasmid DNA by Topo II. Unlike classical anti-topoisomerase drugs, low concentrations of paclitaxel (0.02-500 nM) stimulated Topo II catalytic activity, while higher concentrations over 5 microM inhibited the activity of Topo II. Furthermore, these effects of paclitaxel appear to be mediated through a direct interaction of paclitaxel with Topo II rather than an interaction with DNA or DNA-Topo II complexes. Collectively, the evidence presented suggests the existence of an atypical interaction between Topo II and paclitaxel that may disrupt the normal functioning of the enzyme. PMID:10378675

Dhawan, V; Swaffar, D S

1999-04-01

54

Paclitaxel-coated balloons and aneurysm formation in peripheral vessels.  

PubMed

We report two cases of early aneurysmal vessel dilatation after a paclitaxel-coated balloon (PCB) was used for angioplasty of the peripheral vessels. The first case refers to a failing vein bypass with a tight proximal anastomotic stenosis, whereas the second refers to a distal tibial artery occlusion. A PCB was used to treat both patients. Aneurysmal dilatation of the previously treated segment was noted in both patients during subsequent follow-up imaging. In the absence of other causal factors, we attribute both cases to PCB application. The aneurysms that formed had no detrimental effect on the patients' health and required no further treatment; however, it is important to bear in mind this potential risk of presumed paclitaxel toxicity. PMID:24801552

Diamantopoulos, Athanasios; Gupta, Yuri; Zayed, Hany; Katsanos, Konstantinos

2014-05-01

55

Reduction of Paclitaxel-induced Peripheral Neuropathy with Glutamine1  

Microsoft Academic Search

Purpose: Dose-limiting toxicity of many newer chemo- therapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropa- thy with glutamine administration after high-dose pacli- taxel. Experimental Design: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg\\/m2 given

Linda Vahdat; Kyriakos Papadopoulos; Dale Lange; Shelby Leuin; Elizabeth Kaufman; Diana Donovan; Deborah Frederick; Emilia Bagiella; Amy Tiersten; Gwen Nichols; Thomas Garrett; David Savage; Karen Antman; Charles S. Hesdorffer; Casilda Balmaceda

2001-01-01

56

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel  

Microsoft Academic Search

Purpose: Results of several clinical studies suggest that the combination of doxorubicin (DOX) and paclitaxel (PTX) is highly active\\u000a against solid tumors. Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case of DOX and acute changes\\u000a in cardiac rhythm in the case of PTX. It has been suggested that the addition of dexrazoxane (DZR) to this

Paola Della Torre; Anthony R. Imondi; Claudio Bernardi; Arturo Podestà; Donatella Moneta; Mariagrazia Riflettuto; Guy Mazué

1999-01-01

57

Apoptotic cell death induced by baccatin III, a precursor of paclitaxel, may occur without G2\\/M arrest  

Microsoft Academic Search

Purpose: Paclitaxel has been demonstrated to possess significant cell-killing activity in a variety of tumor cells by induction of\\u000a apoptosis, but the mechanism by which paclitaxel leads to cell death and its relationship with mitotic arrest is not entirely\\u000a clear. In this study, baccatin III, a synthetic precursor of paclitaxel, was used to analyze whether paclitaxel-induced apoptosis\\u000a can be a

Merrill C. Miller III; Korey R. Johnson; Mark C. Willingham; Weimin Fan

1999-01-01

58

Neuropathy-Inducing Effects of Eribulin Mesylate Versus Paclitaxel in Mice with Preexisting Neuropathy  

PubMed Central

Eribulin mesylate (E7389, INN:eribulin mesilate Halaven®) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 × its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 ± 1 and 22.2 ± 1.3 %, p < 0.001) and amplitude (averaging 53.2 ± 2.6 and 72.4 ± 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 ± 2.1 and 59.2 ± 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings. PMID:23637052

Wozniak, Krystyna M.; Wu, Ying; Farah, Mohamed H.; Littlefield, Bruce A.; Nomoto, Kenichi

2014-01-01

59

Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy.  

PubMed

Eribulin mesylate (E7389, INN:eribulin mesilate Halaven(®)) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 × its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 ± 1 and 22.2 ± 1.3 %, p < 0.001) and amplitude (averaging 53.2 ± 2.6 and 72.4 ± 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 ± 2.1 and 59.2 ± 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings. PMID:23637052

Wozniak, Krystyna M; Wu, Ying; Farah, Mohamed H; Littlefield, Bruce A; Nomoto, Kenichi; Slusher, Barbara S

2013-10-01

60

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

61

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

62

Cytotoxic activity of a new paclitaxel formulation, Pacliex, in vitro and in vivo  

Microsoft Academic Search

Background The paclitaxel formulation, Taxol (Bristol-Myers Squibb), is one of the most effective anticancer agents used today. However; it is associated with serious side effects believed to be caused by the Cremophor EL used for its formulation. Aim To evaluate the cytotoxic activity of a new paclitaxel formulation, Pacliex (developed by Oasmia Pharmaceutical, Uppsala, Sweden), a mixed micelles preparation in

Saadia Hassan; Sumeer Dhar; Marie Sandström; Dzmitry Arsenau; Marina Budnikova; Igor Lokot; Nikolai Lobanov; Mats O. Karlsson; Rolf Larsson; Elin Lindhagen

2005-01-01

63

Screening the endophytic flora of Wollemia nobilis for alternative paclitaxel sources  

Microsoft Academic Search

The endophytic flora of Wollemia nobilis was investigated in search for alternative paclitaxel producers. On one hand, metabolic profiling of the obtained specimens using an immunoenzymatic technique was carried out. On the other, we aimed at revealing the genetic background of presumed paclitaxel biosynthesis in the isolates.We found an indication of endophytic taxane production in the extracts of two strains,

Agata Staniek; Herman J. Woerdenbag; Oliver Kayser

2010-01-01

64

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

65

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

66

A Liposomal Formulation Able to Incorporate a High Content of Paclitaxel and Exert Promising Anticancer Effect  

PubMed Central

A liposome formulation for paclitaxel was developed in this study. The liposomes, composed of naturally unsaturated and hydrogenated phosphatidylcholines, with significant phase transition temperature difference, were prepared and characterized. The liposomes exhibited a high content of paclitaxel, which was incorporated within the segregated microdomains coexisting on phospholipid bilayer of liposomes. As much as 15% paclitaxel to phospholipid molar ratio were attained without precipitates observed during preparation. In addition, the liposomes remained stable in liquid form at 4°C for at least 6 months. The special composition of liposomal membrane which could reduce paclitaxel aggregation could account for such a capacity and stability. The cytotoxicity of prepared paclitaxel liposomes on the colon cancer C-26 cell culture was comparable to Taxol. Acute toxicity test revealed that LD50 for intravenous bolus injection in mice exceeded by 40?mg/kg. In antitumor efficacy study, the prepared liposomal paclitaxel demonstrated the increase in the efficacy against human cancer in animal model. Taken together, the novel formulated liposomes can incorporate high content of paclitaxel, remaining stable for long-term storage. These animal data also demonstrate that the liposomal paclitaxel is promising for further clinical use. PMID:21490755

Kan, Pei; Tsao, Chih-Wan; Wang, Ae-June; Su, Wu-Chou; Liang, Hsiang-Fa

2011-01-01

67

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).

68

Effectiveness of paclitaxel and carboplatin combination in heavily pretreated patients with head and neck cancers  

Microsoft Academic Search

A phase II study was conducted to evaluate the activity of paclitaxel and carboplatin in advanced head and neck cancer. Twenty-four patients with measurable locoregional squamous cell carcinoma and metastatic disease were entered. All had been heavily pretreated with radiotherapy, surgery and che- motherapy and were at second recurrence or disease progression when they entered the trial. Patients received Paclitaxel

G. P. Stathopoulos; S. Rigatos; P. Papakostas; G. Fountzilas

1997-01-01

69

Evaluation of biosafety and intracellular uptake of Cremophor EL free paclitaxel elastic liposomal formulation.  

PubMed

The present study examines the acute, sub-acute toxicity, and cytotoxicity of paclitaxel elastic liposomal formulation in comparison to a marketed Cremophor EL (polyoxyethylated castor oil):ethanol (1:1, v/v) based formulation. In the previous study, Cremophor EL free paclitaxel elastic liposomal formulation was developed and characterized. Cytotoxicity of formulation was evaluated by MTT assay using A549 cell lines. Percentage intracellular uptake of paclitaxel elastic liposomal and marketed formulation was determined using a fluorescence activating cell sorting assay (FACS) and fluorescence microscopy techniques. Single and repeated dose toxicity measurement showed no mortality, hematological, biochemical, or histopathological changes up to a dose of 120?mg/kg for paclitaxel elastic liposomal formulation, in comparison the marketed formulation showed toxicity at a dose of 40?mg/kg. Maximum tolerated dose (MTD) for paclitaxel elastic liposomal and marketed formulation was found to be 160?mg/kg and 40?mg/kg, respectively. Results of FACS analysis showed a 94.6?±?2.5% intracellular uptake of fluorescence marker acridine orange (AO) loaded in elastic liposomes; in comparison the AO solution showed only a 19.8?±?1.1% uptake. Paclitaxel elastic liposomal formulation seems to be a better alternative for safe and effective delivery of paclitaxel. This study proves the safety and higher intracellular uptake of paclitaxel elastic liposomal formulation. PMID:22074176

Utreja, Puneet; Jain, Subheet; Tiwary, A K

2012-01-01

70

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

71

First line treatment of advanced non-small-cell lung cancer – specific focus on albumin bound paclitaxel  

PubMed Central

Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC. PMID:24399877

Gupta, Neha; Hatoum, Hassan; Dy, Grace K

2014-01-01

72

Apoptosis induced by paclitaxel-loaded copolymer PLA–TPGS in Hep-G2 cells  

NASA Astrophysics Data System (ADS)

Paclitaxel is an important anticancer drug in clinical use for treatment of a variety of cancers. The clinical application of paclitaxel in cancer treatment is considerably limited due to its serious poor delivery characteristics. In this study paclitaxel-loaded copolymer poly(lactide)–d-?-tocopheryl polyethylene glycol 1000 succinate (PLA–TPGS) nanoparticles were prepared by a modified solvent extraction/evaporation technique. The characteristics of the nanoparticles, such as surface morphology, size distribution, zeta potential, solubility and apoptosis were investigated in vitro. The obtained spherical nanoparticles were negatively charged with a zeta potential of about ?18 mV with the size around 44 nm and a narrow size distribution. The ability of paclitaxel-loaded PLA–TPGS nanoparticles to induce apoptosis in human hepatocellular carcinoma cell line (Hep-G2) indicates the possibility of developing paclitaxel nanoparticles as a potential universal cancer chemotherapeutic agent.

Nguyen, Hoai Nam; Tran Thi, Hong Ha; Le Quang, Duong; Nguyen Thi, Toan; Tran Thi, Nhu Hang; Huong Le, Mai; Thu Ha, Phuong

2012-12-01

73

Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers.  

PubMed

A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6-140fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel. PMID:25466201

Gund, Machhindra; Khanna, Amit; Dubash, Nauzer; Damre, Anagha; Singh, Kishore S; Satyam, Apparao

2014-11-12

74

Anti-tumor efficacy of paclitaxel against human lung cancer xenografts.  

PubMed

We examined paclitaxel for anti-tumor activity against human lung cancer xenografts in nude mice and compared its efficacy with that of cisplatin, currently a key drug for lung cancer chemotherapy. Five non-small cell lung cancers (A549, NCI-H23, NCI-H226, NCI-H460 and NCI-H522) and 2 small cell lung cancers (DMS114 and DMS273) were chosen for this study, since these cell lines have been well characterized as regards in vitro and in vivo drug sensitivity. These cells were exposed to graded concentrations of paclitaxel (0.1 to 1000 nM) for 48 h. The 50% growth-inhibitory concentrations (GI50) for the cell lines ranged from 4 to 24 nM, which are much lower than the achievable peak plasma concentration of paclitaxel. In the in vivo study, 4 cell lines (A549, NCI-H23, NCI-H460, DMS-273) were grown as subcutaneous tumors xenografts in nude mice. Paclitaxel was given intravenously as consecutive daily injections for 5 days at the doses of 24 and 12 mg/kg/day. Against every xenograft, paclitaxel produced a statistically significant tumor growth inhibition compared to the saline control. Paclitaxel at 24 mg/kg/day was more effective than cisplatin at 3 mg/kg/day with the same dosing schedule as above, although the toxicity of paclitaxel was similar to or rather lower than that of cisplatin, in terms of body weight loss. In addition, paclitaxel showed potent activity against 2 other lung cancer xenografts (NCI-H226 and DMS114). Therefore, paclitaxel showed more effective, wider-spectrum anti-tumor activity than cisplatin in this panel of 6 lung cancer xenografts. These findings support the potential utility of paclitaxel in the treatment of human lung cancer. PMID:9473739

Yamori, T; Sato, S; Chikazawa, H; Kadota, T

1997-12-01

75

Pharmacokinetic drug interactions between apigenin, rutin and paclitaxel mediated by P-glycoprotein in rats.  

PubMed

The aim of present study was to investigate the effects of apigenin and rutin on the pharmacokinetics of paclitaxel after oral administration of paclitaxel with apigenin and rutin to rats. Paclitaxel (40 mg/kg) was administered orally alone and in combination with apigenin and rutin (10, 20, and 40 mg/kg) for 15 consecutive days. In the single-dose pharmacokinetic study (SDS), blood samples were collected on 1st day whereas on 15th day in the multiple-dose pharmacokinetic study (MDS). The plasma concentrations of paclitaxel were increased dose-dependently in the combination of apigenin and rutin compared to that of paclitaxel control in SDS and MDS (p < 0.01). The areas under the plasma concentration-time curve (AUC) and the plasma peak concentrations (C max) of paclitaxel with apigenin and rutin were significantly higher (p < 0.01) than that of the control. The AUCs and C max of paclitaxel were increased with apigenin and rutin in the dose-dependent manner. The half-life (t 1/2) was significantly longer than that of the control. Non-everted sacs were filled with paclitaxel 100 ?M in the presence and absence of verapamil (50 ?M), apigenin, and rutin (50, 100 ?M) and incubated at 37 ºC for 60 min. The absorption of paclitaxel was increased in the presence of apigenin, rutin, and verapamil, a typical P-glycoprotein and Cyp3A4 inhibitor. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with apigenin and rutin. PMID:24871039

Kumar, K Kishore; Priyanka, Leena; Gnananath, K; Babu, P Ravindra; Sujatha, S

2014-05-29

76

Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: disposition kinetics and pharmacology distinct from solvent-based paclitaxel.  

PubMed

The aim of this study was to characterize population pharmacokinetics and the exposure-neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80-375 mg/m(2). Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000 ?g/h) was 40-fold greater than that for saturable elimination (8070 ?g/h). Albumin was a significant covariate of paclitaxel elimination (P

Chen, Nianhang; Li, Yan; Ye, Ying; Palmisano, Maria; Chopra, Rajesh; Zhou, Simon

2014-10-01

77

Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: Disposition kinetics and pharmacology distinct from solvent-based paclitaxel  

PubMed Central

The aim of this study was to characterize population pharmacokinetics and the exposure–neutropenia relationship with nanoparticle albumin-bound (nab)-paclitaxel in patients with solid tumors. Plasma and blood concentrations of paclitaxel and neutrophil data were collected from 150 patients with various solid tumors over the nab-paclitaxel dose range of 80–375?mg/m2. Data were analyzed using nonlinear mixed-effect modeling or logistic regression. Pharmacokinetics of nab-paclitaxel were described by a 3-compartment model with saturable distribution and elimination. The rapid disappearance of circulating paclitaxel was driven by its fast distribution to peripheral compartments; maximum rate for saturable distribution (325000??g/h) was 40-fold greater than that for saturable elimination (8070??g/h). Albumin was a significant covariate of paclitaxel elimination (P?

Chen, Nianhang; Li, Yan; Ye, Ying; Palmisano, Maria; Chopra, Rajesh; Zhou, Simon

2014-01-01

78

Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer  

PubMed Central

Purpose To evaluate the efficacy and oral activity of two promising indoles, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1H-indol-5-ylamino)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound IAT], in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. Methods The in vitro drug-like properties, including potency, solubility, metabolic stability, and drug-drug interactions were examined for our two active compounds. An in vivo pharmacokinetic study and antitumor efficacy study were also completed to compare their efficacy with docetaxel. Results Both compounds bound to the colchicine-binding site on tubulin, and inhibited tubulin polymerization, resulting in highly potent cytotoxic activity in vitro. While the potency of paclitaxel and docetaxel was compromised in a multidrug-resistant cell line that overexpresses P-glycoprotein, the potency of compounds II and IATwas maintained. Both compounds had favorable drug-like properties, and acceptable oral bioavailability (21–50%) in mice, rats, and dogs. Tumor growth inhibition of greater than 100% was achieved when immunodeficient mice with rapidly growing paclitaxel-resistant prostate cancer cells were treated orally at doses of 3–30 mg/kg of II or IAT. Conclusions These studies highlight the potent and broad anticancer activity of two orally bioavailable compounds, offering significant pharmacologic advantage over existing drugs of this class for multidrug resistant or taxane-refractory cancers. PMID:22760659

Li, Chien-Ming; Lu, Yan; Chen, Jianjun; Costello, Terrence A.; Narayanan, Ramesh; Dalton, Mara N.; Snyder, Linda M.; Ahn, Sunjoo; Li, Wei; Miller, Duane D.; Dalton, James T.

2013-01-01

79

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

80

Bilateral facial nerve palsy secondary to the administration of high-dose paclitaxel.  

PubMed

Bilateral facial nerve palsy is an uncommon occurrence. We describe a case of bilateral facial nerve palsy secondary to a single cycle of high-dose paclitaxel therapy (825 mg/m2), in a woman with breast cancer. Prior to her high-dose therapy, she had a residual grade 2 peripheral neuropathy following treatment with ten cycles of standard-dose paclitaxel (total dose 3200 mg). The features of the peripheral neuropathy due to standard-dose paclitaxel, which can be both motor and sensory, are well described. Cumulative paclitaxel dose is considered a risk factor for development of the neuropathy. Although facial nerve palsy secondary to paclitaxel is not previously reported, other cranial nerve toxicity has been described. Consistent with reports of the reversibility of paclitaxel-induced peripheral neuropathy, the facial nerve palsies in our patient resolved over 23 months. Ongoing studies of high-dose paclitaxel warrant close attention to its cumulative neurotoxic effects, particularly in patients previously treated with neurotoxic chemotherapy. PMID:10586344

Lee, R T; Oster, M W; Balmaceda, C; Hesdorffer, C S; Vahdat, L T; Papadopoulos, K P

1999-10-01

81

Effects of goshajinkigan, hachimijiogan, and rokumigan on mechanical allodynia induced by Paclitaxel in mice.  

PubMed

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

2014-10-01

82

Paclitaxel Tumor-Priming Enhances siRNA Delivery and Transfection in 3-Dimensional Tumor Cultures  

PubMed Central

The clinical development of siRNA cancer therapeutics is limited by the poor interstitial transport and inefficient transfection in solid tumors. We have shown that paclitaxel pretreatment, by inducing apoptosis, causes expansion of the interstitial space and thereby improves nanoparticle delivery and transport in tumor interstitium (referred to as paclitaxel tumor priming) and efficacy of nanomedicines in tumor-bearing animals. The present study evaluated whether paclitaxel tumor priming improves the delivery and transfection of siRNA in 2- and 3-dimensional cultures of human oropharyngeal carcinoma FaDu cells. We used the fluorescent siGLO and confocal microcopy to monitor transport, and used survivin siRNA and immunostaining and immunoblotting to monitor transfection. Survivin is a chemoresistance gene/protein, inducible by chemotherapy. siRNA was loaded in cationic liposomes. The results showed that pretreatment with 50-200 nM paclitaxel (24 or 48 hr before siRNA) enhanced the total uptake of siGLO into monolayers (~15%, p<0.05), and the depth of penetration into 3-dimensional spheroids and tumor fragment histocultures (2.1- to 2.5-times greater area under the penetration-depth curve). In both monolayer cells and histocultures, paclitaxel pretreatment induced survivin upregulation (p<0.05). Survivin siRNA alone decreased the survivin levels in a dose-dependent manner and applying survivin siRNA after paclitaxel pretreatment completely abolished the paclitaxel-induced survivin increases. These findings indicate that paclitaxel tumor priming did not compromise the siRNA functionality. In summary, paclitaxel tumor priming improved the penetration, transfection and functionality of siRNA in tumors, thus offering a promising and practical means to develop chemo-siRNA cancer gene therapy. PMID:21417439

Wong, Ho Lun; Shen, Zancong; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

2011-01-01

83

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

84

Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature.  

PubMed

Cationic liposomes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Therefore, encapsulation of cytotoxic substances in cationic liposomes is a new approach to target tumor vasculature. It was the aim of our study to quantify the effects of paclitaxel encapsulated in cationic liposomes (MBT-0206) on tumor microvasculature and growth in vivo. Experiments were performed in the dorsal skinfold chamber preparation of Syrian Golden hamsters bearing syngeneic A-Mel-3 melanomas. Tumors were treated with intravenous infusion of MBT-0206 (20 mM) resulting in an effective paclitaxel dose of 5 mg/kg body weight (b.w.). Control animals received conventional paclitaxel in Cremophor EL (Taxol(R); 5 mg/kg b.w.), unloaded cationic liposomes (20 mM) or the solvent 5% glucose, respectively. Using intravital microscopy, tumor growth and effects on intratumoral microvasculature were analyzed. Tumor growth was significantly retarded after treatment with MBT-0206 compared to the treatment with paclitaxel. Analysis of intratumoral microcirculation revealed a reduced functional vessel density in tumors after application of liposomal paclitaxel. At the end of the observation time, vessel diameters were significantly smaller in animals treated with paclitaxel encapsulated in cationic liposomes while red blood cell velocity was less affected. This resulted in a significantly reduced blood flow in vessel segments and a reduced microcirculatory perfusion index in these animals. Histochemical TUNEL stain was vessel-associated after treatment with liposomal paclitaxel in contrast to few apoptotic tumor cells in the control groups. Our data demonstrate that encapsulation of paclitaxel in cationic liposomes significantly increased the antitumoral efficacy of the drug. Remarkable microcirculatory changes indicate that encapsulation of paclitaxel in cationic liposomes resulted in a mechanistic switch from tumor cell toxicity to an antivascular therapy. PMID:15054876

Strieth, Sebastian; Eichhorn, Martin E; Sauer, Birgitta; Schulze, Brita; Teifel, Michael; Michaelis, Uwe; Dellian, Marc

2004-05-20

85

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

86

Cytotoxic Effect of Paclitaxel Incorporated in Nanoparticles Based on Lactic and Glycolic Acid Copolymer  

Microsoft Academic Search

Paclitaxel dosage form on nanoparticles of 200–300 nm based on lactic and glycolic acid copolymer was obtained by the co-precipitation\\u000a method. The possibility of controlled release of paclitaxel at pH 7.4 for 24 h was studied in vitro. Studies on Jurkat\\/WT human T-lymphoblastic leukemia cells showed that incorporation of paclitaxel in the nanoparticles led\\u000a to a 4-fold increase of its cytotoxicity (6.8?×?10?6 M)

V. Bojat; D. S. Baranov; E. A. Oganesyan; Y. M. Hamdy; V. Yu. Balaban’yan; R. N. Alyautdin

2011-01-01

87

Nanoparticle Albumin Bound Paclitaxel in the Treatment of Human Cancer: Nanodelivery Reaches Prime-Time?  

PubMed Central

Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. PMID:23738077

Cucinotto, Iole; Fiorillo, Lucia; Gualtieri, Simona; Arbitrio, Mariamena; Ciliberto, Domenico; Staropoli, Nicoletta; Grimaldi, Anna; Luce, Amalia; Tassone, Pierfrancesco; Caraglia, Michele; Tagliaferri, Pierosandro

2013-01-01

88

Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery  

PubMed Central

A polymer ultrasound contrast agent (UCA) developed in our lab has been shown to greatly reduce in size when exposed to ultrasound, resulting in nanoparticles less than 400 nm in diameter capable of escaping the leaky vasculature of a tumor to provide a sustained release of drug. Previous studies with the hydrophilic drug doxorubicin (DOX) demonstrated enhanced drug delivery to tumors when triggered with ultrasound. However the therapeutic potential has been limited due to the relatively low payload of DOX. This study compares the effects of loading the hydrophobic drug paclitaxel (PTX) on the agent’s acoustic properties, drug payload, tumoricidal activity, and the ability to deliver drugs through 400 nm pores. A maximum payload of 129.46 ± 1.80 ?g PTX/mg UCA (encapsulation efficiency 71.92 ± 0.99 %) was achieved, 20 times greater than the maximum payload of DOX (6.2 ?g/mg), while maintaining the acoustic properties. In vitro, the tumoricidal activity of paclitaxel loaded UCA exposed to ultrasound was significantly greater than controls not exposed to ultrasound (p<0.0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors. PMID:21609756

Cochran, Michael C.; Eisenbrey, John; Ouma, Richard O.; Soulen, Michael; Wheatley, Margaret A.

2011-01-01

89

CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.  

PubMed

Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3×8mg/kg, cumulative dose 24mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. PMID:24681252

Huang, Zhen-Zhen; Li, Dai; Liu, Cui-Cui; Cui, Yu; Zhu, He-Quan; Zhang, Wen-Wen; Li, Yong-Yong; Xin, Wen-Jun

2014-08-01

90

Paclitaxel and carboplatin chemotherapy administered during pregnancy for advanced epithelial ovarian cancer  

Microsoft Academic Search

BackgroundOvarian cancer diagnosed during pregnancy is uncommon. Most chemotherapy use reported has been in combination with cisplatinum. Paclitaxel in combination with carboplatin during pregnancy has not yet been reported.

Luis E Méndez; Antoaneta Mueller; Emery Salom; Víctor Hugo González-Quintero

2003-01-01

91

Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure  

PubMed Central

AIMS To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure. METHODS The concentration of rosiglitazone at 3 h and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects. RESULTS Rosiglitazone concentration was significantly correlated with paclitaxel exposure (P = 0.018) while ERMBT had no predictive value (P = 0.47). CONCLUSIONS The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity. PMID:22680343

Hertz, Daniel L; Walko, Christine M; Bridges, Arlene S; Hull, J Heyward; Herendeen, Jill; Rollins, Kristan; Watkins, Paul B; Dees, E Claire

2012-01-01

92

A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer.  

PubMed Central

The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate. PMID:9461009

Smit, E. F.; Fokkema, E.; Biesma, B.; Groen, H. J.; Snoek, W.; Postmus, P. E.

1998-01-01

93

A case of relapsed visceral Kaposi's sarcoma with bilateral chylothoraces successfully treated with paclitaxel.  

PubMed

Chylothorax is a rare complication of visceral Kaposi's sarcoma. We report a case with bilateral chylothoraces secondary to relapsed visceral Kaposi's sarcoma who was successfully treated with paclitaxel chemotherapy. PMID:25122577

Natarajan, Pavithra; Miller, Alastair

2014-08-13

94

Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy  

NASA Astrophysics Data System (ADS)

Effective anticancer therapy can be achieved by designing a targeted drug-delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug-delivery system, formed by multivalent host-guest interactions between a polymer-cyclodextrin conjugate and a polymer-paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery.

Namgung, Ran; Mi Lee, Yeong; Kim, Jihoon; Jang, Yuna; Lee, Byung-Heon; Kim, In-San; Sokkar, Pandian; Rhee, Young Min; Hoffman, Allan S.; Kim, Won Jong

2014-05-01

95

Effects of Paclitaxel in Combinationwith Ionizing Radiation on Angiogenesis in the Chick EmbryoChorioallantoic Membrane  

Microsoft Academic Search

Purpose: To investigate the combined effects of paclitaxel and single or fractionated doses of ionizing radiation on the angiogenesis process, using as a model the chick embryo choriallantoic membrane (CAM). Material and Methods: Experiments were performed on 9-day CAM, when membranes were irradiated with various single or fractionated doses of X-rays, either alone or in combination with paclitaxel (6.4 µg\\/disk).

Dimitrios Kardamakis; Christos Hadjimichael; Panagiotis Ginopoulos; Stamatis Papaioannou

2004-01-01

96

Bcl-2 down-regulation is a novel mechanism of paclitaxel resistance.  

PubMed

Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of deltapsim after stimulation of the respiratory state. To evaluate the binding of [14C]paclitaxel to isolated mitochondria, mitochondrial proteins were precipitated yielding 18.6 +/- 2.1 cpm/microg of protein. After stimulation of the respiratory state, binding of [14C]paclitaxel increased up to 163.2 +/- 46.7 cpm/microg of protein. CPM values after Bcl-2 immunoprecipitation was 62.8-fold higher than those of the control antibody, thereby indicating the involvement of Bcl-2 in paclitaxel binding. Then, we established a panel of A2780 cell lines resistant to increasing doses of paclitaxel alone or to high doses of paclitaxel/cyclosporin A (A2780 TC cells). In both cases, Bcl-2 expression was consistently down-regulated, whereas levels of other members of the Bcl-2 family, such as Bax and Bcl-x, did not change in paclitaxel-resistant cell lines. When A2780TC cells were stably transfected with a Bcl-2 construct, paclitaxel sensitivity was partially restored, thereby supporting a direct role of Bcl-2 down-regulation in the maintenance of drug-resistance. Finally, we examined Bcl-2 by immunohistochemistry in a small subset of ovarian cancer paclitaxel-resistant patients and we noticed that the protein is down-regulated in this clinical setting with respect to the expression levels found in drug-sensitive tumors. These findings demonstrate that Bcl-2 is an additional intracellular target of taxanes and that its down-regulation is involved in taxane resistance. PMID:12815160

Ferlini, Cristiano; Raspaglio, Giuseppina; Mozzetti, Simona; Distefano, Mariagrazia; Filippetti, Flavia; Martinelli, Enrica; Ferrandina, Gabriella; Gallo, Daniela; Ranelletti, Franco Oreste; Scambia, Giovanni

2003-07-01

97

Adjuvant paclitaxel and carboplatin chemotherapy with involved field radiation in advanced endometrial cancer: A sequential approach  

Microsoft Academic Search

Purpose: To determine the feasibility of adjuvant paclitaxel and carboplatin chemotherapy interposed with involved field radiotherapy for women with advanced endometrial cancer. Methods and Materials: This was a prospective cohort study of women with Stage III and IV endometrial cancer. Adjuvant therapy consisted of 4 cycles of paclitaxel (175 mg\\/m²) and carboplatin (350 mg\\/m²) every 3 weeks, followed sequentially by

Krystine Lupe; Janice. Kwon; David D’Souza; Christine Gawlik; Larry Stitt; Frances Whiston; Patricia Nascu; Eugene Wong; Mark S. Carey

2007-01-01

98

Expanded phase II trial of paclitaxel in metastatic breast cancer: A Southwest Oncology Group study  

Microsoft Academic Search

Background. The study was designed to evaluate the efficacy of paclitaxel in metastatic breast cancer patients. The design was motivated by a report from FDA and NCI staff proposing assessment of pre- and post-treatment symptoms as a means of evaluating treatment effectiveness [1]. Methods. Patients with symptomatic and\\/or measurable metastatic breast cancer with prior treatment received paclitaxel 210 mg\\/m2 as

Charles E. Geyer; Stephanie J. Green; Carol M. Moinpour; Janet O'Sullivan; Donna K. Goodwin; Vikki A. Canfield; Frederick J. Meyers; C. Kent Osborne; Silvana Martino

1998-01-01

99

Development of Lipid-Based Nanoparticles for Enhancing the Oral Bioavailability of Paclitaxel  

Microsoft Academic Search

The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability\\u000a of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as\\u000a lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution,\\u000a surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability

Deepti Pandita; Alka Ahuja; Viney Lather; Biju Benjamin; Tathagata Dutta; Thirumurthy Velpandian; Roop Krishen Khar

2011-01-01

100

Involvement of substance P in peripheral neuropathy induced by paclitaxel but not oxaliplatin.  

PubMed

The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. In von Frey and acetone tests in rats repeated administration of paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both mechanical allodynia and cold hyperalgesia. Paclitaxel-induced peripheral neuropathy was reversed primarily by the acute administration of pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 ?g/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-indole (GR159897), 100 ?g/body i.t.] strongly reversed paclitaxel-induced neuropathy. On the other hand, oxaliplatin-induced peripheral neuropathy was not reversed by pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin. PMID:21233199

Tatsushima, Yoko; Egashira, Nobuaki; Kawashiri, Takehiro; Mihara, Yuki; Yano, Takahisa; Mishima, Kazuto; Oishi, Ryozo

2011-04-01

101

A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer  

PubMed Central

To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160?mg+CsA 700?mg on day 1, followed by oral paclitaxel (Taxol®) 160?mg+CsA 700?mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol®) 160?mg as 3-h infusion on day 15. The median (range) area under the plasma concentration–time curve of paclitaxel was 2.06 (1.15–3.47)??g?h?ml?1 and 1.97 (0.58–3.22)??g?h?ml?1 after oral administration of SMEOF#3 and Taxol®, respectively, and 4.69 (3.90–6.09)??g?h?ml?1 after intravenous Taxol®. Oral SMEOF#3 resulted in a lower median Tmax of 2.0 (0.5–2.0)?h than orally applied Taxol® (Tmax=4.0 (0.8–6.1)?h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19–83)% and 55 (9–70)% for the oral SMEOF#3 and oral Taxol® formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol® was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower Tmax than orally applied Taxol®, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel. PMID:16926835

Veltkamp, S A; Thijssen, B; Garrigue, J S; Lambert, G; Lallemand, F; Binlich, F; Huitema, A D R; Nuijen, B; Nol, A; Beijnen, J H; Schellens, J H M

2006-01-01

102

Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System  

PubMed Central

Background Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models. Methods To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2+/+ and CB2–/– mice. We hypothesize that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. Results We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel's antineoplastic effect. MDA7's neuroprotective effect was absent in CB2-/- mice and was blocked by CB2 antagonists, suggesting that MDA7's action directly involves CB2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced Toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. Conclusions Our findings suggest an innovative therapeutic approach to prevent chemotherapy-induced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae. PMID:22392969

Naguib, Mohamed; Xu, Jijun J.; Diaz, Philippe; Brown, David L.; Cogdell, David; Bie, Bihua; Hu, Jianhua; Craig, Suzanne; Hittelman, Walter N.

2012-01-01

103

Rapid and sensitive determination of paclitaxel in mouse plasma by high-performance liquid chromatography  

Microsoft Academic Search

This report describes a rapid, simple and sensitive isocratic high-performance liquid chromatography with diode array UV detection for micro-sample analysis of paclitaxel in mouse plasma. The analysis utilized a Capcell-pak octadecyl analytical column and a mobile phase consisting of acetonitrile–0.1% phosphoric acid in deionized water (55:45, v\\/v). Paclitaxel and n-hexyl p-hydroxybenzoic acid (internal standard) were extracted from plasma by one-step

Sang-Heon Lee; Sun D Yoo; Kyu-Hyun Lee

1999-01-01

104

Synergy of a Herpes OncolyticVirus and Paclitaxel for Anaplastic Thyroid Cancer  

PubMed Central

Purpose Novel therapeutic regimens are needed to improve the dismal outcomes of patients with anaplastic thyroid cancer (ATC). Oncolytic herpes simplex virus have shown promising activity against human ATC. We studied the application of oncolytic herpes simplex virus (G207 and NV1023) in combination with currently used chemotherapeutic drugs (paclitaxel and doxorubicin) for the treatment of ATC. Experimental Design and Results All four agents showed dose-response cytotoxicity in vitro for the human ATC cell lines KAT4 and DRO90-1. G207, combined with paclitaxel, showed synergistic cytotoxicity. Chou-Talalay combination indices ranged from 0.56 to 0.66 for KAT4, and 0.68 to 0.74 for DRO90-1at higher affected fractions. Paclitaxel did not enhance G207 viral entry and early gene expression or G207 viral replication. Paclitaxel combined with G207 compared with single-agent treatment or controls showed significantly increased microtubule acetylation, mitotic arrest, aberrant chromatid separation, inhibition of metaphase to anaphase progression, and apoptosis. A single i.t. injection of G207 combined with biweekly i.p. paclitaxel injections in athymic nude mice bearing KAT4 flank tumors showed significantly reduced mean tumor volume (74 F 38 mm3) compared with G207 alone (388 F 109 mm3), paclitaxel alone (439 F 137 mm3), and control (520 F 160 mm3) groups at 16 days. There was no morbidity in vivo attributable to therapy. Conclusions Mechanisms of paclitaxel antitumoral activity, including microtubule acetylation, mitotic block, and apoptosis, were enhanced by G207, which also has direct oncolytic effects. Combination of G207 and paclitaxel therapy is synergistic in treating ATC and holds promise for patients with this fatal disease. PMID:18316577

Lin, Shu-Fu; Gao, Sizhi Paul; Price, Daniel L.; Li, Sen; Chou, Ting-Chao; Singh, Paramjeet; Huang, Yu-Yao; Fong, Yuman; Wong, Richard J.

2009-01-01

105

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 Central

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

106

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

107

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

108

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

109

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

110

The Burgeoning Role of Paclitaxel in Advanced Pulmonary Malignancy.  

PubMed

Historically, the treatment of advanced non-small cell lung cancer (NSCLC) with cisplatin-based therapy has been a nearly futile effort. Median survival was seldom greater than six months, and fewer than 20% of those with metastatic NSCLC survived more than one year. In addition, toxicity often equaled, if not exceeded, benefit. Over the past five years, however, we have witnessed an explosion of new agents in advanced lung carcinoma. These new agents-in particular the taxanes, gemcitabine, vinorelbine, and topoisomerase I inhibitors-have breathed new life into clinical research. The therapeutic gains, though modest, are real. Paclitaxel, to a large extent, given either alone or in combination with platinols, has led the charge. PMID:10388088

Langer; Ettinger

1998-01-01

111

Late coronary thrombosis in paclitaxel-eluting stents. Case reports.  

PubMed

Drug-eluting stent (DES) implantation has reduced angiographic and clinical restenosis that actually develops in less than 10% of treated patients. DESs also tend to delay the endothelialisation process increasing the risk of stent thrombosis. Subacute stent thrombosis may complicate long-term success of coronary angioplasty; it is a sudden event and usually causes acute myocardial infarction or sudden cardiac death. Patients undergoing DES implantation should be treated with dual antiplatelet therapy for at least 3-6 months. We describe two cases presenting with ST-elevation acute myocardial infarction due to stent thrombosis that occurred late after deployment of a paclitaxel-eluting stent, after discontinuation of antiplatelet therapy. It is important, for clinical cardiologists and general practitioners, to know the potential risk of late thrombosis of DES patients and, consequently, the implications regarding management of antiplatelet therapy. PMID:17413307

Cassin, Matteo; De Biasio, Marzia; Macor, Franco; Burelli, Claudio; Vendrametto, Fauzia; Driussi, Mauro; Nicolosi, Gian Luigi

2007-04-01

112

Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.  

PubMed

Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed. PMID:24810040

Kusari, Souvik; Singh, Satpal; Jayabaskaran, Chelliah

2014-06-01

113

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

114

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

115

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her2 positive advanced breast cancer  

Microsoft Academic Search

Background  A randomized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment\\u000a of patients with advanced breast cancer overexpressing HER-2.\\u000a \\u000a \\u000a \\u000a Patients and methods  Among 124 patients randomized, 123 are assessable for toxicity and 118 for response. Patients received weekly paclitaxel single\\u000a agent (80 mg\\/m2) or combined with trastuzumab (4 mg\\/kg loading dose, then weekly 2 mg\\/kg). HER-2 overexpression

Giampietro Gasparini; Massimo Gion; Luigi Mariani; Paola Papaldo; Diana Crivellari; Gianfranco Filippelli; Alessandro Morabito; Vittorio Silingardi; Francesco Torino; Antonella Spada; Matelda Zancan; Livia De Sio; Antonio Caputo; Francesco Cognetti; Antonio Lambiase; Dino Amadori

2007-01-01

116

Paclitaxel and concurrent radiation therapy for locally advanced adenocarcinomas of the pancreas, stomach, and gastroesophageal junction.  

PubMed

An effective locoregional therapy is needed for adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) may enhance the effect of radiation therapy (RT). Paclitaxel synchronizes cells at G2/M, a relatively radiosensitive phase of the cell cycle. We have shown that response to paclitaxel and concurrent RT (paclitaxel/RT) was not affected by p53 mutations in non-small cell lung cancer. This finding suggested that paclitaxel/RT was a rational treatment approach for other malignancies that frequently harbor p53 mutations, such as upper gastrointestinal malignancies. We completed a phase I study of paclitaxel/RT for locally advanced pancreatic and gastric cancer. The maximum tolerated dose of paclitaxel was 50 mg/m2/wk for 6 weeks with abdominal RT. The dose-limiting toxicities were abdominal pain within the radiation field, nausea, and anorexia. Phase II studies are now under way. Twenty-five patients with locally advanced pancreatic cancer have been entered at the phase II dose level of paclitaxel 50 mg/m2/wk with concurrent RT (total dose, 50 Gy). Thus far, the only grade 3/4 toxicities have been hypersensitivity reactions (n = 2), asymptomatic grade 4 neutropenia (n = 3), and nonneutropenic biliary sepsis (n = 1). Of the first 18 assessable patients with pancreatic cancer treated on the phase II study, six obtained a partial response, for a preliminary response rate of 33%. In the phase II study for locally advanced gastric cancer, 20 patients have been enrolled. Of the first 19 patients who have completed treatment, nine (47%) had grade 3/4 toxicities, including nausea, anorexia, esophagitis, and gastritis. Of the first 16 patients with gastric cancer, complete and partial responses have been observed in one and eight patients, respectively, for a preliminary response rate of 56%. We have also completed treatment on 24 patients with potentially resectable adenocarcinomas of the gastroesophageal junction with neoadjuvant paclitaxel 60 mg/m2 and cisplatin 25 mg/m2, weekly for 4 weeks, with concurrent RT (total dose, 40 Gy) followed by surgical resection. Ten patients (41%) had grade 3/4 toxicities, including neutropenia, nausea, and dehydration. Of 24 patients, four complete responses (17%) and 14 partial responses (58%) were observed, for an overall response rate of 75%. Severe esophagitis was uncommon, making this a well-tolerated outpatient regimen for adenocarcinomas of the distal esophagus. These findings demonstrate that paclitaxel-based chemoradiation for locally advanced upper gastrointestinal malignancies is well-tolerated with substantial activity. PMID:10210540

Safran, H; Akerman, P; Cioffi, W; Gaissert, H; Joseph, P; King, T; Hesketh, P J; Wanebo, H

1999-04-01

117

A novel biosensor for quantitative monitoring of on-target activity of paclitaxel  

NASA Astrophysics Data System (ADS)

This study describes a system for quantifying paclitaxel activity using the C-terminus of ?-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of ?-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of ?-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle.This study describes a system for quantifying paclitaxel activity using the C-terminus of ?-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of ?-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of ?-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr01105h

Townley, H. E.; Zheng, Y.; Goldsmith, J.; Zheng, Y. Y.; Stratford, M. R. L.; Dobson, P. J.; Ahmed, A. A.

2014-12-01

118

The enhanced longevity and liver targetability of Paclitaxel by hybrid liposomes encapsulating Paclitaxel-conjugated gold nanoparticles.  

PubMed

Organic and inorganic drug delivery systems both demonstrate their own advantages and challenges in practical applications. Combining these two drug delivery strategies in one system is expected to solve their current issues and achieve desirable functions. In this paper, gold nanoparticles (GNPs) and liposomes have been chosen as the model systems to construct a hybrid system and investigate its performance for the tumor therapy of Paclitaxel (PTX). The thiol-terminated polyethylene glycol (PEG400)-PTX derivative has been covalently modified on the surface of GNPs, followed by the encapsulation of PTX-conjugated GNPs (PTX-PEG400@GNPs) in liposomes. The hybrid liposomes solve the solubility and stability problems of gold conjugates and show high drug loading capacity. In vitro PTX release from the hybrid system maintains the similar sustained behavior demonstrated in its conjugates. Under the protection of a biocompatible liposome shell, encapsulated PTX shows enhanced circulation longevity and liver targetability compared to Taxol(®) and PTX-PEG400@GNPs suspension in the pharmacokinetic and biodistribution studies. These indicate that encapsulating drug-conjugated inorganic nanoparticles inside organic carriers maintains the superiority of both vehicles and improves the performance of hybrid systems. Although these attributes of hybrid liposomes lead to a better therapeutic capacity in a murine liver cancer model than that of the comparison groups, it shows no significant difference from Taxol(®) and conjugate suspension. This result could be due to the delayed and sustained drug release from the system. However, it indicates the promising potential for these hybrid liposomes will allow further construction of a compound preparation with improved performance that is based on their enhanced longevity and liver targetability of Paclitaxel. PMID:25455782

Bao, Quan-Ying; Zhang, Ning; Geng, Dong-Dong; Xue, Jing-Wei; Merritt, Mackenzie; Zhang, Can; Ding, Ya

2014-12-30

119

Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients  

PubMed Central

Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m2 in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m2 as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration–time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 ± 1.67 ?M.h. In our previously performed study of 120 mg/m2 oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 ± 2.29 ?M.h. After i.v. administration of paclitaxel the mean AUC was 15.92?± 2.46 ?M.h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139311

Malingré, M M; Beijnen, J H; Rosing, H; Koopman, F J; Jewell, R C; Paul, E M; Huinink, W W Ten Bokkel; Schellens, J H M

2001-01-01

120

Gene and microRNA expression reveals sensitivity to paclitaxel in laryngeal cancer cell line.  

PubMed

Paclitaxel is a widely used chemotherapy drug for advanced laryngeal cancer patients. However, the fact that there are 20-40% of advanced laryngeal cancer patients do not response to paclitaxel makes it necessary to figure out potential biomarkers for paclitaxel sensitivity prediction. In this work, Hep2, a laryngeal cancer cell line, untreated or treated with lower dose of paclitaxel for 24 h, was applied to DNA microarray chips for gene and miR expression profile analysis. Expression of eight genes altered significantly following paclitaxel treatment, which was further validated by quantitative real-time PCR. Four up-regulated genes were ID2, BMP4, CCL4 and ACTG2, in which ID2 and BMP4 were implicated to be involved in several drugs sensitivity. While the down-regulated four genes, MAPK4, FASN, INSIG1 and SCD, were mainly linked to the endoplasmic reticulum and fatty acid biosynthesis, these two cell processes that are associated with drug sensitivity by increasing evidences. After paclitaxel treatment, expression of 49 miRs was significantly altered. Within these miRs, the most markedly expression-changed were miR-31-star, miR-1264, miR-3150b-5p and miR-210. While the miRs putatively modulated the mRNA expression of the most significantly expression-altered genes were miR-1264, miR-130a, miR-27b, miR-195, miR-1291, miR-214, miR-1277 and miR-1265, which were obtained by miR target prediction and miRNA target correlation. Collectively, our study might provide potential biomarkers for paclitaxel sensitivity prediction and drug resistance targets in laryngeal cancer patients. PMID:23826416

Xu, Cheng-Zhi; Xie, Jin; Jin, Bin; Chen, Xin-Wei; Sun, Zhen-Feng; Wang, Bao-Xing; Dong, Pin

2013-01-01

121

Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation.  

PubMed

Paclitaxel is indispensable in treating human cancers. Due to poor drug solubility and efflux systems in the gastrointestinal tract, peroral delivery of paclitaxel has been a significant challenge. We developed a mucoadhesive oral formulation (DHP107) that can directly and effectively deliver paclitaxel to intestinal endothelial cells without concomitant use of P-glycoprotein inhibitors. Here, we evaluated the tissue distribution of paclitaxel, the antitumor efficacy and the absorption mechanism of DHP107. DHP107, which contains 10 mg/mL of paclitaxel in a mixture of monoolein, tricarprylin, and Tween 80 was administered p.o. to female BALB/c mice at a 50 mg/kg dose. Diluted Taxol was administered via bolus tail-vein injection at 10 mg/kg as a control. Blood and tissue samples were harvested at various time points and analyzed by high-performance liquid chromatography. Tissue sections were observed using light microscopy after immunohistochemical and Oil Red O staining. By day 27, tumor volume after DHP107 and Taxol treatments was one-third of that in the untreated group. After p.o. administration, paclitaxel was widely distributed in various organs (T(max) = 2 h), especially liver, spleen, and lung. DHP107 was effectively absorbed through the intestinal lipid transport system. DHP107 changed spontaneously into <100-mum droplets and micelles in the intestine, which in turn adhered to mucoepithelial cells, were absorbed via lipid uptake mechanism, and formed lipid bodies in the epithelium. Paclitaxel in DHP107 was effectively absorbed through the gastrointestinal tract via lipid uptake mechanism and was distributed in various tissues. The detailed uptake mechanism is currently under investigation. PMID:18089717

Hong, Jung Wan; Lee, In-Hyun; Kwak, Young Hak; Park, Young Taek; Sung, Ha Chin; Kwon, Ick Chan; Chung, Hesson

2007-12-01

122

Thermosensitive and mucoadhesive sol-gel composites of paclitaxel/dimethyl-?-cyclodextrin for buccal delivery.  

PubMed

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

Choi, Soon Gil; Lee, Sang-Eun; Kang, Bong-Seok; Ng, Choon Lian; Davaa, Enkhzaya; Park, Jeong-Sook

2014-01-01

123

Weekly Paclitaxel in the Treatment of Advanced or Metastatic Breast Cancer Previously Treated or Not Treated with Docetaxel: A Phase II Study  

Microsoft Academic Search

Background: Paclitaxel has been approved for 3-weekly administration in Japan. Recent reports suggest that weekly paclitaxel can achieve a higher tumor response and lower toxicity. Methods: This study was designed to investigate the usefulness and tolerability of weekly paclitaxel by 1-hour infusion in patients with metastatic breast cancer who were previously treated with docetaxel or other anticancer agents. Results: Thirty-five

Reiki Nishimura; Takahiro Ogawa; Masato Kato; Maki Tanaka; Yuzo Hamada; Takao Shibata; Emi Ishikawa; Toshihiro Koga; Shoshu Mitsuyama; Kazuo Tamura

2005-01-01

124

The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.  

PubMed

Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 ?M), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter. PMID:25402202

Kathawala, Rishil J; Wei, Liuya; Anreddy, Nagaraju; Chen, Kang; Patel, Atish; Alqahtani, Saeed; Zhang, Yun-Kai; Wang, Yi-Jun; Sodani, Kamlesh; Kaddoumi, Amal; Ashby, Charles R; Chen, Zhe-Sheng

2015-01-01

125

Spinal CCL2 and microglial activation are involved in paclitaxel-evoked cold hyperalgesia.  

PubMed

The antineoplastic paclitaxel induces a sensory neuropathy that involves the spinal release of neuroinflammatory mediators and activation of glial cells. Although the chemokine CCL2 can evoke glial activation and its participation in neuropathic pain has been demonstrated in other models, its involvement in paclitaxel-evoked neuropathy has not been previously explored. Paclitaxel-evoked cold hypernociception was assessed in mice by the unilateral cold plate test and the effects on cold hyperalgesia of the CCR2 antagonist RS 504393, the CCR1 antagonist J113863, the microglial inhibitor minocycline or an anti-CCL2 antibody were tested. Furthermore, ELISA measurements of CCL2 concentration and immunohistochemical assays of Iba-1 and GFAP, markers of microglial and astroglial cells respectively, were performed in the lumbar spinal cord. Cold hypernociception measured 3 days after the administration of paclitaxel (10mg/kg) was inhibited by the s.c. (0.3-3mg/kg) or i.t. (1-10 ?g) administration of RS 504393 but not of J113863 (3-30 mg/kg). CCL2 levels measured by ELISA in the lumbar spinal cord were augmented in mice treated with paclitaxel and the i.t. administration of an anti-CCL2 antibody completely suppressed paclitaxel-evoked cold hyperalgesia, strongly suggesting that CCL2 is involved in the hypernociception evoked by this taxane. Besides, the implication of microglial activation is supported by the increase in the immunolabelling of Iba-1, but not GFAP, in the spinal cord of paclitaxel-treated mice and by the inhibition of cold hyperalgesia produced by the i.t. administration of the microglial inhibitor minocycline (1-10 nmol). Finally, the neutralization of spinal CCL2 by the i.t. administration of a selective antibody for 3 days almost totally inhibited paclitaxel-evoked microglial activation. In conclusion, our results indicate that paclitaxel-evoked cold hypernociception depends on the activation of CCR2 due to the spinal release of CCL2 and the subsequent microglial activation. PMID:23562605

Pevida, Marta; Lastra, Ana; Hidalgo, Agustín; Baamonde, Ana; Menéndez, Luis

2013-06-01

126

The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance.  

PubMed

A prominent mechanism of drug resistance to taxanes is the overexpression of class III beta-tubulin. The seco-taxane IDN5390 was chosen for its selective activity in paclitaxel-resistant cells with an overexpression of class III beta-tubulin. Moreover, the combined treatment paclitaxel/IDN5390 yielded a strong synergism, which was also evident in cell-free tubulin polymerization assays. In the presence of an anti-class III beta-tubulin as a blocking antibody, tubulin polymerization induced by paclitaxel and IDN5390 was enhanced and not affected, respectively, whereas synergism was abolished, thereby indicating that IDN5390 activity is not modulated by class III beta-tubulin levels. Such properties can be explained by taking into consideration the composition of class III beta-tubulin paclitaxel binding site; in fact, Ser277 interacting with paclitaxel C group in class I is replaced by an Arginine in class III. IDN5390 that has an open and flexible C ring and an acidic alpha-unsaturated enol-keton moiety better fits with class III beta-tubulin than paclitaxel at the binding site. Taking altogether, these findings indicate that the concomitant treatment IDN5390/paclitaxel is able to successfully target class I and III beta-tubulin and the combined use of two taxanes with diverse spectrum activity against tubulin isotypes could represent a novel approach to overcome paclitaxel resistance. PMID:15781655

Ferlini, Cristiano; Raspaglio, Giuseppina; Mozzetti, Simona; Cicchillitti, Lucia; Filippetti, Flavia; Gallo, Daniela; Fattorusso, Caterina; Campiani, Giuseppe; Scambia, Giovanni

2005-03-15

127

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

128

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

129

Predictive value of serum interleukin-8 levels in ovarian cancer patients treated with paclitaxel-containing regimens.  

PubMed

Previous findings showed that paclitaxel induces interleukin-8 (IL-8) transcription and secretion in ovarian cancer cells in vitro. We hypothesized that paclitaxel treatment, which is a standard care for ovarian cancer patients, may increase the secretion of IL-8, resulting in the elevated serum IL-8 levels. In this study, we investigated the relationship between paclitaxel exposure and IL-8 levels of an ovarian and a breast carcinoma cell line in vitro and serums of patients with ovarian carcinoma. Both MDAH 2774 ovarian and MCF-7 breast carcinoma cell lines were sensitive to paclitaxel-mediated cytotoxicity. However, supernatant levels of IL-8 assessed by enzyme-linked immunosorbent assay before and after treatment with different concentrations of paclitaxel were significantly lower in MCF-7 than in MDAH 2774. Serum IL-8 levels were measured in serum samples from patients with ovarian carcinoma before and after paclitaxel-containing treatment regimens. Forty-eight patients were included in the study. The basal level of IL-8 after paclitaxel-containing treatment was found to be significantly higher in the serums of patients who had high tumor burden than in patients who had optimal debulking surgery and low tumor burden. These data strongly suggest that IL-8 may be an important predictive marker for tumor volume as well as sensitivity to paclitaxel. PMID:15823106

Uslu, R; Sanli, U A; Dikmen, Y; Karabulut, B; Ozsaran, A; Sezgin, C; Muezzinoglu, G G; Omay, S B; Goker, E

2005-01-01

130

Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel  

PubMed Central

Berberine is the major constituent of Coptis chinese and is commonly used in Chinese herbal medicine to treat patients with gastrointestinal disorders. In this study, using flow cytometry, we have found that a 24-h berberine treatment up-regulated the multidrug-resistant transporter (pgp-170) expression in two oral (KB, OC2), two gastric (SC-M1, NUGC-3) and two colon (COLO 205, CT 26) cancer cell lines. Decreased retention of rhodamine 123 was observed in berberine-treated cells as compared to vehicle control. To examine whether the berberine modulated pgp-170 expression in cancer cells is associated with changes in drug resistance, we determined the cytotoxicity, cell cycle progression and cell morphology of Paclitaxel-treated cells. Paclitaxel (1 nM–10 ?M) treatment for 24 h induced cytotoxicity in OC2, SC-M1 and COLO 205 cells in a dose-dependent manner. Pretreatment of cells with 32 ?M berberine for 24 h prior to Paclitaxel treatment resulted in increased viability as compared to that of Paclitaxel-treated cells. In addition, Paclitaxel-induced apoptosis and/or G2/M arrest in these three cancer cell lines. Pretreatment of cells with berberine prior to Paclitaxel blocked the Paclitaxel-induced cell cycle responses and morphological changes. These results together suggest that berberine modulated the expression and function of pgp-170 that leads to reduced response to Paclitaxel in digestive track cancer cells. © 1999 Cancer Research Campaign PMID:10507765

Lin, H-L; Liu, T-Y; Wu, C-W; Chi, C-W

1999-01-01

131

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

132

Acetaminophen Enhances Cisplatin- and Paclitaxel-mediated Cytotoxicity to SKOV3 Human Ovarian Carcinoma  

PubMed Central

Background Ovarian cancer is commonly treated with cisplatin/paclitaxel but many tumors become resistant. Acetaminophen reduced glutathione and enhanced chemotherapy efficacy in treating hepatic cancer. The objective of this study was to examine if acetaminophen enhances the cytotoxicity of cisplatin/paclitaxel in ovarian cancer. Materials and Methods SKOV3 human ovarian carcinoma cells in vitro and a subcutaneous tumor nude rat model were used and treated with cisplatin/paclitaxel with or without acetaminophen. Results In vitro, acetaminophen enhanced apoptosis induced by cisplatin and paclitaxel with similar effects on glutathione, reactive oxygen species and mitochondrial membrane potential but different effects on nuclear factor erythroid 2-related factor 2 (NRF2) translocation. In vivo, acetaminophen was uniformly distributed in tissue and significantly reduced hepatic glutathione. Acetaminophen enhanced cisplatin chemotherapeutic effect by reducing tumor recurrence Conclusion Our results suggest that acetaminophen as a chemoenhancing adjuvant could improve the efficacy of cisplatin and paclitaxel in treating patients with ovarian carcinoma and other tumor types. PMID:23749887

Wu, Y. Jeffrey; Neuwelt, Alexander J.; Muldoon, Leslie L.; Neuwelt, Edward A.

2013-01-01

133

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

134

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

135

Prostaglandins from a zoanthid: paclitaxel-like neurite-degenerating and microtubule-stabilizating activities.  

PubMed

Two prostaglandins, PGA2 and PGB2, were isolated from the Okinawan zoanthid, Palythoa kochii, during a search for paclitaxel-like neurite-degenerating compounds from natural sources using a cell-based assay method. In the presence of PGA2 at 30 microM, the neuronal processes induced in PC12 cells by the nerve growth factor (NGF) degenerated over 24 h, whereas PGB2 had no effect on the neuronal processes of PC12 cells. This activity of PGA2 was similar to that of the microtubule-stabilizing agents, paclitaxel (Taxol) and epothilone A, unlike the microtubule-depolymerizing agent, colchicine, which brought about quick neurite degeneration within 3 h. PGA2 stimulated tubulin polymerization, although less potently than paclitaxel. An examination of structure-activity relationships across several PGs suggests that the cyclopentenone ring structure and the orientation of its dipolar moment played an important role in the paclitaxel-like neurite-degenerating activity. These results suggest that the cyclopentenone-type PGs can interact with microtubules to inhibit their function like paclitaxel. PMID:16556989

Han, Chunguang; Qi, Jianhua; Shi, Xiaojin; Sakagami, Youji; Shibata, Takahiro; Uchida, Koji; Ojika, Makoto

2006-03-01

136

Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer  

PubMed Central

ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells. PMID:24810093

Gao, Bo; Russell, Amanda; Beesley, Jonathan; Chen, Xiao Qing; Healey, Sue; Henderson, Michelle; Wong, Mark; Emmanuel, Catherine; Galletta, Laura; Johnatty, Sharon E.; Bowtell, David; Bowtell, David; Chenevix-Trench, Georgia; deFazio, Anna; Gertig, Dorota; Green, Adle; Webb, Penelope; Hung, Jillian; Moore, Sue; Traficante, Nadia; Fereday, Sian; Harrap, Karen; Sadkowsky, Troy; Pandeya, Nirmala; Stuart-Harris, Robin; Kirsten, Fred; Rutovitz, Josie; Clingan, Peter; Glasgow, Amanda; Proietto, Anthony; Braye, Stephen; Otton, Greg; Shannon, Jennifer; Bonaventura, Tony; Stewart, James; Begbie, Stephen; Friedlander, Michael; Bell, David; Baron-Hay, Sally; Ferrier, Alan; Gard, Greg; Nevell, David; Pavlakis, Nick; Valmadre, Sue; Young, Barbara; Camaris, Catherine; Crouch, Roger; Edwards, Lyndal; Hacker, Neville; Marsden, Donald; Robertson, Greg; Beale, Phillip; Beith, Jane; Carter, Jonothan; Dalrymple, Chris; Hamilton, Anne; Houghton, Roger; Russell, Peter; Links, Matthew; Grygiel, John; Hill, Jane; Brand, Alison; Byth, Karen; Jaworski, Richard; Harnett, Paul; Sharma, Raghwa; Achen, Anita; Wain, Gerard; Ward, Bruce; Papadimos, David; Crandon, Alex; Cummings, Margaret; Horwood, Ken; Obermair, Andreas; Perrin, Lew; Wyld, David; Nicklin, Jim; Davy, Margaret; Oehler, Martin K; Hall, Chris; Dodd, Tom; Healy, Tabitha; Pittman, Ken; Henderson, Doug; Miller, John; Pierdes, John; Blomfield, Penny; Challis, David; McIntosh, Robert; Parker, Andrew; Brown, Bob; Rome, Robert; Allen, David; Grant, Peter; Hyde, Simon; Laurie, Rohan; Robbie, Melissa; Healy, David; Jobling, Tom; Manolitsas, Tom; McNealage, Jane; Rogers, Peter; Susil, Beatrice; Sumithran, Eric; Simpson, Ian; Phillips, Kelly; Rischin, Danny; Fox, Stephen; Johnson, Daryl; Waring, Paul; Lade, Stephen; Loughrey, Maurice; O’Callaghan, Neil; Murray, William; Billson, Virginia; Pyman, Jan; Neesham, Debra; Quinn, Michael; Underhill, Craig; Bell, Richard; Ng, Leong-Fook; Blum, Robert; Ganju, Vinod; Hammond, Ian; Leung, Yee; McCartney, Anthony; Buck, Martin; Haviv, Izak; Purdie, David; Whiteman, David; Zeps, Nikolajs; Malt, Mary-Rose; Mellon, Anne; Robertson, Randall; Bergh, Trish Vanden; Jones, Marian; Mackenzie, Patricia; Maidens, Jane; Nattress, Kath; Chiew, Yoke-Eng; Stenlake, Annie; Sullivan, Helen; Alexander, Barbara; Ashover, Pat; Brown, Sue; Corrish, Tracy; Green, Lyn; Jackman, Leah; Ferguson, Kaltin; Martin, Karen; Martyn, Adam; Ranieri, Barbara; White, Jo; Jayde, Victoria; Bowes, Leanne; Mamers, Pamela; Galletta, Laura; Giles, Debra; Hendley, Joy; Alsop, Katherine; Schmidt, Trudy; Shirley, Helen; Ball, Colleen; Young, Cherry; Viduka, Suzanna; Tran, Hoa; Bilic, Sanela; Glavinas, Lydia; Brooks, Julia; Haber, Michelle; Norris, Murray; Harnett, Paul; Chenevix-Trench, Georgia; Balleine, Rosemary L.; deFazio, Anna

2014-01-01

137

Peripheral Neuropathy Caused by Paclitaxel and Docetaxel: An Evaluation and Comparison of Symptoms  

PubMed Central

The purpose of this study was to explore the prevalence, severity, distress, and timing of neuropathic symptoms in cancer patients receiving taxanes and to explore neuropathy-related interference with activities. In this descriptive, cross-sectional study, 68 adult outpatients receiving paclitaxel (n = 36) and docetaxel (n = 32) completed the Chemotherapy Induced Peripheral Neuropathy Assessment Tool and a demographic questionnaire. Muscle or joint aches were the most prevalent symptom. Muscle or joint aches were also the most severe and distressing symptom in persons receiving paclitaxel. Participants receiving paclitaxel reported that neuropathic symptoms interfered with a mean of 7.3 (standard deviation [SD] = 4.1) of 14 activities. Nerve pain was the most severe and distressing symptom in persons receiving docetaxel. Participants receiving docetaxel reported that neuropathic symptoms interfered with a mean of 7.1 (SD = 4.1) of 14 activities. Numbness in the feet was the most frequent or constant symptom in persons receiving paclitaxel or docetaxel. Patients receiving paclitaxel and docetaxel experienced similar symptoms of peripheral neuropathy and interference with activities. Continued focus on treatment of painful neuropathy including myalgias and arthralgias is needed. PMID:25032002

Tofthagen*, Cindy; McAllister, R. Denise; Visovsky, Constance

2013-01-01

138

A novel biosensor for quantitative monitoring of on-target activity of paclitaxel.  

PubMed

This study describes a system for quantifying paclitaxel activity using the C-terminus of ?-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of ?-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of ?-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle. PMID:25483994

Townley, H E; Zheng, Y; Goldsmith, J; Zheng, Y Y; Stratford, M R L; Dobson, P J; Ahmed, A A

2015-01-21

139

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

140

Constitutive Androstane Receptor Ligands Modulate the Anti-Tumor Efficacy of Paclitaxel in Non-Small Cell Lung Cancer Cells  

PubMed Central

Background Lung tumors are the leading cause of cancer deaths worldwide and paclitaxel has proven to be useful for patients with lung cancer, however, acquired resistance is a major problem. To overcome this problem, one promising option is the use of Constitutive Androstane Receptor (CAR) ligands in combination with chemotherapeutics against cancer cells. Therefore, we wish to elucidate the effects of CAR ligands on the antineoplastic efficacy of paclitaxel in lung cancer cells. Methodology/Principal Findings Our results from cell viability assays exposing CAR agonist or inverse-agonist to mouse and human lung cancer cells modulated the antineoplastic effect of paclitaxel. The CAR agonists increased the effect of Paclitaxel in 6 of 7 lung cancer cell lines, whereas the inverse-agonist had no effect on paclitaxel cytotoxicity. Interestingly, the mCAR agonist TCPOBOP enhanced the expression of two tumor suppressor genes, namely WT1 and MGMT, which were additively enhanced in cells treated with CAR agonist in combination with paclitaxel. Also, in silico analysis showed that both paclitaxel and CAR agonist TCPOBOP docked into the mCAR structure but not the inverse agonist androstenol. Paclitaxel per se increases the expression of CAR in cancer cells. At last, we analyzed the expression of CAR in two public independent studies from The Cancer Genome Atlas (TCGA) of Non Small Cell Lung Cancer (NSCLC). CAR is expressed in variable levels in NSCLC samples and no association with overall survival was noted. Conclusions/Significance Taken together, our results demonstrated that CAR agonists modulate the antineoplastic efficacy of paclitaxel in mouse and human cancer cell lines. This effect was probably related by the enhanced expression of two tumor suppressor genes, viz. WT1 and MGMT. Most of NSCLC cases present CAR gene expression turning it possible to speculate the use of CAR modulation by ligands along with Paclitaxel in NSCLC therapy. PMID:24959746

Fukumasu, Heidge; Rochetti, Arina L.; Pires, Pedro R. L.; Silva, Edson R.; Mesquita, Ligia G.; Strefezzi, Ricardo F.; De Carvalho, Daniel D.; Dagli, Maria L.

2014-01-01

141

Delivery of Paclitaxel Using PEGylated Graphene Oxide as a Nanocarrier.  

PubMed

Paclitaxel (PTX) is an extensively used potent chemotherapy drug; however, low water solubility, poor bioavailability, and emergence of drug resistance in patients limited its biological application. In this report, we proposed a new drug delivery system for cancer therapy based on graphene oxide (GO), a novel 2D nanomaterial obtained from the oxidation of natural graphite, to improve the utilization rate of PTX. PTX was first connected to biocompatible 6-armed poly(ethylene glycol), followed by covalent introduction into the surface of GO sheets via a facile amidation process under mild conditions, affording the drug delivery system, GO-PEG-PTX (size 50-200 nm). GO-PEG nanosized carrier could quickly enter into human lung cancer A549 and human breast cancer MCF-7 cells verified by inverted fluorescence microscope using fluorescein isothiocyanate as probe. This nanocarrier was nontoxic to A549 and MCF-7 cells without linking with PTX. Nevertheless, GO-PEG-PTX 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 based on PEGylated GO may find widespread application in biomedicine. PMID:25546399

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

2015-01-21

142

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

143

Diverticular Bleeding of the Colon during Combination Chemotherapy with Bevacizumab and Paclitaxel for Recurrent Breast Cancer  

PubMed Central

Background Bevacizumab has been increasingly used in combination chemotherapy with paclitaxel for treatment of metastatic or recurrent breast cancer. The aim of this report is to underline possible risks associated with the new combination chemotherapy. Case Presentation A 39-year-old woman with recurrent breast cancer was treated with bevacizumab and paclitaxel. Positron emission tomography revealed breast cancer metastasis to the left supraclavicular lymph nodes and right axillary lymph nodes, with no distant metastasis. Results After the third cycle of bevacizumab and paclitaxel, the patient developed a bloody bowel discharge. Emergent colonoscopy demonstrated diverticular bleeding on one of the multiple diverticula in the ascending colon. The bleeding point was successfully clipped colonoscopically. Conclusion The factors for diverticular bleeding are believed to be non-steroidal anti-inflammatory drugs, constipation, and bevacizumab. We recommend reviewing anamneses for diverticulitis, multiple prior abdominal surgeries, peritoneal carcinomatosis, and regular use of certain drugs. PMID:23467459

Nakayama, Yoshie; Ito, Yoshinori; Tanabe, Masahiko; Takahashi, Shunji

2013-01-01

144

[Exudative onycholysis and acute bacterial paronychia related to BIBF-1120 and paclitaxel: response to topical therapy].  

PubMed

A case of a 50 years-old breast cancer patient treated with weekly paclitaxel and BIBF 1120 is reported herein. At the end of the twelfth cycle of chemotherapy, the patient developed distal onycholysis with intense hyponychium serous exudates, pain and malodor in all her fingernails. It was treated with topical fusidic acid and 1% methylprednisolone aceponate two times daily, with an excellent clinical response from the first three days of treatment. Bacterial paronychia with nail plate loss of the fifth left fingernail was observed a week after the topical therapy was started, with positive cultures for Methicillin susceptible Staphylococcus aureus. There are few reported cases of exudative onycholysis associated with chemotherapy. However, these are especially related to paclitaxel. No recurrences of nail disturbances were observed weeks after the end of chemotherapy. Topical corticosteroids and fusidic acid could be considered as a therapeutic option when exudative onycholysis related to paclitaxel is established PMID:24758102

Freites-Martínez, Azael; Martinez-Sánchez, Diego; de Pablo, Nieves Puente; Calderón-Komaromy, Angélica; Córdoba, Susana; Burbujo, Jesús

2014-03-01

145

Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel--a review.  

PubMed

Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The taxanes are administered as intravenous solutions in a short administration schedule. Distribution of both taxanes is rapid, with large volumes of distribution and significant binding to plasma proteins. The metabolism of paclitaxel is mediated primarily by the P450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after intravenous administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use. PMID:24637579

de Weger, Vincent A; Beijnen, Jos H; Schellens, Jan H M

2014-05-01

146

A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties  

PubMed Central

The use of chemotherapy to treat cancer is effective, but chemoresistance reduces this efficacy. Chemotherapy resistance involves several mechanisms, including the cancer stem cell (CSC) concept. The aim of the present study was to assess whether paclitaxel-resistant epithelial ovarian carcinoma is capable of generating cells with CSC-like properties. Using the paclitaxel-resistant A2780/PTX cell line, it was demonstrated that high aldehyde dehydrogenase 1 (ALDH1) activity identifies CSCs from diverse sources. Furthermore, the A2780/PTX cells had a strong ability to form colonies in soft agar assays. Notably, it was demonstrated that the inhibition of the PI3K signaling pathway abolished colony formation. These data suggest that there is a link between paclitaxel resistance and CSC enrichment. It is possible that therapeutic benefits, such as the restoration of chemosensitivity or the suppression of tumorigenicity, may be enabled by gaining further insights into the mechanisms underlying chemoresistance and the generation of CSCs. PMID:24179511

HAN, XIAOFENG; DU, FANGFANG; JIANG, LI; ZHU, YIFEI; CHEN, ZHEN; LIU, YANJUN; HONG, TINGTING; WANG, TENG; MAO, YONG; WU, XIAOHONG; BRUCE, IAIN C.; JIN, JIAN; MA, XIN; HUA, DONG

2013-01-01

147

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

148

Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer  

PubMed Central

Objective The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer. Methods To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 µL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls. Results Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses). Conclusion Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model. PMID:24761217

Hahn, Ho-Suap; Lee, Ki-Heon; Lee, In-Ho; Lee, Jae-Ho; Whang, Chang-Sung; Jo, Yeong-Woo

2014-01-01

149

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

150

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens.  

PubMed

Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone. PMID:14974481

Kloover, J S; den Bakker, M A; Gelderblom, H; van Meerbeeck, J P

2004-01-26

151

High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome  

PubMed Central

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ? 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775?mg/m2infused over 24 hours, doxorubicin 165?mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100?mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775?mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725?mg/m2infused over 24 hours in combination with with doxorubicin 165?mg/m2and cyclophosphamide 100?mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11401310

Somlo, G; Doroshow, J H; Synold, T; Longmate, J; Reardon, D; Chow, W; Forman, S J; Leong, L A; Margolin, K A; Jr, R J Morgan; Raschko, J W; Shibata, S I; Tetef, M L; Yen, Y; Kogut, N; Schriber, J; Alvarnas, J

2001-01-01

152

Development and application of a validated gradient elution HPLC method for simultaneous determination of 5-fluorouracil and paclitaxel in dissolution samples of 5-fluorouracil/paclitaxel-co-eluting stents.  

PubMed

The combined use of 5-fluorouracil and paclitaxel is common in clinical trials. However, there are few methods for simultaneous determination of 5-fluorouracil and paclitaxel; most reported approaches can only quantitate either 5-fluorouracil or paclitaxel. This paper proposes a new gradient elution HPLC method for simultaneous determination of 5-fluorouracil and paclitaxel using a photodiode array detector, C?? column (250 mm × 4.6 mm, 5 ?m) with methanol and 0.5% H?PO? aqueous solution as the mobile phase components. The injection volume was 50 ?l and the column temperature was maintained at 30 °C. The method was validated according to USP Category I requirements. The validation characteristics included system suitability, linearity, analytical range, LOD, LOQ, accuracy, precision, specificity, stability, ruggedness and robustness. The calibration curves exhibited linear concentration ranges of 0.2-40 ?g/ml for 5-fluorouracil and 1.5-150 ?g/ml for paclitaxel with correlation coefficients larger than 0.99990. The lower limits of quantitation were 2 ng/ml for 5-fluorouracil and 0.75 ?g/ml for paclitaxel, respectively. The intra and inter-day precision and accuracy were found to be well within acceptable limits (i.e., 5%). The results demonstrate that this method is reliable, reproducible and suitable for simultaneous quantitation of the two drugs in the release media of 5-fluorouracil/paclitaxel-co-eluting stents. PMID:22075374

Chen, Weiluan; Shen, Yuanyuan; Rong, Haojun; Lei, Lei; Guo, Shengrong

2012-02-01

153

DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non-small cell lung cancer cell line  

PubMed Central

The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel. In present study, NCI-H460, a NSCLC cell line with different sensitivity to paclitaxel and docetaxel, was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel. And the complex signaling pathways regulating the drug response were identified, and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI-H460 cells. Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different. Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton (ACTC1, MYL2 and MYH2), tyrosine-protein kinases (ERRB4, KIT and TIE1) and focal adhesion pathway (MYL2, IGF1 and FLT1), while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction (SHH, DRD5 and ADM2), cytokine-cytokine receptor interaction (IL1A and IL6) and cell cycleregulation (CCNB1, CCNE2 and PCNA). Moreover, we also confirmed some different expression patterns with real time PCR. Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application. PMID:23923072

Che, Chun-Li; Zhang, Yi-Mei; Zhang, Hai-Hong; Sang, Yu-Lan; Lu, Ben; Dong, Fu-Shi; Zhang, Li-Juan; Lv, Fu-Zhen

2013-01-01

154

Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial  

PubMed Central

Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival. Patients and methods: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel (arm A) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned. Results: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively. Conclusions: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms. PMID:20439345

Stathopoulos, G. P.; Antoniou, D.; Dimitroulis, J.; Michalopoulou, P.; Bastas, A.; Marosis, K.; Provata, A.; Yiamboudakis, P.; Veldekis, D.; Lolis, N.; Georgatou, N.; Toubis, M.; Pappas, Ch.; Tsoukalas, G.

2010-01-01

155

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

156

A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer  

Microsoft Academic Search

Paclitaxel (PTX) is one of the most effective chemotherapeutic drugs for the treatment of a variety of cancers. However, it is associated with serious side effects caused by PTX itself and the Cremophor EL emulsifier. In the present study, we report the development of a well-defined amphiphilic linear-dendritic copolymer (named as telodendrimer) composed of polyethylene glycol (PEG), cholic acid (CA,

Kai Xiao; Juntao Luo; Wiley L. Fowler; Yuanpei Li; Joyce S. Lee; Li Xing; R. Holland Cheng; Li Wang; Kit S. Lam

2009-01-01

157

Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer.  

PubMed Central

Single-agent therapy with paclitaxel is effective against both squamous cell carcinoma and adenocarcinoma of the oesophagus. However, only limited data are available on the combination of paclitaxel with other cytotoxic drugs in this entity. Patients with unresectable stage III, recurrent or metastatic tumours were treated in a multicentre setting with paclitaxel 90 mg m(-2) given over 3 h intravenously, followed by cisplatin 50 mg m(-2). The courses were repeated every 14 days. Twenty patients with squamous cell carcinoma or adenocarcinoma of the oesophagus were evaluable for response. The overall remission rate was 40% (8/20), including 15% (3/20) clinically complete responses. Clinical benefit response, defined as relief of dysphagia and/or significant gain in weight, was achieved in 70% of the patients. Neutropenia of CTC grade 3 occurred only in 10% of the patients; no grade 4 neutropenia and no severe thrombocytopenia was encountered. CTC grade 4 neurotoxicity was seen in 5% of patients. Cisplatin/paclitaxel administered every 14 days, was effective in patients with poor prognosis oesophageal cancer and toxicity was acceptable. PMID:9716036

Petrasch, S.; Welt, A.; Reinacher, A.; Graeven, U.; König, M.; Schmiegel, W.

1998-01-01

158

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

159

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

160

Bioadhesive Drug Delivery System Using Glyceryl Monooleate for the Intravesical Administration of Paclitaxel  

Microsoft Academic Search

Background: Many reports have shown that the efficacy of intravesical therapy for bladder cancer is in part limited by the poor penetration of drugs into the urothelium. The present study evaluated the effect of glyceryl monooleate (GMO) on the absorption of intravesically administered paclitaxel in a rabbit model of bladder cancer. Methods: Urine, plasma, and tissue pharmacokinetics were determined in

Seung-Ju Lee; Sae Woong Kim; Hesson Chung; Yeong Taek Park; Young Wook Choi; Yong-Hyun Cho; Moon Soo Yoon

2005-01-01

161

A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer  

PubMed Central

Background Many emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines. Methods A phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines. Results Twenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1–14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%). Conclusion The schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines. PMID:16723016

Tomao, Silverio; Romiti, Adriana; Tomao, Federica; Di Seri, Marisa; Caprio, Giuliana; Spinelli, Gian Paolo; Terzoli, Edmondo; Frati, Luigi

2006-01-01

162

Paclitaxel-induced stomal neuropathy: a unique cause of pain in a patient with ileal conduit  

Microsoft Academic Search

We present a case of unusual chemotherapy-induced neurotoxicity in a patient who had undergone radical cystoprostatectomy and ileal conduit diversion for invasive bladder cancer. On routine computed tomography scan several years later, he was diagnosed with metastatic transitional cell carcinoma involving the retroperitoneal lymph nodes. The patient received systemic chemotherapy, including a combination of paclitaxel (Taxol) and gemcitabine (Gemzar). During

Menachem Laufer; Mark P Schoenberg; Mario A Eisenberger

2000-01-01

163

Formulation, characterization and hypersensitivity evaluation of an intravenous emulsion loaded with a paclitaxel-cholesterol complex.  

PubMed

The objective of this paper was to develop a novel Cremophor-free, autoclave stable, intravenous emulsion for paclitaxel (PACE). A paclitaxel-cholesterol complex was used as the drug carrier to improve the solubility of paclitaxel in the oil phase of emulsions. The complex and PACE were prepared by rotary evaporation and high-pressure homogenization, respectively. Effects of oil phases, emulsifiers and pH values on the characteristics of PACE were investigated. PACE was characterized with regard to its appearance, morphology, osmolality, pH value, particle size, zeta potential, encapsulation efficiency and stability. Hypersensitivity was evaluated by guinea pig hypersensitivity reaction. The final formulation was composed of the complex, soybean oil, medium-chain triglyceridel, soybean lecithin, poloxamer 188 and glycerol. The resulting PACE had an encapsulation efficiency of 97.3% with a particle size of 135 nm and a zeta potential of -38.3 mV. Osmolality and pH of the formulation were 383 mOsmol/kg and 4.5, respectively. The formulation survived autoclaving at 115 °C for 30 min and remained stable for at least 12 months at 6 °C. PACE also exhibited a better tolerance than an equal dose of Cremophor-based paclitaxel injection in guinea pigs, as no obvious hypersensitivity reaction was observed. These results suggested that PACE has a great potential for industrial-scale production and clinical applications. PMID:21372412

Xia, Xue-Jun; Guo, Rui-Fang; Liu, Yu-Ling; Zhang, Peng-Xiao; Zhou, Cui-Ping; Jin, Du-Jia; Wang, Ren-Yun

2011-01-01

164

[Schedule dependency of i.v.-paclitaxel against SC-M 109 mouse lung cancer].  

PubMed

Although paclitaxel was shown to have a broad spectrum of antitumor activity against various experimental tumors, the optimal treatment schedule of this drug is not yet determined. In the present study, a trial was carried out to determine the optimal treatment schedule of paclitaxel given i.v. against M 109 mouse lung cancer implanted SC. Schedules examined were: day 1 (d 1) single administration, d 1, 5, 9 intermittent administration, and d 1-5 and d 1-9 daily consecutive administration. As the result, a significant increase of the lifespan was firstly demonstrated by d 1-9 schedule. The optimal dose was as low as 6.5 mg/kg/day (20 mg/m2/day, total 180 mg/m2) and no toxicity was observed with respect to the weight loss. Since the concentration and total amount of Cremophor EL (polyoxyethylene castor oil), which is suspected to be a causative agent for high incidence rate of hypersensitivity reactions by clinical formulation of paclitaxel, inevitably decrease in such a low dose setting, these results should be taken into considerations when exploring the optimal schedule of paclitaxel clinically. PMID:7908794

Fujimoto, S

1994-04-01

165

Investigation of the release behavior of DEHP from infusion sets by paclitaxel-loaded polymeric micelles.  

PubMed

The current clinical formulation of paclitaxel (Taxol) contains 1:1 blend of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. Cremophor EL and dehydrated ethanol are well known to leach di-(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) infusion bags and PVC administration sets. DEHP is a possible hepatotoxin, carcinogen, teratogen and mutagen. Long-term exposure to DEHP may cause health risks. As an alternative formulation for paclitaxel, paclitaxel-loaded polymeric micelles (PLPM), made of monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) diblock copolymer, has demonstrated clear advantages over Taxol in pharmacokinetics and therapeutic index. Paclitaxel in either PLPM or Taxol formulations, diluted in 0.9% sodium chloride injection, was stable in the PVC infusion bags. The PLPM formulation significantly reduced the amount of DEHP extracted from PVC infusion bags and PVC administration sets. For PLPM diluted in 0.9% sodium chloride injection, the total amount of DEHP delivered over the simulated infusion period was 0.7 mg for 3h and 2.0 mg for 24 h, which was less than 2.9% of the DEHP extracted by Taxol. These results confirmed that there is negligible risk of DEHP exposure from diluted PLPM i.v. infusion using PVC infusion bags and PVC administration sets. PMID:15778068

Kim, Sung Chul; Yoon, Hye Jeong; Lee, Jang Won; Yu, Jaewon; Park, Eun-Seok; Chi, Sang-Cheol

2005-04-11

166

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

E-print Network

-resistance in and therapeutics for breast cancer. Mentor: Brittney-Shea Herbert, Department of Medical and Molecular Genetics IUMolecular Mechanisms of Paclitaxel Resistance and Resveratrol Sensitivity in MDA-MB-231 Breast Cancer Cells Alyssa A. Sprouse1 , and Brittney-Shea Herbert2 1 Department of Pharmacology and Toxicology

Zhou, Yaoqi

167

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles  

PubMed Central

Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid–polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ?3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ?50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD. PMID:22087004

Chan, Juliana M.; Drum, Chester L.; Bronson, Roderick T.; Golomb, Gershon; Langer, Robert; Farokhzad, Omid C.

2011-01-01

168

Designing Paclitaxel Drug Delivery Systems Aimed at Improved Patient Outcomes: Current Status and Challenges  

PubMed Central

Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01?mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper. PMID:22934190

Surapaneni, Madhu S.; Das, Sudip K.; Das, Nandita G.

2012-01-01

169

Exploration of paclitaxel (Taxol) as a treatment for malignant tumors in cats: a descriptive case series.  

PubMed

Paclitaxel, an effective chemotherapeutic agent in human oncology, has received little evaluation in feline patients. The diluent used to solubilize paclitaxel, polyoxyethylated castor oil (Cremophor EL), causes anaphylactoid reactions in human and dogs, which limits enthusiasm for use of this agent in veterinary oncology. Nine feline patients with measurable malignant tumors were treated with paclitaxel at a dosage of 80 mg/m(2) intravenously every 21 days for up to two doses. Adverse effects, including evidence of toxicity and anaphylactoid reactions, were assessed. Tumor response, progression and patient time to progression (TTP) were also recorded. Adverse effects included grade III and IV thrombocytopenia, grade III gastrointestinal signs (vomiting and constipation) and hypersensitivity reactions, seen in a total of five patients. Anaphylactoid reactions resolved with appropriate management. Stable disease and partial response were observed in 56% of feline patients. Median TTP was 28 days (range 15-45 days). Intravenous paclitaxel is a safe treatment option for feline malignant tumor patients. Future investigation is warranted to explore the effectiveness and appropriate application of this agent for specific tumor types. PMID:24820996

Kim, Jennifer; Doerr, Mary; Kitchell, Barbara E

2014-05-12

170

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

171

Hyaluronic acid-paclitaxel conjugate inhibits growth of human squamous cell carcinomas of the head and neck via a hyaluronic acid-mediated mechanism.  

PubMed

Chemotherapeutic regimens incorporating taxanes significantly improve outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN). However, treatment with taxanes is limited by toxicities, including bone marrow suppression and peripheral neuropathies. We proposed that conjugating taxanes to targeting carrier molecules would increase antitumor efficacy and decrease toxicity. The cell surface proteoglycan, CD44, is expressed on most SCCHNs, and we hypothesized that it is an attractive candidate for targeted therapy via its natural ligand, hyaluronic acid (HA). We determined whether HA-paclitaxel conjugates were able to decrease tumor growth and improve survival in orthotopic nude mouse human SCCHN xenograft models. HA-paclitaxel concentration-dependent growth inhibition of human SCCHN cell lines OSC-19 and HN5 in vitro, very similarly to free paclitaxel treatment. Tumor cell uptake of FITC-labeled HA-paclitaxel was significantly blocked with free HA, indicating the dependence of uptake on CD44. HA-paclitaxel administered intravenously once per week for three weeks at 120 mg/kg paclitaxel equivalents, far above the paclitaxel maximum tolerated dose, exerted superior tumor growth control to that of paclitaxel in both orthotopic OSC-19-luciferase and HN5 xenograft models in vivo. Mouse survival following HA-paclitaxel administration was prolonged compared with that of controls in mice implanted with either of these xenografts. Mice treated with HA-paclitaxel displayed increased TUNEL(+) cells in tumor tissue, as well as markedly reduced microvessel density compared to those treated with free paclitaxel. No acute histopathological changes were observed in mice treated with HA-paclitaxel. Thus, we conclude that HA-paclitaxel effectively inhibits tumor growth in human SCCHN xenografts via an HA-mediated mechanism and this conjugate should be considered for further preclinical development for this disease. PMID:21903450

Galer, Chad E; Sano, Daisuke; Ghosh, Sukhen C; Hah, Jeong H; Auzenne, Edmund; Hamir, Amirali N; Myers, Jeffrey N; Klostergaard, Jim

2011-11-01

172

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

173

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

174

Cisplatin improves antitumor activity of weekly nab-paclitaxel in patients with metastatic breast cancer  

PubMed Central

Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m2 on day 1, day 8, and day 15, followed by cisplatin 75 mg/m2 on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients. PMID:24672237

Sun, Si; Tang, Lichen; Zhang, Jian; Lv, Fangfang; Wang, Zhonghua; Wang, Leiping; Zhang, Qunling; Zheng, Chunlei; Qiu, Lixin; Jia, Zhen; Lu, Yunhua; Liu, Guangyu; Shao, Zhimin; Wang, Biyun; Hu, Xichun

2014-01-01

175

Carboxymethyl-chitosan-tethered lipid vesicles: hybrid nanoblanket for oral delivery of paclitaxel.  

PubMed

We describe the development and evaluation of a hybrid lipopolymeric system comprising carboxymethyl chitosan (CMC), covalently tethered to phosphatidylethanolamine units on the surface of lipid nanovesicles, for oral delivery of paclitaxel. The bioploymer is intended to act as a blanket, thereby shielding the drug from harsh gastrointestinal conditions, whereas the lipid nanovesicle ensures high encapsulation efficiency of paclitaxel and its passive targeting to tumor. CMC-tethered nanovesicles (LN-C-PTX) in the size range of 200-300 nm improved the gastrointestinal resistance and mucoadhesion properties as compared with unmodified lipid nanovesicles (LN-PTX). Conjugation of CMC did not compromise the cytotoxic potential of paclitaxel yet facilitated the interaction and uptake of the nanovesicles by murine melanoma (B16F10) cells through an ATP-dependent process. CMC-conjugated nanovesicles, upon oral administration in rats, improved the plasma concentration profile of paclitaxel, with 1.5 fold increase in its bioavailability and 5.5 folds increase in elimination half life in comparison with Taxol. We also found that CMC in addition to providing a gastric resistant coating also imparted stealth character to the nanovesicles, thereby reducing their reticuloendothelial system (RES)-mediated uptake by liver and spleen and bypassing the need for PEGylation. In vivo efficacy in subcutaneous model of B16F10 showed significantly improved tumor growth inhibition and survival with CMC-tethered nanovesicles as compared with unmodified nanovesicles, both administered orally. LN-C-PTX exhibited therapeutic efficacy comparable to Taxol and Abraxane and also showed reduced toxicity and improved survival. Overall, these results suggest the therapeutic potential of CMC tethered nanovesicles as a platform for oral administration of paclitaxel and also unravel the ability of CMC to impart stealth character to the nanoparticles, thereby preventing their RES clearance. PMID:23721348

Joshi, Nitin; Saha, Rama; Shanmugam, Thanigaivel; Balakrishnan, Biji; More, Prachi; Banerjee, Rinti

2013-07-01

176

Losartan competitively inhibits CYP2C8-dependent paclitaxel metabolism in vitro.  

PubMed

The present study aimed to characterize the inhibitory effects of losartan, an angiotensin II receptor blocker, on CYP2C8. Inhibition experiments were based on human lymphoblast-expressed recombinant CYP2C8 (rCYP2C8) and paclitaxel as a CYP2C8 substrate. The disappearance of paclitaxel (initial concentration: 7.5?µmol/L) was monitored over time at different concentrations of losartan (0, 100, 500 and 1000?µmol/L). For Dixon and Cornish-Bowden plots, various concentrations of losartan (final concentration: 0, 50, 100 and 250?µmol/L) and paclitaxel (final concentration: 3.75, 7.5 and 15?µmol/L) were used. Losartan exhibited significant inhibitory effects on paclitaxel disappearance at losartan concentrations of ?100?µmol/L (p<0.05). Losartan at 50?µmol/L inhibited the disappearance of paclitaxel by about 60%. Both plots showed that losartan exerted competitive inhibition of rCYP2C8, and its apparent Ki value was estimated to be 40.7?µmol/L. The degree of inhibition (R value) for rCYP2C8 after oral administration of losartan (100?mg) was estimated to be 1.2, using the maximum hepatic input total blood concentration (7.3?µmol/L). The present results show that losartan acts as a competitive inhibitor of CYP2C8-dependent drug metabolism in vitro. Subjects with a low clearance of losartan, resulting in a high average systemic blood concentration of losartan after repeated oral administration, should be carefully monitored for possible adverse reactions during co-medication with CYP2C8 substrate drugs. PMID:25177037

Mukai, Yuji; Toda, Takaki; Hayakawa, Toru; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

2014-01-01

177

Glutamine as a Neuroprotective Agent in High-dose Paclitaxel-induced Peripheral Neuropathy: A Clinical and Electrophysiologic Study  

Microsoft Academic Search

AimsThe appearance of peripheral neuropathy is the dose-limiting toxicity in many chemotherapy protocols, and glutamine has been proposed as a potentially neuroprotective agent in patients receiving paclitaxel.

M. D. Stubblefield; L. T. Vahdat; C. M. Balmaceda; A. B. Troxel; C. S. Hesdorffer; C. L. Gooch

2005-01-01

178

Sustained delivery of paclitaxel using thermogelling poly(PEG/PPG/PCL urethane)s for enhanced toxicity against cancer cells.  

PubMed

A multiblock poly(ether ester urethane)s comprising poly(?-caprolactone), poly(ethylene glycol), and poly(propylene glycol) segments was synthesized. The aqueous copolymer solution exhibited thermogelling behavior at a critical gelation concentration of 3 wt %. The chemical structure and molecular characteristic of the copolymers were studied by gel permeation chromatography, NMR, and fourier transform infrared spectroscopy (FTIR). Rheological characterizations on the thermogel were carried out. Drug release studies using paclitaxel showed that sustained drug release of more than 2 weeks can be achieved with this system. The paclitaxel-loaded gels showed efficiency in the control of the growth of HeLa cells when compared with the paclitaxel dissolved in solution or paclitaxel encapsulated in Pluronics F127. The results demonstrated that the copolymers could be potentially used in chemotherapeutic applications. PMID:22619090

Loh, Xian Jun; Yee, Benjamin Jia Han; Chia, Fu Siong

2012-10-01

179

Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat  

PubMed Central

The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, while the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel. PMID:22037390

Xiao, Wen Hua; Zheng, Huaien; Zheng, Felix Y.; Nuydens, Rony; Meert, Theo F.; Bennett, Gary J.

2011-01-01

180

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations  

PubMed Central

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1–5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200?mg?m?2?day?1 temozolomide and 225?mg?m?2?day?1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted. PMID:15756276

Azzabi, A; Hughes, A N; Calvert, P M; Plummer, E R; Todd, R; Griffin, M J; Lind, M J; Maraveyas, A; Kelly, C; Fishwick, K; Calvert, A H; Boddy, A V

2005-01-01

181

FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines  

Microsoft Academic Search

Paclitaxel is used to treat breast cancers, but the mechanisms by which it induces apoptosis are poorly understood. Consequently, we have studied the role of the FoxO transcription factors in determining cellular response to paclitaxel. Western blotting revealed that in a panel of nine breast cancer cell lines expression of FoxO1a and FoxO3a correlated with the expression of the pro-apoptotic

A. Sunters; S. Fernandez de Mattos; M. Stahl; J. J. Brosens; G. Zoumpoulidou; C. A. Saunders; P. J. Coffer; R. H. Medema; R. C. Coombes; E. W.-F. Lam

2003-01-01

182

Role of Activating Transcription Factor 3 on TAp73 Stability and Apoptosis in Paclitaxel-Treated Cervical Cancer Cells  

PubMed Central

Taxol (paclitaxel) is a potent anticancer drug that has been found to be effective against several tumor types, including cervical cancer. However, the exact mechanism underlying the antitumor effects of paclitaxel is poorly understood. Here, paclitaxel induced the apoptosis of cervical cancer HeLa cells and correlated with the enhanced activation of caspase-3 and TAp73, which was strongly inhibited by TAp73? small interfering RNA (siRNA). In wild-type activating transcription factor 3 (ATF3)–overexpressed cells, paclitaxel enhanced apoptosis through increased ? and ? isoform expression of TAp73; however, these events were attenuated in cells containing inactive COOH-terminal–deleted ATF3 [ATF3(?C)] or ATF3 siRNA. In contrast, paclitaxel-induced ATF3 expression did not change in TAp73? -overexpressed or TAp73? siRNA–cotransfected cells. Furthermore, paclitaxel-induced ATF3 translocated into the nucleus where TAp73? is expressed, but not in ATF3 (?C) or TAp73? siRNA–transfected cells. As confirmed by the GST pull-down assay, ATF3 bound to the DNA-binding domain of p73, resulting in the activation of p21 or Bax transcription, a downstream target of p73. Overexpression of ATF3 prolonged the half-life of TAp73? by inhibiting its ubiquitination and thereby enhancing its transactivation and proapoptotic activities. Additionally, ATF3 induced by paclitaxel potentiated the stability of TAp73?, not its transcriptional level. Chromatin immunoprecipitation analyses show that TAp73? and ATF3 are recruited directly to the p21 and Bax promoter. Collectively, these results reveal that overexpression of ATF3 potentiates paclitaxel-induced apoptosis of HeLa cells, at least in part, by enhancing TAp73?'s stability and its transcriptional activity. The investigation shows that ATF3 may function as a tumor-inhibiting factor through direct regulatory effects on TAp73?, suggesting a functional link between ATF3 and TAp73?. PMID:18644986

Oh, Yeo Kyoung; Lee, Hyun Jung; Jeong, Mi-Hee; Rhee, Marie; Mo, Ji-Won; Song, Eun Hyeon; Lim, Joong-Yeon; Choi, Kyung-Hee; Jo, Inho; Park, Sang Ick; Gao, Bin; Kwon, Yongil; Kim, Won-Ho

2013-01-01

183

Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits  

Microsoft Academic Search

Objectives:To assess the biocompatibility of controlled release microspheres prepared from different polymeric biomaterials in various size ranges in rabbit synovial joints and based on these data, design and evaluate the efficacy of an intra-articular, paclitaxel-loaded microspheres formulation in rabbit models of arthritis. Methods:Paclitaxel-loaded microspheres of poly(lactide-co-glycolide) (PLGA), poly(L-lactic acid) (PLA) and poly(caprolactone) (PCL) were prepared in different size ranges and

R. T. Liggins; T. Cruz; W. Min; L. Liang; W. L. Hunter; H. M. Burt

2004-01-01

184

Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial  

Microsoft Academic Search

Summary Background Everolimus-eluting and paclitaxel-eluting stents, compared with bare metal stents, reduced the risk of restenosis in clinical trials with strict inclusion and exclusion criteria. We compared the safety and effi cacy of the second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice. Methods We randomly assigned 1800 consecutive patients (aged 18-85 years) undergoing percutaneous coronary intervention at one centre to

Elvin Kedhi; Kaiyum Sheik Joesoef; Eugene McFadden; Jochem Wassing; Carlos van Mieghem; Dick Goedhart; Pieter Cornelis Smits

2010-01-01

185

Proteomic analysis of the proteins that are associated with the resistance to paclitaxel in human breast cancer cells.  

PubMed

Cancers frequently develop resistance to paclitaxel but the underlying molecular mechanisms remain to be determined. We have investigated the proteins that are associated with the paclitaxel resistance in human breast cancer MCF-7 cells using proteomic analysis. Paclitaxel resistant human breast cancer MCF-7 cells (MCF-7/P) were established by escalating the concentrations of paclitaxel to drug-sensitive MCF-7 cells (MCF-7/S). The global protein profiles of MCF-7/P and MCF-7/S were compared using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Eleven proteins were upregulated while six proteins were downregulated in MCF-7/P cells. Western blot and real-time PCR analyses showed that the protein and mRNA levels of heterogeneous nuclear ribonucleoprotein (hnRNP C1/C2), SET nuclear oncogene (SET), aspartate aminotransferase (AAT), transgelin-2 (TAGLN2) were increased, while those of nucleoside-diphosphate kinase A (NDKA) were decreased in MCF-7/P cells. Accordingly, knockdown of TAGLN2 by siRNA sensitized MCF-7/P cells to paclitaxel and reduced the multidrug resistance (MDR). Our identification of differential proteins, particularly transgelin-2, provides new insights into the mechanism of MDR to paclitaxel and novel biological targets for breast cancer treatment. PMID:24292090

Chen, Siying; Dong, Qian; Hu, Sasa; Cai, Jiangxia; Zhang, Weipeng; Sun, Jinyao; Wang, Taotao; Xie, Jiao; He, Hairong; Xing, Jianfeng; Lu, Jun; Dong, Yalin

2014-02-01

186

Everolimus-Eluting versus Paclitaxel-Eluting Stents in Percutaneous Coronary Intervention: Meta-Analysis of Randomized Trials  

PubMed Central

Background. Individual randomized trials have suggested that everolimus-eluting stents may have improved clinical outcomes compared to paclitaxel-eluting stents, but individual trials are underpowered to examine outcomes such as mortality and very late stent thrombosis. Methods. Medline, Cochrane, and conference proceedings were searched for randomized trials comparing everolimus versus paclitaxel-eluting stents for percutaneous coronary intervention. Results. 6792 patients were included from 4 randomized controlled trials. Stent thrombosis was reduced with everolimus stents versus paclitaxel stents (0.7% versus 2.3%; OR: 0.32; CI: 0.20–0.51; P < 0.00001). The reductions in stent thrombosis were observed in (i) early stent thrombosis (within 30 days) (0.2% versus 0.9%; OR: 0.24; P = 0.0005), (ii) late (day 31–365) (0.2% versus 0.6%; OR: 0.32; P = 0.01), and (iii) very late stent thrombosis (>365 days) (0.2% versus 0.8%; OR: 0.34; P = 0.009). The rates of cardiovascular mortality were 1.2% in everolimus group and 1.6% in paclitaxel group (OR: 0.85; P = 0.43). Patients receiving everolimus-eluting stents had significantly lower myocardial infarction events and target vessel revascularization as compared to paclitaxel-eluting stents. Interpretation. Everolimus compared to paclitaxel-eluting stents reduced the incidence of early, late, and very late stent thrombosis as well as target vessel revascularization. PMID:22655192

Alazzoni, Ashraf; Al-Saleh, Ayman; Jolly, Sanjit S.

2012-01-01

187

The ClC-3 chloride channel associated with microtubules is a target of paclitaxel in its induced-apoptosis  

PubMed Central

Recent evidences show that cationic fluxes play a pivotal role in cell apoptosis. In this study, the roles of Cl? channels in paclitaxel-induced apoptosis were investigated in nasopharyngeal carcinoma CNE-2Z cells. Chloride current and apoptosis were induced by paclitaxel and inhibited by chloride channel blockers. Paclitaxel-activated current possessed similar properties to volume-activated chloride current. After ClC-3 was knocked-down by ClC-3-siRNA, hypotonicity-activated and paclitaxel-induced chloride currents were obviously decreased, indicating that the chloride channel involved in paclitaxel-induced apoptosis may be ClC-3. In early apoptotic cells, ClC-3 was up-regulated significantly; over-expressed ClC-3 was accumulated in cell membrane to form intercrossed filaments, which were co-localized with ?-tubulins; changes of ultrastructures and decrease of flexibility in cell membrane were detected by atomic force microscopy. These suggest that ClC-3 is a critical target of paclitaxel and the involvement of ClC-3 in apoptosis may be associated with its accumulation with membrane microtubules and its over activation. PMID:24026363

Zhang, Haifeng; Li, Huarong; Yang, Lili; Deng, Zhiqin; Luo, Hai; Ye, Dong; Bai, Zhiquan; Zhu, Linyan; Ye, Wencai; Wang, Liwei; Chen, Lixin

2013-01-01

188

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer  

Microsoft Academic Search

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m?2 PPX or 75 mg m?2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9

L Paz-Ares; H Ross; M O'Brien; A Riviere; U Gatzemeier; J Von Pawel; E Kaukel; L Freitag; W Digel; H Bischoff; R García-Campelo; N Iannotti; P Reiterer; I Bover; J Prendiville; A J Eisenfeld; F B Oldham; B Bandstra; J W Singer; P Bonomi

2008-01-01

189

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

190

Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, ThymitaqTM) and paclitaxel  

PubMed Central

A clinical study of nolatrexed dihydrochloride (AG337, ThymitaqTM) in combination with paclitaxel was performed. The aims were to optimize the schedule of administration and determine any pharmacokinetic (PK) interactions between the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three different schedules of administration of the two drugs: (1) paclitaxel 0–3 h, nolatrexed 24–144 h; (2) nolatrexed 0–120 h, paclitaxel 48–51 h; (3) nolatrexed 0–120 h, paclitaxel 126–129 h. Paclitaxel was administered at a dose of 80 mg m?2over 3 h and nolatrexed at a dose of 500 mg m?2day?1as a 120-h continuous intravenous infusion. Plasma concentrations of both drugs were determined by high performance liquid chromatography. In vitro growth inhibition studies using corresponding schedules were performed using two head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, synergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, patients on schedules 1 and 3 had a higher clearance of paclitaxel (322–520 ml min?1m?2) than those on schedule 2 (165–238 ml min?1m?2). Peak plasma concentrations (1.66–1.93 vs 0.86–1.32 ?M) and areas under the curve (392–565 vs 180–291 ?M min?1) of paclitaxel were correspondingly higher on schedule 2. The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatrexed and paclitaxel may be safely given together when administered sequentially at the doses used in this study. Studies in vitro suggest some synergy, however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during nolatrexed infusion. © 2000 Cancer Research Campaign PMID:10789718

Hughes, A N; Griffin, M J; Newell, D R; Calvert, A H; Johnston, A; Kerr, B; Lee, C; Liang, B; Boddy, A V

2000-01-01

191

Study of Paclitaxel-Treated HeLa Cells by Differential Electrical Impedance Flow Cytometry  

PubMed Central

This work describes the electrical investigation of paclitaxel-treated HeLa cells using a custom-made microfluidic biosensor for whole cell analysis in continuous flow. We apply the method of differential electrical impedance spectroscopy to treated HeLa cells in order to elucidate the changes in electrical properties compared with non-treated cells. We found that our microfluidic system was able to distinguish between treated and non-treated cells. Furthermore, we utilize a model for electrical impedance spectroscopy in order to perform a theoretical study to clarify our results. This study focuses on investigating the changes in the electrical properties of the cell membrane caused by the effect of paclitaxel. We observe good agreement between the model and the obtained results. This establishes the proof-of-concept for the application in cell drug therapy. PMID:25587422

Kirkegaard, Julie; Clausen, Casper Hyttel; Rodriguez-Trujillo, Romen; Svendsen, Winnie Edith

2014-01-01

192

[A case of S-1-resistant recurrent gastric cancer successfully treated with weekly administration of paclitaxel].  

PubMed

We report a case of recurrent gastric cancer with peritoneal dissemination and paraaortic lymph node metastases, successfully treated with weekly administration of paclitaxel. The patient was a 63-year-old man who underwent distal gastrectomy with lymph node dissection for advanced gastric cancer in February 2005. After the operation, adjuvant chemotherapy with S-1 was started and continued. He complained of abdominal distention, anorexia and nausea in April 2006. Therefore, paclitaxel (PTX) was administered at a dose of 60 mg/m(2)/day for 3 weeks followed by a week rest. Clinical symptoms were relieved, and abdominal X-ray findings showing intestinal obstruction disappeared after 2 courses. CT scan revealed metastatic lymph nodes were reduced after 3 courses. Grade 1 peripheral neuropathy and grade 2 leukocytopenia were noted, but no serious adverse reaction appeared. Weekly administration of PTX may be a promising regimen as second-line chemotherapy for S-1-resistant recurrent gastric cancer. PMID:17637549

Takashima, Takeshi; Ito, Tatsuya; Sato, Takashi; Hirata, Koichi

2007-07-01

193

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

194

Phase behavior study of paclitaxel loaded amphiphilic copolymer in two solvents by dissipative particle dynamics simulations  

NASA Astrophysics Data System (ADS)

DPD simulations were employed to study the phase behavior of paclitaxel loaded PEO 11- b-PLLA 9 in water and N, N-Dimethylformamide. Different ordered structures were observed in water-rich solvents. All the structures were greatly affected by solvents compositions. By varying the fractions of each component, a phase diagram of paclitaxel loaded PEO 11- b-PLLA 9 in water and DMF was mapped. For all ordered structures, bicontinuous, lamella, rod, and spherical structures with different sizes could be easily observed for their wide distribution in the phase diagram. While the HPL, dumbbell, and spherical structures with uniform size were difficult to be obtained, due to their narrow distribution.

Guo, Xin Dong; Tan, Jeremy Pang Kern; Zhang, Li Juan; Khan, Majad; Liu, Shao Qiong; Yang, Yi Yan; Qian, Yu

2009-05-01

195

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

196

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

197

[A case of facial nerve palsy induced by nab-paclitaxel].  

PubMed

The patient was a 60-year-old woman who underwent total mastectomy and axillary lymph node dissection for right breast cancer. She was treated with adjuvant chemotherapy( epirubicin plus cyclophosphamide[EC]and paclitaxel), hormone therapy, and radiation therapy. Multiple lung, lymph node, and bone metastases were detected after 4 years. The patient subsequently received nab-paclitaxel (nabPTX, 260 mg/m2, triweekly) and zoledronate therapy. Ptosis of her right eyebrow and the right angle of her mouth were observed after 8 courses of nabPTX, and peripheral right facial nerve palsy was diagnosed. She underwent rehabilitation, and facial nerve palsy improved after 9 months. Peripheral facial nerve palsy is a very rare adverse event of nabPTX. This is the first case report of peripheral facial nerve paralysis associated with nab- PTX. PMID:24394117

Minatani, Naoko; Kosaka, Yoshimasa; Sengoku, Norihiko; Kikuchi, Mariko; Nishimiya, Hiroshi; Waraya, Mina; Enomoto, Takumo; Tanino, Hirokazu; Watanabe, Masahiko

2013-11-01

198

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

199

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

PubMed

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

Arpino, Grazia; De Placido, Sabino; De Angelis, Carmine

2015-01-01

200

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

201

Review of phase II trials of Taxol (paclitaxel) in patients with advanced ovarian cancer.  

PubMed

The efficacy and safety of paclitaxel in the treatment of advanced ovarian cancer has been assessed in several phase II trials. McGuire and associates at the Johns Hopkins Oncology Cancer reported results from a phase II trial in which paclitaxel-administered as a 24-hour intravenous (i.v.) infusion with premedication to avoid acute hypersensitivity reactions-yielded one complete response (CR) and 11 partial responses (PRs) (overall response rate, 30%) among 40 previously treated patients with ovarian cancer evaluable for response; 25 of the patients had been refractory to cisplatin therapy. Among 30 evaluable patients who took part in a study at the Albert Einstein Cancer Center, paclitaxel (180 to 250 mg/m2 as a 24-hour i.v. infusion every 21-28 days) produced an overall response rate of 20% (1 CR, 5 PRs). Four responding patients were resistant to previous cisplatin therapy. Median survival for responders was 27 months, and 6 months for nonresponders (P = 0.0001). The Gynecologic Oncology Group confirmed the activity of paclitaxel (175 mg/m2 as a continuous 24-hour i.v. infusion) in 41 evaluable cisplatin-resistant patients, among whom 15 (37%) responded (5 CR, 10 PR). A total of 8 of 27 (29%) patients with cisplatin-refractory disease responded (2/27 CR, 6/27 PR). Among 14 patients whose disease progressed more than 6 months following cisplatin therapy, 3 had CRs and 4 had PRs. Finally, the National Cancer Institute Treatment Referral Center protocol enrolled more than 2,000 patients; preliminary analysis of 1,000 patients included 663 evaluable for response with measurable disease. There are 27 CRs and 119 PRs; median time to progression for responding patients is 7 months.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7865430

Einzig, A I

1994-01-01

202

Paclitaxel (Taxol) in relapsed and refractory ovarian cancer: the UK and Eire experience.  

PubMed

The purpose of our study was to investigate the efficacy and toxicity of paclitaxel in patients with relapsed or refractory epithelial ovarian cancer in the context of a large multicentre study performed in the UK and Eire. Patients with previously treated epithelial carcinoma of the ovary or fallopian tube who fulfilled the eligibility criteria were entered in the study. Eligibility criteria included: measurable or evaluable disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; up to three prior chemotherapy regimens, one of which had to contain a platinum agent; adequate haematological, renal and hepatic function; and no significant cardiac history. Patients received either 175 mg m-2 or 135 mg m-2 paclitaxel. The lower dose was administered to patients who had received more than two prior chemotherapy regimens. Paclitaxel was given by i.v. infusion over 3 h every 21 days. Response was assessed at three-cycle intervals or earlier if required. A total of 155 patients were registered for the study in the UK of whom 140 were eligible for response and toxicity evaluation, and 12 patients were assessed for toxicity only. Hair loss was the most frequently reported toxicity, with 74% (119/152) of patients reporting grade 3 alopecia. The most frequently reported serious toxicity was neutropenia, with 49% (74/152) of patients experiencing neutropenia grade 3 or 4. The response rate was 16% [two complete responders (CR), 20 partial responders (PR)], the median duration of response was 275 days and median survival was 244 days. Paclitaxel is active in relapsed and platinum-resistant epithelial ovarian cancer. It is well tolerated and can be given in an out-patient setting. The UK and Eire experience is very similar to that of US investigators in this group of patients. Further work is required to assess the optimal use of the drug in both first- and second-line therapy. PMID:7547214

Gore, M E; Levy, V; Rustin, G; Perren, T; Calvert, A H; Earl, H; Thompson, J M

1995-10-01

203

Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice.  

PubMed

Chemotherapy-induced neurotoxicity is a significant problem associated with successful treatment of many cancers. Tubulin is a well-established target of antineoplastic therapy; however, tubulin-targeting agents, such as paclitaxel and the newer epothilones, induce significant neurotoxicity. Eribulin mesylate, a novel microtubule-targeting analogue of the marine natural product halichondrin B, has recently shown antineoplastic activity, with relatively low incidence and severity of neuropathy, in metastatic breast cancer patients. The mechanism of chemotherapy-induced neuropathy is not well understood. One of the main underlying reasons is incomplete characterization of pathology of peripheral nerves from treated subjects, either from patients or preclinically from animals. The current study was conducted to directly compare, in mice, the neuropathy-inducing propensity of three drugs: paclitaxel, ixabepilone, and eribulin mesylate. Because these drugs have different potencies and pharmacokinetics, we compared them on the basis of a maximum tolerated dose (MTD). Effects of each drug on caudal and digital nerve conduction velocity, nerve amplitude, and sciatic nerve and dorsal root ganglion morphology at 0.25 × MTD, 0.5 × MTD, 0.75 × MTD, and MTD were compared. Paclitaxel and ixabepilone, at their respective MTDs, produced significant deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes, as well as moderate to severe degenerative pathologic changes in dorsal root ganglia and sciatic nerve. In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. Overall, our findings indicate that eribulin mesylate induces less neuropathy in mice than paclitaxel or ixabepilone at equivalent MTD-based doses. PMID:21498637

Wozniak, Krystyna M; Nomoto, Kenichi; Lapidus, Rena G; Wu, Ying; Carozzi, Valentina; Cavaletti, Guido; Hayakawa, Kazuhiro; Hosokawa, Satoru; Towle, Murray J; Littlefield, Bruce A; Slusher, Barbara S

2011-06-01

204

Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel  

Microsoft Academic Search

BackgroundPaclitaxel (PTX) is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol® (the current commercialized drug). We hypothesize that PTX-loaded micelles (M-PTX) may enhance tumor radiosensitivity by increasing the tumor

Fabienne Danhier; Pierre Danhier; Nicolas Magotteaux; Géraldine De Preter; Bernard Ucakar; Oussama Karroum; Bénédicte Jordan; Bernard Gallez; Véronique Préat

2012-01-01

205

Liposomal doxorubicin and nab-paclitaxel: nanoparticle cancer chemotherapy in current clinical use.  

PubMed

Liposomal doxorubicin and nab-paclitaxel are nanoparticle formulations of traditional cancer chemotherapy drugs which have ample clinical experience both pre- and post-nanoparticle modification. The alterations in pharmacokinetics, pharmacodynamics, efficacy, and toxicity compared with their parent compounds are instructive for future development of nanoparticle-based therapies. In this article we review the current status of these agents, emphasizing the alterations in clinical behavior resulting from the nanoparticle formulation of the parent compound. PMID:20217610

Gaitanis, Alexander; Staal, Stephen

2010-01-01

206

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

207

Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy  

Microsoft Academic Search

Background: We investigated the possible use of clinical signs of chemotherapy-induced peripheral neurotoxicity (CIPN) or of nerve growth factor (NGF) circulating levels to predict the final outcome of CIPN. Patients and methods: Sixty-two women affected by locally advanced squamous cervical carci- noma treated with TP (paclitaxel 175 mg\\/m2 over a 3 h infusion plus cisplatin 75 mg\\/m2) or TIP (TP

G. Cavaletti; G. Bogliun; L. Marzorati; A. Zincone; M. Piatti; N. Colombo; D. Franchi; M. T. La Presa; A. Lissoni; A. Buda; F. Fei; S. Cundari; C. Zanna

2004-01-01

208

Targeted Delivery of Paclitaxel to EphA2-Expressing Cancer Cells  

PubMed Central

Purpose YSA is an EphA2-targeting peptide that effectively delivers anti-cancer agents to prostate cancer tumors (1). Here, we report on how we increased the drug-like properties of this delivery system. Experimental Design By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo. Results dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared to vehicle or paclitaxel treatments. Conclusion This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anti-cancer agents to a variety of tumor types. Translational Relevance Overexpression of the EphA2 positively correlates with tumor malignancy and poor prognosis. For this reason, EphA2 is an attractive target for cancer cell specific drug delivery. In this study, we report on the development of dYNH, an EphA2 targeting peptide that when coupled to paclitaxel (PTX) has favorable pharmacological properties and possesses powerful anti-tumor activity in vivo. dYNH-PTX may allow for an expanded therapeutic index of paclitaxel as well as precluding the need for complex formulations and long infusion times. PMID:23155185

Wang, Si; Noberini, Roberta; Stebbins, John L.; Das, Swadesh; Zhang, Ziming; Wu, Bainan; Mitra, Sayantan; Billet, Sandrine; Fernandez, Ana; Bhowmick, Neil A.; Kitada, Shinichi; Pasquale, Elena B.; Fisher, Paul B.; Pellecchia, Maurizio

2012-01-01

209

Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing  

Microsoft Academic Search

Background. Paclitaxel-induced peripheral neuropathy (PN) may be severeand dose-limiting at initial doses = 275 mg\\/M2, but itsneurotoxicity at doses = 250 mg\\/M2 has been incompletelycharacterized. The purposes of this study were to characterize and quantifypaclitaxel-induced PN and to determine the utility of quantitative sensorytesting (QST). Methods. We prospectively examined clinically and by QST 37women with metastatic breast cancer, treated with

Peter a. Forsyth; Casilda Balmaceda; Kendra Peterson; Andrew D. Seidman; Penny Brasher; Lisa M. Deangelis

1997-01-01

210

In vitro synergy of paclitaxel (Taxol) and vinorelbine (navelbine) against human melanoma cell lines.  

PubMed

Paclitaxel (PTXL) (Taxol), a taxane, and vinorelbine (VRB), a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target, but inhibit growth by binding to different sites. We evaluated in vitro the antiproliferative activity of these two drugs as single agents and in combination, against two human melanoma cell lines, G361 and StM111a. The SRB (sulphorhodamine B) assay was used to determine growth inhibition. Possible drug-drug interaction at the cellular level was assessed by constructing Isoboles (Isobologram analysis) and applying the concept of an 'envelope of additivity'. Both agents were active in the nanomolar range at clinically achievable concentrations. The mean IC50 for G361 was 46.6 nM (PTXL) and 19.9 nM (VRB) after a 1 h drug exposure. Mean IC50 (1 h) for StM111a was 9.7 nM (PTXL) and 26.9 nM (VRB). Isobole analysis at the isoeffect levels of 25%, 50% and 75% indicated that drug interaction was predominantly synergistic (supra-additive) when paclitaxel and VRB were added concurrently for 1 h to cultures of StM11 1a or G361. In some experiments, this synergy was observed with particularly low concentrations of paclitaxel (3 nM) and VRB (0.01 nM). A new points were located within the envelope of additivity or in the subadditive (antagonism) region of the isobole. An overall synergy was also found if the data were analysed by the median effect analysis. The effect of these agents on the cytoskeleton and ultrastructure were studied with immunofluorescence and electron microscopy, respectively. These results confirm the in vitro inhibitory activity of paclitaxel and VRB against malignant melanoma, but more importantly the two drugs appear to act synergistically at relatively low concentrations. PMID:9155533

Photiou, A; Shah, P; Leong, L K; Moss, J; Retsas, S

1997-03-01

211

B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation  

PubMed Central

In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present work we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable shRNA or transient siRNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3 mediated paclitaxel resistance, and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells, along with the expression of its direct downstream targets Mcl-1 and Survivin. The phosphorylation of Jak2, an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3- expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knock down tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong anti-tumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data demonstrate that in breast cancer cells B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners. PMID:21518725

Liu, Hao; Tekle, Christina; Chen, Yih-Wen; Kristian, Alexandr; Zhao, Yuhua; Zhou, Ming; Liu, Zixing; Ding, Yan; Wang, Bin; Mælandsmo, Gunhild Mari; Nesland, Jahn Marthin; Fodstad, Oystein; Tan, Ming

2012-01-01

212

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

213

Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo.  

PubMed

Intracellular events following paclitaxel binding to microtubules that lead to cell death remain poorly understood. Because reactive oxygen species (ROS) are involved in the cytotoxicity of anticancer agents acting through independent molecular targets, we explored the role of ROS in paclitaxel cytotoxicity. Within 15 min after in vitro exposure of A549 human lung cancer cells to paclitaxel, a concentration-dependent intracellular increase in O(o)(2)(-) and H(2)O(2) levels was detected by spectrofluorometry. Addition of N-acetylcysteine (NAC) or glutathione, two H(2)O(2) scavenger, induced a 4-fold increase in paclitaxel IC(50). Delaying NAC co-incubation by 4 hr, resulted in a 3-fold reduction in cell protection. The glutathione synthesis inhibitor, buthionine sulfoximine significantly increased paclitaxel cytotoxicity and H(2)O(2) accumulation, but did not modify O(o)(2)(-) levels. Co-incubation with diphenylene iodonium suggested that paclitaxel induced-O(o)(2)(-) production was in part associated with increased activity of cytoplasmic NADPH oxidase. Concomitant treatment with inhibitors of caspases 3 and 8 increased cell survival but did not prevent the early accumulation of H(2)O(2.) To evaluate the role of ROS in paclitaxel antitumoral activity, mice were injected with LLC1 lung cancer cells and treated with paclitaxel i.p. and/or NAC. The antitumoral activity of paclitaxel in mice was abolished by NAC. In conclusion, the accumulation of H(2)O(2) is an early and crucial step for paclitaxel-induced cancer cell death before the commitment of the cells into apoptosis. These results suggest that ROS participate in vitro and in vivo to paclitaxel cytotoxicity. PMID:16450384

Alexandre, Jérôme; Batteux, Frédéric; Nicco, Carole; Chéreau, Christiane; Laurent, Alexis; Guillevin, Loïc; Weill, Bernard; Goldwasser, François

2006-07-01

214

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

215

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

216

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

217

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

218

Development and evaluation of paclitaxel nanoparticles using a quality-by-design approach.  

PubMed

The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett-Burman design and finally nanoparticles were optimized using Box-Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems. PMID:23918313

Yerlikaya, Firat; Ozgen, Aysegul; Vural, Imran; Guven, Olgun; Karaagaoglu, Ergun; Khan, Mansoor A; Capan, Yilmaz

2013-10-01

219

Double layer paclitaxel delivery systems based on bioresorbable terpolymer with shape memory properties.  

PubMed

The growing interest in the bioresorbable polymers contributed to developing a number of commercially available controlled drug delivery systems. Due to a variety of drugs and their physicochemical properties, there is a necessity of choosing an appropriate drug carrier. Terpolymer with shape memory properties was used to obtain double layer matrices composed of drug free matrix and paclitaxel containing layer. The in vitro degradation and drug release study were conducted at 37 °C in PBS (pH 7.4). The investigated materials were characterized by GPC (gel permeation chromatography) and DSC (differential scanning calorimetry). HPLC (high-pressure liquid chromatography) was applied to analyze the amount of released paclitaxel. The main purpose of this work was to determine the usefulness of the studied terpolymer as an anti-restenotic drug vehicle. Based on the obtained results it was established that polymer's degradation proceeded regularly and provided even paclitaxel release profiles. Double layer systems allowed to modify the amount of released drug which may be considered while developing the self-expanding drug-eluting stents tailoring different clinical indications. PMID:24491529

Musia?-Kulik, Monika; Kasperczyk, Janusz; Smola, Anna; Dobrzy?ski, Piotr

2014-04-25

220

A retrospective study of paclitaxel combining nedaplatin chemotherapy for esophageal cancer.  

PubMed

The aim of this study was to evaluate the efficacy and tolerability of the combination of paclitaxel and nedaplatin in patients with advanced esophageal cancer. Patients (n=310) with recurrent or metastatic esophageal squamous cell carcinoma, who had a maximum of one previous chemotherapy regimen, were enrolled in this study. All patients had bidimensionally measurable disease. Patients received 175?mg/m of paclitaxel over a 3?h infusion, followed by nedaplatin 80?mg/m in a 1?h infusion on day 1 every 3 weeks for up to 6 treatment cycles. The overall response rate was 47.7%, with complete and partial response rates of 6.1 and 41.7%, respectively. The median time to progression for all patients was 6.8 months (95% confidence interval, 6.2-7.4 months) and the 3-year disease-free survival probability was 3 (15.8%). The major toxicity observed was cumulative neutropenia, with 29% patients developing grade 4 toxicity. There was no treatment-related death. The most common nonhematologic toxicity encountered with this regimen was pain and cumulative peripheral neuropathy, with 26% patients experiencing grade 2 or 3 toxicity. The combination of paclitaxel and nedaplatin shows significant antitumor activity and a favorable toxicity profile in patients with metastatic carcinoma of esophageal cancer. PMID:25222530

Du, Jianping; Hu, Changlu; Zhang, Yuliu; Hu, Bing; Wang, Fen; Zhang, Yumei

2015-01-01

221

[A case of advanced gastric cancer effectively treated with weekly paclitaxel as neoadjuvant chemotherapy].  

PubMed

We report a patient with advanced gastric cancer responding remarkably to neoadjuvant chemotherapy consisting of weekly paclitaxel. The patient was a 50-year-old male who had large advanced gastric cancer, suspected of invasion to the duodenum and pancreas and severe lymph node metastasis [cT4 (pancreas), cN2, cH0, cP0, cM0, cStage IV]. He was treated with weekly paclitaxel as neoadjuvant chemotherapy. According to gastroscope and CT findings, a significant tumor reduction was obtained after 3 courses. Therefore, distal gastrectomy with D2 nodal dissection were performed. The histological diagnosis was pT2, pN2, pStage IIIA, and the histological effect of the main tumor was judged to be Grade 2. The patient has now been in good health without recurrence for 3 years after surgery. This case suggests that neoadjuvant chemotherapy with weekly paclitaxel is a potentially effective regimen for advanced gastric cancer. PMID:24196077

Saito, Yasufumi; Ikeda, Masahiro; Takahashi, Tadateru; Ishida, Nobuki; Nakano, Ryosuke; Kurayoshi, Manabu; Nakatani, Tamaki; Toyota, Kazuhiro; Sadamoto, Seiji; Mandai, Koichi

2013-10-01

222

Development and validation of the HPLC method for simultaneous estimation of Paclitaxel and topotecan.  

PubMed

A simple, rapid, accurate and precise high performance liquid chromatography (HPLC) method for simultaneous analysis of Paclitaxel and Topotecan was developed. Different analytical parameters, such as linearity, accuracy, precision, specificity with intentional degradation, limit of detection and limit of quantification (LOQ), were determined according to the ICH guidelines. Acetonitrile-water (70:30, 0.1% trifluoroacetic acid) was run on a Phenomenex Luna C-18(2) column in isocratic mode at a flow rate of 1.2 mL/min for simultaneous analysis of the two drugs using a UV detector set at 227 nm. The proposed method showed a retention time (Rt) of 14.56 min for Topotecan and 23.81 min for Paclitaxel with a continuous run up to 30 min. The linearity of the calibration curves for each analyte in the desired concentration range was found to be good (r(2) > 0.9995). The recovery ranged from 97.9 to 101% for each drug with a relative standard deviation (%RSD) of <2%. Peaks corresponding to each of the drugs exhibited  positive values for the minimum peak purity index over the entire range of integrated chromatographic peak indicating high purity of the peaks. Stability analysis revealed that the drugs remained stable for sufficient time. Thus, the developed method was found to be robust and it can be employed to quantify Paclitaxel and Topotecan in commercial sample and rat blood/serum. PMID:23843442

Jain, Ankit; Gulbake, Arvind; Jain, Ashish; Shilpi, Satish; Hurkat, Pooja; Kashaw, Sushil; Jain, Sanjay K

2014-08-01

223

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

224

Weekly paclitaxel as a radiation sensitizer for locally advanced gastric and pancreatic cancers: the Brown University Oncology Group experience.  

PubMed

Many patients with cancer of the stomach or pancreas have locally advanced, unresectable disease at diagnosis or will develop an early local or regional recurrence despite potentially curative surgery. Effective local treatment could increase the proportion of patients able to undergo surgery and decrease locoregional recurrences, which should improve overall survival. External beam radiation (RT) by itself has little effect. Standard treatment, such as RT with concurrent administration of 5-fluorouracil-based chemotherapy as a radiation sensitizer, has, at best, a modest impact on locoregional recurrences and survival. The use of a more effective radiosensitizer might improve the efficacy of local treatment. Paclitaxel synchronizes cells at G2M, the phase of the cell cycle during which cells are most sensitive to the effects of ionizing radiation, and has been demonstrated to sensitize a variety of human cell lines to the effects of RT. In patients with locally advanced non-small cell lung cancer (NSCLC), the Brown University Oncology Group (BrUOG) has demonstrated a high response rate to low-dose weekly paclitaxel with concurrent RT. In addition, we demonstrated that the response to paclitaxel/RT was not affected by mutations in the p53 tumor suppressor gene. This suggested that paclitaxel/RT would be a rational treatment approach for other malignancies with a high frequency of p53 mutations, such as gastric and pancreatic cancers. We have completed a phase I study of weekly paclitaxel and concurrent radiation for locally advanced gastric and pancreatic cancers. The maximum tolerated dose of paclitaxel was 50mg/m2/week for six weeks with 50 Gray (Gy) abdominal radiation. The dose limiting toxicities were abdominal pain, nausea and anorexia. Preliminary response data from ongoing phase II studies suggest that preoperative paclitaxel/RT has substantial activity in patients with locally advanced gastric and pancreatic cancers, though whether this will translate into improved disease-free and overall survival in these patients is not known. PMID:9206986

Sikov, W M; Safran, H

1997-05-01

225

Synergy of Nab-paclitaxel and Bevacizumab in Eradicating Large Orthotopic Breast Tumors and Preexisting Metastases12  

PubMed Central

Introduction Patients with metastatic disease are considered incurable. We previously showed that nabpaclitaxel (nanoparticle albumin-embedded paclitaxel) combined with anti-vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, eradicates orthotopic small-sized breast tumors and metastasis. Here, we assessed this therapy in two models of advanced (450–600 mm3) breast tumors and delineated VEGF-A-dependent mechanisms of tumor resistance. Methods Mice with luciferase-tagged advanced MDA-MB-231 and MDA-MB-435 tumors were treated with saline, nab-paclitaxel (10 or 30 mg/kg), bevacizumab (4 mg/kg), or combined drugs. Lymphatic and lung metastases were measured by luciferase assay. Proinflammatory and survival pathways were measured by ELISA, Western blot and immunohistochemistry. Results Nab-paclitaxel transiently suppressed primary tumors by 70% to 90% but had no effect on metastasis. Coadministration of bevacizumab increased the response rate to 99%, including 71% of complete responses in MDA-MB-231-bearing mice treated concurrently with 30 mg/kg of nab-paclitaxel. This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA-MB-231 and MDA-MB-435 models. The mechanism involves paclitaxel-induced NF-?B pathway that upregulates VEGF-A and other tumor prosurvival proteins. Conclusions Bevacizumab prevents tumor recurrence and metastasis promoted by nab-paclitaxel activation of NF-?B pathway. Combination therapy with high-dosed nab-paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases. These findings strongly support translating this regimen into clinics. PMID:21472137

Volk, Lisa D; Flister, Michael J; Chihade, Deena; Desai, Neil; Trieu, Vuong; Ran, Sophia

2011-01-01

226

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

227

Safety of nanoparticle albumin-bound paclitaxel administered to breast cancer patients with clinical contraindications to paclitaxel or docetaxel: Four case reports  

PubMed Central

Taxanes, including paclitaxel (PTX) and docetaxel (DOC), are poorly soluble in water due to their hydrophobic properties and thus, require solvents. However, use of these solvents has been associated with toxic responses, including a hypersensitivity reaction (HSR). Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel formulation of PTX, which allows reconstitution of the agent with a saline solution instead of solvents and administration without premedication for HSRs. The current study reports the safe administration of nab-PTX to four breast cancer patients considered clinically to have contraindications to PTX or DOC. Two of the patients had previously experienced HSRs to PTX or DOC and the other two patients had contraindications to steroids as a premedication for HSRs, since one patient suffered from diabetes and the other was a carrier of the hepatitis B virus. All 4 patients were safely administered nab-PTX. In conclusion, administration of nab-PTX appears to be effective for patients that have previously experienced HSRs to other taxanes or in those with contraindications to steroids. PMID:24137430

KIMURA, KOSEI; TANAKA, SATORU; IWAMOTO, MITSUHIKO; FUJIOKA, HIROYA; TAKAHASHI, YUKO; SATO, NAYUKO; TERASAWA, RISA; TOMINAGA, TOMO; IKARI, AYANA; UCHIYAMA, KAZUHISA

2013-01-01

228

Paclitaxel-associated subungual pyogenic granuloma: report in a patient with breast cancer receiving paclitaxel and review of drug-induced pyogenic granulomas adjacent to and beneath the nail.  

PubMed

Subungual and periungual pyogenic granuloma occur in association with certain systemic medications. Paclitaxel is an antitumor drug of the taxane family used in the management of breast cancer. Taxanes have many associated nail changes that may occur in patients receiving either docetaxel or paclitaxel for systemic chemotherapy. The nail changes in a 68-year-old woman with metastatic breast cancer who presented for nail changes after receiving 12 cycles of weekly paclitaxel are described herein: nail plate red-brown discoloration, onycholysis with leukonychia, proximal subungual hemorrhage, and subungual pyogenic granuloma. The literature on systemic medications associated with the development of subungual and periungual pyogenic granulomas is reviewed; drugs associated with the development of pyogenic granuloma at the locations include antineoplastics, antiretrovirals, epidermal growth factor receptor inhibitors, immunosuppressants and retinoids. In conclusion, subungual pyogenic granuloma can occur not only in patients receiving docetaxel, but also in patients treated with paclitaxel. And, paclitaxel should be included in the list of drugs associated with the occurrence of subungual pyogenic granuloma. PMID:22270214

Paul, Laura J; Cohen, Philip R

2012-02-01

229

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

230

Ephrin type-A receptor 2 regulates sensitivity to paclitaxel in nasopharyngeal carcinoma via the phosphoinositide 3-kinase/Akt signalling pathway  

PubMed Central

Ephrin type-A receptor 2 (EphA2) is a receptor tyrosine kinase that is associated with cancer cell metastasis. There has been little investigation into its impact on the regulation of sensitivity to paclitaxel in nasopharyngeal carcinoma (NPC). In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5-8F cells, compared with control cells exposed to the same concentrations of paclitaxel. Flow cytometry and western blot analysis demonstrated that over-expression of EphA2 decreased NPC cancer cell sensitivity to paclitaxel by regulating paclitaxel-mediated cell cycle progression but not apoptosis in vitro. This was accompanied by alterations in the expression of cyclin-dependent kinase inhibitors, p21 and p27, and of inactive phosphorylated-retinoblastoma protein. Furthermore, paclitaxel stimulation and EphA2 over-expression resulted in activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway in NPC cells. Inhibition of the PI3K/Akt signalling pathway restored sensitivity to paclitaxel in 5-8F cells over-expressing EphA2, which indicated that the PI3K/Akt pathway is involved in EphA2-mediated paclitaxel sensitivity. The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC. PMID:25351620

WANG, YUNYUN; LIU, YONG; LI, GUO; SU, ZHONGWU; REN, SHULING; TAN, PINGQING; ZHANG, XIN; QIU, YUANZHENG; TIAN, YONGQUAN

2015-01-01

231

The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas.  

PubMed

Paclitaxel is a main ingredient in the combination chemotherapy treatment of advanced human cervical squamous cell carcinomas. We investigated the roles and underlying molecular mechanisms of PinX1 in cervical squamous cell carcinomas (CSCC) cells response to paclitaxel and its clinical significances. The expression dynamics of PinX1 was first examined by immunohistochemistry in 122 advanced CSCC patients treated with cisplatin/paclitaxel chemotherapy. The expression of PinX1 was significantly associated with the effects of cisplatin/paclitaxel chemotherapy in advanced CSCCs (P<0.05). High expression of PinX1 correlated with CSCC's response to cisplatin/paclitaxel chemotherapy, and was an independent predictor of shortened survival (P<0.05). A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on CSCC cells chemosensitivity to paclitaxel and underlying mechanisms. In CSCC cells, the levels of PinX1 were only associated with the cytotoxicity and sensitivity of paclitaxel, in which knockdown of PinX1 dramatically enhanced paclitaxel cytotoxicity, whereas the reestablishment of PinX1 levels substantially reduced the paclitaxel-induced killing effect. In addition, we identified that the ability of PinX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel, and further studies demonstrated that shortened distance between sisters kinetochores by nocodazole confers upon PinX1-replenished cells a sensitivity to the death inducing paclitaxel effects. Furthermore, our study of CSCC cells xenografts in nude mice confirmed the role of PinX1 in paclitaxel sensitivity in vivo. Our data reveal that PinX1 could be used as a novel predictor for CSCC patient response to paclitaxel, and the role of PinX1-mediated paclitaxel sensitivity might represent a new direction for the development of a new generation of microtubule drugs. PMID:25045845

Tian, Xiao-Peng; Qian, Dong; He, Li-Ru; Huang, He; Mai, Shi-Juan; Li, Chang-Peng; Huang, Xiao-Xia; Cai, Mu-Yan; Liao, Yi-Ji; Kung, Hsiang-fu; Zeng, Yi-Xin; Xie, Dan

2014-10-10

232

Synergistic anti-tumoral effect of paclitaxel (Taxol)+AS101 in a murine model of B16 melanoma: association with ras-dependent signal-transduction pathways.  

PubMed

Optimal doses of paclitaxel (Taxol) combined with the immunomodulator AS101, previously shown to have anti-tumoral effects, administered to B16 melanoma-bearing mice decreased tumor volume and resulted in over 60% cure. Paclitaxel+AS101 directly inhibited the clonogenicity of B16 melanoma cells in a synergistic, dose-dependent manner. We suggest that this results from both reduced paclitaxel-induced bone marrow toxicity and induction of differential signal-transduction pathways, which lead to apoptosis of tumor cells. Paclitaxel+AS101 synergistically activated c-raf-1 and MAPK ERK1 and ERK2. This activation was essential for the synergistic induction of p21(waf) protein. Cell-cycle analysis of B16 cells treated with both compounds revealed an increased accumulation in G(2)M, though AS101 alone produced significant G(1) arrest. These activities were ras-dependent. AS101+paclitaxel induced significant synergistic phosphorylation (inactivation) of the anti-apoptotic protein Bcl-2. Whereas phosphorylation of Bcl-2 by paclitaxel was raf-dependent only, the synergistic effect of both compounds together was ras-, raf- and MAPK-dependent. No effect of the combined treatment on Bax protein expression was observed. We suggest that AS101 renders more cells susceptible to Bcl-2 phosphorylation by paclitaxel, possibly by increasing the accumulation of paclitaxel-induced cells in G(2)M. Exposure of B16 cells to clinically achievable concentrations of paclitaxel+AS101 increased the rate of apoptosis of treated cells. Apoptosis induced by AS101 alone was both raf- and MAPK-dependent, while that induced by paclitaxel was raf-dependent only. PMID:10738258

Kalechman, Y; Longo, D L; Catane, R; Shani, A; Albeck, M; Sredni, B

2000-04-15

233

Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway.1  

PubMed Central

Objectives To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines. Methods ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway. Results Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC50 values of 1–5 nM and 5–10 nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5 mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index <1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line. Conclusions Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer. PMID:22252099

Hanna, Rabbie K.; Zhou, Chunxiao; Malloy, Kimberly M.; Gehrig, Paola A; Bae-Jump, Victoria L.

2012-01-01

234

Reversal of paclitaxel resistance in epithelial ovarian carcinoma cells by a MUC1 aptamer-let-7i chimera.  

PubMed

The purpose of this study was to establish tumor tissue specific delivery of let-7i miRNA to reverse paclitaxel-induced chemoresistance. A chimera that combines MUC1 aptamer and let-7i miRNA was tested in OVCAR-3 ovarian cancer cells. Results demonstrated that the chimera can specifically be delivered into OVCAR-3 cells and the released let-7i significantly sensitized the role of paclitaxel in inhibiting cell proliferation, inducing cell apoptosis, and decreasing long-term cell survival. The chimera achieved reversal of chemoresistance through downregulation of cyclin D1, cyclin D2, Dicer 1, and PGRMC1 expressions. Our study indicated that this MUC1/let-7i chimera can specifically reverse chemoresistance to paclitaxel. PMID:22812695

Liu, Nenghui; Zhou, Changju; Zhao, Jingfeng; Chen, Yuxiang

2012-10-01

235

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

236

Preparative isolation of paclitaxel and related taxanes from cell cultures of Taxus chinensis using reversed-phase flash chromatography.  

PubMed

In this study, paclitaxel, baccatin III, taxuyunnanine C and sinenxane C were successfully separated by reversed-phase flash chromatography on a manually packed C18 column from Taxus chinensis cell culture extract. The crude cell culture extract was first treated with Al2O3 column chromatography and then divided into two parts: fraction 1 and fraction 2. Ten milligrams of baccatin III and 19 mg of paclitaxel were obtained from 100 mg dried fraction 1. Fifty-two milligrams of taxuyunnanine C and 11 mg sinenxane C were obtained from 100 mg dried fraction 2. The purities of the four compounds were 98.02%, 98.53%, 98.93% and 98.76%, respectively. Their structures were characterised by using UV, MS and NMR. These results indicate that paclitaxel and related taxanes including baccatin III can be obtained from cell culture in a highly pure state using reversed-phase flash chromatography. PMID:25109635

Liang, Zhi-Kun; Huang, Ruo-Gu; Xie, Zhi-Sheng; Xu, Xin-Jun

2015-02-01

237

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

238

Nanocarrier-assisted sub-cellular targeting to the site of mitochondria improves the pro-apoptotic activity of paclitaxel.  

PubMed

Many drug molecules exert their biological action on intracellular molecular targets present on or inside various cellular organelles. Consequently, it has become more evident that the efficiency and efficacy of drug action is dependent largely on how well an unaided drug molecule is able to reach its intracellular target. We hypothesized that the biological action of such drug molecules might be improved by specific delivery to the appropriate sub-cellular site by a pharmaceutical carrier designed for the purpose. To test our hypothesis, we used paclitaxel, a molecule that has recently been shown to have pro-apoptotic biological targets on the mitochondria but has a quantitative structure-activity relationship-predicted cytosolic accumulation and no affinity for mitochondria. Using a mitochondria-specific nanocarrier system (DQAsomes) prepared from the amphiphilic quinolinium derivative dequalinium chloride to deliver paclitaxel to mitochondria in cells, we report that it is possible to improve the pro-apoptotic action of paclitaxel. PMID:18686127

D'Souza, Gerard G M; Cheng, Shing-Ming; Boddapati, Sarathi V; Horobin, Richard W; Weissig, Volkmar

2008-08-01

239

Polymeric Micelles for Delivery of Poorly Soluble Drugs: Preparation and Anticancer Activity In Vitro of Paclitaxel Incorporated into Mixed Micelles Based on Poly(ethylene Glycol)-Lipid Conjugate and Positively Charged Lipids  

PubMed Central

Paclitaxel-loaded mixed polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-PE), solid triglycerides (ST), and cationic Lipofectin® lipids (LL) have been prepared. Micelles with the optimized composition (PEG-PE/ST/LL/paclitaxel = 12/12/2/1 by weight) had an average micelle size of about 100 nm, and zeta-potential of about 26 mV. Micelles were stable and did not release paclitaxel when stored at 4°C in the darkness (just 2.9% of paclitaxel have been lost after 4 months with the particle size remaining unchanged). The release of paclitaxel from such micelles at room temperature was also insignificant. However, at 37°C, approx. 16% of paclitaxel was released from PEG-PE/ST/LL/paclitaxel micelles in 72 h, probably, because of phase transition in the ST-containing micelle core. In vitro anticancer effects of PEG-PE/ST/LL/paclitaxel and control micelles were evaluated using human mammary adenocarcinoma (BT-20) and human ovarian carcinoma (A2780) cell lines. Paclitaxel in PEG-PE/ST/LL micelles demonstrated the maximum anti-cancer activity. Cellular uptake of fluorescently-labeled paclitaxel-containing micelles by BT-20 cells was investigated using a fluorescence microscopy. It seems that PEG-PE/ST/LL micelles, unlike micelles without the LL component, could escape from endosomes and enter the cytoplasm of BT-20 cancer cells thus increasing the anticancer efficiency of the micellar paclitaxel. PMID:15848957

WANG, JUNPING; MONGAYT, DIMITRY; TORCHILIN, VLADIMIR P.

2006-01-01

240

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

241

Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells  

PubMed Central

Background Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models. Methods MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release. Results SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells. Conclusion SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types.

Lin, Yingjia; Jiang, Dan; Li, Yang; Han, Xinye; Yu, Di; Park, Jeong Hill; Jin, Ying-Hua

2014-01-01

242

Encapsulation of paclitaxel into a bio-nanocomposite. A study combining inelastic neutron scattering to thermal analysis and infrared spectroscopy  

NASA Astrophysics Data System (ADS)

The anticancer drug paclitaxel was encapsulated into a bio-nanocomposite formed by magnetic nanoparticles, chitosan and apatite. The aim of this drug carrier is to provide a new perspective against breast cancer. The dynamics of the pure and encapsulated drug were investigated in order to verify possible molecular changes caused by the encapsulation, as well as to follow which interactions may occur between paclitaxel and the composite. Fourier transformed infrared spectroscopy, thermal analysis, inelastic and quasi-elastic neutron scattering experiments were performed. These very preliminary results suggest the successful encapsulation of the drug.

Martins, Murillo L.; Orecchini, Andrea; Aguilera, Luis; Eckert, Juergen; Embs, Jan; Matic, Aleksander; Saeki, Margarida J.; Bordallo, Heloisa N.

2015-01-01

243

Inherent and Acquired Resistance to Paclitaxel in Hepatocellular Carcinoma: Molecular Events Involved  

PubMed Central

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and is a major cause of cancer related deaths worldwide. Only 10 to 20% of HCC can be surgically excised. Therefore, chemotherapeutic intervention and treatment is essential for achieving favorable prognosis. However, therapeutic outcome of chemotherapy is generally poor owing to inherent resistance of cancer cells to the treatment or due to development of acquired resistance. To differentiate and delineate the molecular events, we developed drug resistant Hep3B cells (DRC) by treating cells with the increasing concentration of paclitaxel. We also developed a unique single cell clone of Hep3B cells (SCC) by selecting single cell colonies and screening them for resistant phenotype. Interestingly, both DRC and SCC were resistant to paclitaxel in comparison to parental Hep3B cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, level of P-glycoprotein (P-gp) was elevated in DRC. In addition, Caveolin-1 (Cav-1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) protein levels were elevated in DRC whereas in SCC, FASN and CYP450 levels were elevated. Downregulation of these molecules by respective siRNAs and/or by specific pharmacological inhibitors resensitized cells to paclitaxel. Interestingly, these drug resistant cells were also less sensitive to vinblastine, doxorubicin and methotrexate with the exception of cisplatin. Our results suggested that differential levels of P-gp, Cav-1 and FASN play a major role in acquired resistant phenotype whereas FASN level was associated with the presentation of inherent resistant phenotype in HCC. PMID:23613870

Meena, Avtar Singh; Sharma, Aanchal; Kumari, Ratna; Mohammad, Naoshad; Singh, Shivendra Vikram; Bhat, Manoj Kumar

2013-01-01

244

Paclitaxel and carboplatin in patients with metastatic urothelial cancer: results of a phase II trial.  

PubMed Central

The present phase II trial was undertaken to assess the efficacy and toxicity of a combination of paclitaxel and carboplatin as first-line chemotherapy in patients with metastatic transitional cell carcinoma of the urothelium. Twenty patients (age range 50-79 years; inclusion criteria: WHO performance status 0-2, no previous cytotoxic treatment) with metastatic transitional cell carcinoma of the urothelium were recruited and received cytotoxic treatment with paclitaxel at a dosage of 175 mg m(-2) administered over a 3-h infusion and carboplatin given at an AUC of 5 mg ml(-1) min (according to creatinine clearance) administered every 21 days. A total of 65% of patients achieved remissions (CR+PR), with CR occurring in 40% of patients. A further 15% of patients experienced stable disease. Remissions occurred after 2.4 +/- 0.8 (mean +/- standard deviation; range two to four) treatment cycles. The mean duration of responses (CR+PR) was 8.5 +/- 5.5 months. After a mean observation period of 11.4 +/- 4.8 months, 16 patients (80%) are alive. Toxicity included alopecia of WHO grade 3 in all patients, leucopenia of WHO grades 1 and 2 in ten patients, grade 3 in eight and grade 4 in two patients and, finally, severe thrombocytopenia grade 3 in only three patients. Non-haematological toxicity consisted of polyneuropathy of WHO grade 1 in 13 patients and grade 2 in five patients. We thus conclude that a combination of paclitaxel and carboplatin at the given dosage and schedule constitutes an active, well-tolerated first-line cytotoxic treatment for patients with metastatic urothelial cancer. PMID:9703285

Zielinski, C. C.; Schnack, B.; Grbovic, M.; Brodowicz, T.; Wiltschke, C.; Steger, G.; Pflüger, H.; Marberger, M.

1998-01-01

245

Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer  

PubMed Central

BACKGROUND No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease. RESULTS The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contra-lateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption. CONCLUSIONS Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.) PMID:25564897

Tolaney, Sara M.; Barry, William T.; Dang, Chau T.; Yardley, Denise A.; Moy, Beverly; Marcom, P. Kelly; Albain, Kathy S.; Rugo, Hope S.; Ellis, Matthew; Shapira, Iuliana; Wolff, Antonio C.; Carey, Lisa A.; Overmoyer, Beth A.; Partridge, Ann H.; Guo, Hao; Hudis, Clifford A.; Krop, Ian E.; Burstein, Harold J.; Winer, Eric P.

2015-01-01

246

A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer  

PubMed Central

Paclitaxel (PTX) is one of the most effective chemotherapeutic drugs for the treatment of a variety of cancers. However, it is associated with serious side effects caused by PTX itself and the Cremophor EL emulsifier. In the present study, we report the development of a well-defined amphiphilic linear–dendritic copolymer (named as telodendrimer) composed of polyethylene glycol (PEG), cholic acid (CA, a facial amphiphilic molecule) and lysine, which can form drug-loaded core/shell micelles when mixed with hydrophobic drug, such as PTX, under aqueous condition. We have used PEG5k-CA8, a representive telodendrimer, to prepare paclitaxel-loaded nanoparticles (PTX-PEG5k-CA8 NPs) with high loading capacity (7.3 mg PTX/mL) and a size of 20–60 nm. This novel nanoformulation of PTX was found to exhibit similar in vitro cytotoxic activity against ovarian cancer cells as the free drug (Taxol®) or paclitaxel/ human serum albumin nanoaggregate (Abraxane®). The maximum tolerated doses (MTDs) of PTX-PEG5k-CA8 NPs after single dose and five consective daily doses in mice were approximately 75 and 45 mg PTX/kg, respectively, which were 2.5-fold higher than those of Taxol®. In both subcutaneous and orthotopic intraperitoneal murine models of ovarian cancer, PTX-PEG5k-CA8 NPs achieved superior toxicity profiles and antitumor effects compared to Taxol® and Abraxane® at equivalent PTX doses, which were attributed to their preferential tumor accumulation, and deep penetration into tumor tissue, as confirmed by near infrared fluorescence (NIRF) imaging. PMID:19660809

Xiao, Kai; Luo, Juntao; Fowler, Wiley; Li, Yuanpei; Lee, Joyce; Wang, Li; Lam, Kit S.

2009-01-01

247

Neurosteroid 3?-Androstanediol Efficiently Counteracts Paclitaxel-Induced Peripheral Neuropathy and Painful Symptoms  

PubMed Central

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/2days) 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

Taleb, Omar; Mensah-Nyagan, Ayikoe Guy

2013-01-01

248

Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma.  

PubMed

Invasive brain glioma is the most lethal type of cancer and is highly infiltrating. This leads to an extremely poor prognosis and makes complete surgical removal of the tumor virtually impossible. Non-penetration of therapeutic drugs across the blood-brain barrier (BBB), brain cancer stem cells (CSCs), and brain cancer vasculogenic mimicry (VM) results in relapse after surgical and radio therapy. We developed a functional targeting chemotherapy for transporting drugs across the BBB, destroying VM channels, and eliminating CSCs and cancer cells in the brain. The studies were undertaken on brain glioma cells in vitro and in brain glioma-bearing rats. Using paclitaxel as the anticancer drug and artemether as the regulator of apoptosis and inhibitor of VM channels, a kind of functional targeting paclitaxel plus artemether liposomes was developed by modifying two new functional materials: a mannose-vitamin E derivative conjugate (MAN-TPGS1000) and a dequalinium-lipid derivative conjugate (DQA-PEG2000-DSPE). The transport mechanism across the BBB was associated with receptor-mediated endocytosis by MAN-TPGS1000 conjugate via glucose transporters and adsorptive-mediated endocytosis by DQA-PEG2000-DSPE conjugate via electric charge-based interactions. The efficacy was related to the destruction of VM channels by regulating VM indicators, as well as the induction of apoptosis in brain cancer cells and CSCs by activating apoptotic enzymes and pro-apoptotic proteins and inhibiting anti-apoptotic proteins. These data suggest that the chemotherapy using functional targeting paclitaxel plus artemether liposomes could provide a new strategy for treating invasive brain glioma. PMID:24726749

Li, Xiu-Ying; Zhao, Yao; Sun, Meng-Ge; Shi, Ji-Feng; Ju, Rui-Jun; Zhang, Cheng-Xiang; Li, Xue-Tao; Zhao, Wei-Yu; Mu, Li-Min; Zeng, Fan; Lou, Jin-Ning; Lu, Wan-Liang

2014-07-01

249

Compatibility of Paclitaxel Injection Diluent with Two Reduced-Phthalate Administration Sets for the Acclaim Pump.  

PubMed

The purpose of this project was to evaluate the compatibility of paclitaxel admixtures with the two reduced-phthalate administration sets designed for use with the Acclaim Infusion Control Device. The first is a nitroglycerin set composed of polyethylene tubing, while the second is made using tris(2-ethyl-hexyl) trimellitate (TOTM)-plasticized polyvinyl chloride tubing. Both sets utilize a diethylhexyl phthalate (DEHP)-plasicized pumping segment. The potential for extraction of DEHP from the pumping segments and TOTM plasticizer from the plastic matrix by the Cremophor EL surfactant present in the paclitaxel injection was evaluated. Diethylhexyl phthalate and TOTM plasticizer extraction was tested using the paclitaxel diluent at concentrations equivalent to 0.3 and 1.2 mg/mL over three-hour and four-day infusions. All samples were prepared in triplicate in polyolefin bags of 5% dextrose injection and deliverd through the administration sets into glass collection flasks. Both DEHP and TOTM content were determined using high-performance liquid chromatographic methods. None of the admixtures delivered rapidly over three hours or slowly over four days through the TOTM-plasticized set exhibited any detectable TOTM. Similarly, no DEHP was detected in the effluent form either set with the simulated 0.3-mg/mL admixtures delivered over three hours. The simulated 1.2-mg/mL admixture delivered over three hours yielded only a barely detectable, but not quantifiable, trace of DEHP. However, slow delivery of both concentrations over four days through both sets resulted in leached DEHP in concentrations ranging from about 30 to 150 micrograms/mL at both one and four days. The two reduced-phthalate administration sets tested in this study are suitable for the administration of paclitaxel infusions of short duration, for up to three hours. However, the sets cannot be recommended for administration over longer-duration delivery times ranging from one to four days due to leaching of DEHP plasticizer from the pumping segments. PMID:23989703

Xu, Quanyun A; Trissel, Lawrence A

1998-01-01

250

Synthesis of novel pH-sensitive chitosan graft copolymers and micellar solubilization of paclitaxel  

Microsoft Academic Search

Herein, highly pH-sensitive graft copolymers, N-octyl-N-(2-carboxylbenzoyl) chitosan derivatives, were synthesized and characterized by FTIR, 1H NMR, 13C NMR, differential scanning calorimetry and X-ray diffraction spectrometry. The polymers can form micelles solublizing paclitaxel, with critical micellar concentrations ranged from 0.07 to 0.32mg\\/ml, drug-loading rate ranged from 30.7% to 65.3% and entrapment efficiency ranged from 44.2% to 61.4%. Additionally, the result shows

Hongxia Li; Jia Liu; Song Ding; Can Zhang; Wenbin Shen; Qidong You

2009-01-01

251

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

252

A Randomized Trial Investigating the Efficacy and Safety of Water Soluble Micellar Paclitaxel (Paccal Vet) for Treatment of Nonresectable Grade 2 or 3 Mast Cell Tumors in Dogs  

PubMed Central

Background Effective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early-phase studies. Hypothesis/Objectives The objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was ?p = ?L (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively). Animals Two hundred and fifty-two dogs with advanced stage nonresectable grade 2 or 3 MCT. Methods Prospective multicenter randomized double-blind positive-controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE). Results Overall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)-treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty-seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7). Conclusions and Clinical Importance Paclitaxel (micellar)’s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols. PMID:22390318

Vail, D.M.; von Euler, H.; Rusk, A.W.; Barber, L.; Clifford, C.; Elmslie, R.; Fulton, L.; Hirschberger, J.; Klein, M.; London, C.; Martano, M.; McNiel, E.A.; Morris, J.S.; Northrup, N.; Phillips, B.; Polton, G.; Post, G.; Rosenberg, M.; Ruslander, D.; Sahora, A.; Siegel, S.; Thamm, D.; Westberg, S.; Winter, J.; Khanna, C.

2013-01-01

253

Paclitaxel-loaded iron platinum stealth immunomicelles are potent MRI imaging agents that prevent prostate cancer growth in a PSMA-dependent manner  

PubMed Central

Background and methods: Problems with the clinical management of prostate cancer include the lack of both specific detection and efficient therapeutic intervention. We report the encapsulation of superparamagnetic iron platinum nanoparticles (SIPPs) and paclitaxel in a mixture of polyethyleneglycolated, fluorescent, and biotin-functionalized phospholipids to create multifunctional SIPP-PTX micelles (SPMs) that were conjugated to an antibody against prostate-specific membrane antigen (PSMA) for the specific targeting, magnetic resonance imaging (MRI), and treatment of human prostate cancer xenografts in mice. Results: SPMs were 45.4 ± 24.9 nm in diameter and composed of 160.7 ± 22.9 ?g/mL iron, 247.0 ± 33.4 ?g/mL platinum, and 702.6 ± 206.0 ?g/mL paclitaxel. Drug release measurements showed that, at 37°C, half of the paclitaxel was released in 30.2 hours in serum and two times faster in saline. Binding assays suggested that PSMA-targeted SPMs specifically bound to C4-2 human prostate cancer cells in vitro and released paclitaxel into the cells. In vitro, paclitaxel was 2.2 and 1.6 times more cytotoxic than SPMs to C4-2 cells at 24 and 48 hours of incubation, respectively. After 72 hours of incubation, paclitaxel and SPMs were equally cytotoxic. SPMs had MRI transverse relaxivities of 389 ± 15.5 Hz/mM iron, and SIPP micelles with and without drug caused MRI contrast enhancement in vivo. Conclusion: Only PSMA-targeted SPMs and paclitaxel significantly prevented growth of C4-2 prostate cancer xenografts in nude mice. Furthermore, mice injected with PSMA-targeted SPMs showed significantly more paclitaxel and platinum in tumors, compared with nontargeted SPM-injected and paclitaxel-injected mice. PMID:22915856

Taylor, Robert M; Sillerud, Laurel O

2012-01-01

254

Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)- b -poly(?-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity  

Microsoft Academic Search

Purpose  Develop a Cremophor® and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene\\u000a glycol)-b-poly(?-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.\\u000a \\u000a \\u000a \\u000a Methods  Hydrophobic prodrugs of paclitaxel were synthesized via DCC\\/DMAP or anhydride chemistry to overcome the poor loading (<1%\\u000a w\\/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A

M. Laird Forrest; Jaime A. Yáñez; Connie M. Remsberg; Yusuke Ohgami; Glen S. Kwon; Neal M. Davies

2008-01-01

255

Weekly Paclitaxel Combined with Local Hyperthermia in the Therapy of Breast Cancer Locally Recurrent after Mastectomy – a Pilot Experience  

Microsoft Academic Search

SummaryBackground: The combination of chemotherapy and hyperthermia (HT) is a promising approach in the treatment of malignant tumors. In the present report we evaluate the efficacy and toxicity of a combination of weekly paclitaxel combined with local hyperthermia in breast cancer. Patients and Methods: 7 patients were treated for inoperable local recurrence of breast cancer after mastectomy, irradiation, and chemotherapy

Z. Zoul; S. Filip; B. Melichar; J. Petera

2004-01-01

256

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours  

PubMed Central

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30?mg and administered with paclitaxel 80?mg?m?2 on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33–69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30?mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30?mg when combined with weekly paclitaxel 80?mg?m?2, warranting further clinical investigation. PMID:19127256

Campone, M; Levy, V; Bourbouloux, E; Berton Rigaud, D; Bootle, D; Dutreix, C; Zoellner, U; Shand, N; Calvo, F; Raymond, E

2009-01-01

257

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. 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

258

[Weekly paclitaxel therapy leading to complete disappearance of multiple liver metastases and subsequent surgical resection for advanced gastric cancer].  

PubMed

A 59-year-old man visited our hospital. After examination he was diagnosed with advanced gastric cancer with multiple liver metastases. At first, chemotherapy of S-1/CDDP was administered. After two weeks, he had severe diarrhea and anorexia, so the therapy was discontinued. Weekly paclitaxel was selected as the next therapy. Depending on the leukocytopenia, doses and intervals were controlled. After 4 courses, CT and MRI revealed that the liver metastases had disappeared, while the primary lesion remained. Seven months after beginning treatment, distal gastrectomy was performed. After the operation, 6 courses of paclitaxel therapy were given at the same doses and the same intervals as before the operation. Two years have passed since the operation, and no recurrence was seen on CT and MRI. Because of the relatively low frequency of adverse events in the digestive system, continued treatment with paclitaxel is possible. These findings show that paclitaxel is an effective drug for advanced gastric cancer with liver metastasis. PMID:21498997

Jin, Yasuyuki; Hasuo, Kimiatsu; Tsuchida, Kazuhito; Sawazaki, Sho; Hayashi, Shigeya; Rino, Yasushi; Masuda, Munetaka

2011-04-01

259

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

E-print Network

prostatectomy alone leads to cancer' cure in about 50 of cases . Relapse is mostly due to distantProstate 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

Boyer, Edmond

260

Determination of Paclitaxel Distribution in Solid Tumors by Nano-Particle Assisted Laser Desorption Ionization Mass Spectrometry Imaging  

PubMed Central

A sensitive, simple and reproducible protocol for nanoparticle-assisted laser desorption/ionization mass spectrometry imaging technique is described. The use of commercially available TiO2 nanoparticles abolishes heterogeneous crystallization, matrix background interferences and enhances signal detection, especially in the low mass range. Molecular image normalization was based on internal standard deposition on tissues, allowing direct comparison of drug penetration and distribution between different organs and tissues. The method was applied to analyze the distribution of the anticancer drug paclitaxel, inside normal and neoplastic mouse tissue sections. Spatial resolution was good, with a linear response between different in vivo treatments and molecular imaging intensity using therapeutic drug doses. This technique distinguishes the different intensity of paclitaxel distribution in control organs of mice, such as liver and kidney, in relation to the dose. Animals treated with 30 mg/kg of paclitaxel had half of the concentration of those treated with 60 mg/kg. We investigated the spatial distribution of paclitaxel in human melanoma mouse xenografts, following different dosage schedules and found a more homogeneous drug distribution in tumors of mice given repeated doses (5×8 mg/kg) plus a 60 mg/kg dose than in those assigned only a single 60 mg/kg dose. The protocol can be readily applied to investigate anticancer drug distribution in neoplastic lesions and to develop strategies to optimize and enhance drug penetration through different tumor tissues. PMID:23991120

Zucchetti, Massimo; Pretto, Francesca; Carrà, Andrea; D’Incalci, Maurizio; Giavazzi, Raffaella; Davoli, Enrico

2013-01-01

261

Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl- l-carnitine  

Microsoft Academic Search

Acetyl-l-carnitine (ALC) improves non-oncological neuropathies. We tested oral ALC (1 g tid) for 8 weeks in 25 patients with neuropathy grade ?3 (common toxicity criteria – CTC) during paclitaxel or cisplatin therapy, or grade ?2 persisting for at least three months after discontinuing the drugs. An independent neurologist assessed patients before and after ALC. All patients except one reported symptomatic

Giulia Bianchi; Giordano Vitali; Augusto Caraceni; Sabrina Ravaglia; Giuseppe Capri; Sante Cundari; Claudio Zanna; Luca Gianni

2005-01-01

262

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

263

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

PubMed Central

PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wild-type 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 anti-mitotic, 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 anti-angiogenesis therapy such as sunitinib or sorafinib. PMID:22843210

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

2013-01-01

264

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

265

Randomized Phase 3 Trial of Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer  

Microsoft Academic Search

quence, they have also been studied in the adjuvant setting. Methods After breast cancer surgery, women with lymph node - positive disease were randomly assigned to treat- ment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study — 5-year disease-free survival (DFS) — was assessed by Kaplan - Meier analysis.

Miguel Martín; Álvaro Rodríguez-Lescure; Amparo Ruiz; Emilio Alba; Lourdes Calvo; Manuel Ruiz-Borrego; César A. Rodríguez; José Antonio López García; María Dolores Guitián; Sergio Almenar; Jesús Fernando González-Palacios; Francisco Vera; José Palacios; Manuel Ramos; Jose Manuel Gracia Marco; Ana Lluch; Isabel Alvarez; José Ignacio Mayordomo; Antonio Antón; José Manuel Baena; Arrate Plazaola; Alfonso Modolell; Jose Ramón Mel; Enrique Aranda; Encarna Adrover; José Valero Álvarez

266

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

267

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

268

Reversing paclitaxel resistance in ovarian cancer cells via inhibition of the ABCB1 expressing side population.  

PubMed

The majority of deaths in ovarian cancer are caused by recurrent metastatic disease which is usually multidrug resistant. This progression has been hypothesised to be due in part to the presence of cancer stem cells, a subset of cells which are capable of self-renewal and are able to survive chemotherapy and migrate to distant sites. Side population (SP) cells, identified by the efflux of the DNA-binding dye Hoechst 33342 through ATP-binding cassette (ABC) transporters, are a known adult stem cell group and have been suggested as a cancer stem cell in various cancers. Despite the identification of SP cells in cancer cell lines and patient samples, little attention has been paid to the identification of specific ABC transporters within this cell fraction which efflux Hoechst dye and thus may facilitate drug resistance. In this study, we demonstrate that SP cells can be detected in both ovarian cancer cell lines and ascitic fluid samples, and these SP cells possess stem cell and drug resistance properties. We show that ABCB1 is the functioning ABC transporter in ovarian cancer cell lines, and expression of ABCB1 is associated with a paclitaxel-resistant phenotype. Moreover, silencing of ABCB1 using a specific morpholino oligonucleotide results in an inhibition of the SP phenotype and a sensitising of ovarian cancer cell lines to paclitaxel. ABCB1 should therefore be considered as a therapeutic target in ovarian cancer. PMID:24993095

Eyre, Rachel; Harvey, Ian; Stemke-Hale, Katherine; Lennard, Thomas W J; Tyson-Capper, Alison; Meeson, Annette P

2014-10-01

269

De Novo Characterization of a Cephalotaxus hainanensis Transcriptome and Genes Related to Paclitaxel Biosynthesis  

PubMed Central

Cephalotaxus hainanensis, an endangered plant, is known to contain several metabolites with anti-cancer activity. Despite its clinical impact, the alkaloid metabolism of this species has remained largely uncharacterized. The potential of Cephalotaxus for metabolic engineering of medically interesting compounds has, so far, not been exploited, due to the almost complete lack of molecular information. We have therefore performed a high throughput RNA-seq analysis and assembled the transcriptome de novo. Raw reads comprising 4.3 Gbp were assembled de novo into 39,416 unique sequences (unigenes) with a mean length of 1,089.8 bp and a total assembly size of 45.8 Mbp, which equals to more than 50 times the number of Cephalotaxaceae sequences currently deposited in the GenBank (as of August 2013). As proof of principle for medically interesting pathways, gene fragments related to paclitaxel biosynthesis were searched and detected. To verify their functionality, the metabolic product paclitaxel, and its precursor baccatin III, were identified in the leaves of C. hainanensis by HPLC, and shown to be induced by MeJA. This finding demonstrates exemplarily the potential of the annotated transcriptome as information resource for the biotechnological exploitation of plant secondary metabolism. PMID:25203398

Cong, Hanqing; Wang, Rongxiang; Yin, Junmei; Qian, Dan; Wang, Zhunian; Nick, Peter

2014-01-01

270

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

271

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

272

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

273

[A case of thymic cancer effectively treated by weekly paclitaxel combined with carboplatin].  

PubMed

A 65-year-old woman with left chest pain, back pain, and palpitation that had persisted for 2 months was referred to our hospital. Computed tomography of her chest showed an anterior mediastinal tumor with mediastinal lymphadenopathy, left pleural effusion, and pericardial effusion. Endobronchial ultrasound-guided transbronchial needle aspiration of the subcarinal lymphadenopathy was performed. The pathological findings and other examinations such as bone scintigraphy suggested advanced thymic cancer (stage IV b according to the Masaoka classification of thymic epithelial tumors). The patient was treated with combination chemotherapy of carboplatin(area under the curve [AUC]=6, 656 mg/body, day 1) and weekly paclitaxel (70 mg/m², 100 mg/body, days 1, 8, and 15). After 4 cycles of chemotherapy, a partial response was achieved and the pericardial effusion disappeared. The patient did not experience any severe toxicity, except for grade 1 nausea, grade 2 anemia, and grade 2 alopecia. Weekly paclitaxel combined with carboplatin appears to be a useful regimen with minimal toxicity for advanced thymic cancer. PMID:25596057

Kondo, Rie; Watanabe, Satoshi; Ishikawa, Daisuke; Tanaka, Tomohiro; Ohshima, Yasuyoshi; Asakawa, Katsuaki; Sakagami, Takuro; Okajima, Masaaki; Miura, Satoru; Hayashi, Yoshiki; Tanaka, Junta; Kagamu, Hiroshi; Yoshizawa, Hirohisa; Narita, Ichiei

2014-12-01

274

Cellular uptake of solid lipid nanoparticles and cytotoxicity of encapsulated paclitaxel in A549 cancer cells.  

PubMed

The aim of this study was to investigate the cellular uptake of solid lipid nanoparticles (SLN) and cytotoxicity of its paclitaxel delivery system. The conjugate of octadecylamine-fluorescein isothiocyanate (ODA-FITC) was synthesized, and used as a marker to prepare fluorescent SLN. The cellular uptakes of fluorescent SLN with different lipid material were evaluated by fluorescence microscopy and the measurement of fluorescence intensity. The order of cellular uptake ability was glycerol tristearate SLN>monostearin SLN>stearic acid SLN>Compritol 888 ATO SLN (ATO888 SLN). The cellular cytotoxicities of paclitaxel were highly enhanced by the encapsulation of lipid matrix. Due to the lower drug entrapment efficiency of glycerol tristearate SLN, monostearin SLN was considered as the best lipid material to improve the cytotoxicity of drug. The polyethylene glycol monostearate (PEG-SA) and the synthesized conjugate of folic acid-stearic acid (FA-SA) were further introduced into monostearin SLN, respectively. The PEG and folate modified SLN could enhance the cellular uptake of SLN and the cellular cytotoxicity of drug by the membrane disturb ability of PEG chains on the SLN surface and the improved endocytosis mediated by folate receptor. PMID:17714896

Yuan, Hong; Miao, Jing; Du, Yong-Zhong; You, Jian; Hu, Fu-Qiang; Zeng, Su

2008-02-01

275

Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system.  

PubMed

Paclitaxel is a potent chemotherapeutic agent currently administered intravenously in polyoxyethylated castor oil (Cremophor EL) and dehydrated ethanol (1:1) for the treatment of solid tumors. The objective of this work was to develop a novel self-emulsifying drug delivery system (SEDDS) devoid of cremophor for the i.v./oral delivery of paclitaxel and to investigate the in vitro cytotoxicity of the combined excipients. The SEDDS formulations were characterized in terms of droplet size using a ternary phase diagram. The Caco-2 cell line was used to monitor the cytotoxicity of the excipients. Cell viability was determined colorimetrically at 570 nm utilizing the MTT assay. The distribution of the formulations on the phase diagram indicated the presence of macroemulsions ( approximately 1 microm), submicron emulsions (50-200 nm), and microemulsions (below 10 nm). An increase in the sodium deoxycholate excipient content led to an increase in physical stability but caused more chemical degradation of the drug and more cytotoxicity. The drug in the novel SEDDS was chemically stable for at least 1 year when kept as a two-part formulation. The drug loading was increased by approximately fivefold compared to the marketed i.v. formulation; the excipients presented a significantly reduced cytotoxicity and led to a stable microemulsion. PMID:14603486

Gursoy, Neslihan; Garrigue, Jean-Sebastien; Razafindratsita, Alain; Lambert, Gregory; Benita, Simon

2003-12-01

276

Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery  

NASA Astrophysics Data System (ADS)

Novel thermo-sensitive nanoparticles self-assembled from poly(N,N-diethylacrylamide- co-acrylamide)-block-poly(?-benzyl L-glutamate) were designed for targeted drug delivery in localized hyperthermia. The lower critical solution temperature (LCST) of nanoparticles was adjusted to a level between physiological body temperature (37 °C) and that used in local hyperthermia (about 43 °C). The temperature-dependent performances of the core-shell nanoparticles were systemically studied by nuclear magnetic resonance (NMR), circular dichroism (CD), fluorescence spectroscopy, dynamic light scattering (DLS), and atom force microscopy (AFM). The mean diameter of the nanoparticles increased slightly from 110 to 129 nm when paclitaxel (PTX), a poorly water-soluble anti-tumor drug, was encapsulated. A stability study in bovine serum albumin (BSA) solution indicated that the PTX loaded nanoparticles may have a long circulation time under physiological environments as the LCST was above physiological body temperature and the shell remained hydrophilic at 37 °C. The PTX release profiles showed thermo-sensitive controlled behavior. The proliferation inhibiting activity of PTX loaded nanoparticles was evaluated against Hela cells in vitro, compared with Taxol (a formulation of paclitaxel dissolved in Cremophor EL and ethanol). The cytotoxicity of PTX loaded nanoparticles increased obviously when hyperthermia was performed. The nanoparticles synthesized here could be an ideal candidate for thermal triggered anti-tumor PTX delivery system.

Li, Yuanpei; Pan, Shirong; Zhang, Wei; Du, Zhuo

2009-02-01

277

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

278

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

279

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours  

PubMed Central

Background: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. Methods: A total of 22 patients received paclitaxel (135–175?mg?m?2) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90–240?mg) daily. Results: One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180?mg combined with paclitaxel 175?mg?m?2. A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months. Conclusion: The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions. PMID:20877350

van Herpen, C M L; Eskens, F A L M; de Jonge, M; Desar, I; Hooftman, L; Bone, E A; Timmer-Bonte, J N H; Verweij, J

2010-01-01

280

Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer  

PubMed Central

Introduction Elevated expression of erbB3 rendered erbB2-overexpressing breast cancer cells resistant to paclitaxel via PI-3 K/Akt-dependent upregulation of Survivin. It is unclear whether an erbB3-targeted therapy may abrogate erbB2-mediated paclitaxel resistance in breast cancer. Here, we study the antitumor activity of an anti-erbB3 antibody MM-121/SAR256212 in combination with paclitaxel against erbB2-overexpressing breast cancer. Methods Cell growth assays were used to determine cell viability. Cells undergoing apoptosis were quantified by a specific apoptotic ELISA. Western blot analyses were performed to assess the protein expression and activation. Lentiviral vector containing shRNA was used to specifically knockdown Survivin. Tumor xenografts were established by inoculation of BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with paclitaxel and/or MM-121/SAR256212 to determine whether the antibody (Ab) enhances paclitaxel’s antitumor activity. Immunohistochemistry was carried out to study the combinatorial effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly facilitated paclitaxel-mediated anti-proliferative/anti-survival effects on SKBR3 cells transfected with a control vector or erbB3 cDNA. It specifically downregulated Survivin associated with inactivation of erbB2, erbB3, and Akt. MM-121 enhances paclitaxel-induced poly(ADP-ribose) polymerase (PARP) cleavage, activation of caspase-8 and -3, and apoptosis in both paclitaxel-sensitive and -resistant cells. Specific knockdown of Survivin in the trastuzumab-resistant BT474-HR20 cells dramatically enhanced paclitaxel-induced apoptosis, suggesting that increased Survivin caused a cross-resistance to paclitaxel. Furthermore, the studies using a tumor xenograft model-established from BT474-HR20 cells revealed that either MM-121 (10 mg/kg) or low-dose (7.5 mg/kg) paclitaxel had no effect on tumor growth, their combinations significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed that the combinations of MM-121 and paclitaxel significantly reduced the cells with positive staining for Ki-67 and Survivin, and increased the cells with cleaved caspase-3. Conclusions The combinations of MM-121 and paclitaxel not only inhibit tumor cell proliferation, but also promote erbB2-overexpressing breast cancer cells to undergo apoptosis via downregulation of Survivin in vitro and in vivo, suggesting that inactivation of erbB3 with MM-121 enhances paclitaxel-mediated antitumor activity against erbB2-overexpressing breast cancers. Our data supports further exploration of the combinatorial regimens consisting of MM-121 and paclitaxel in breast cancer patients with erbB2-overexpressing tumors, particularly those resistant to paclitaxel. PMID:24168763

2013-01-01

281

Paclitaxel-loaded polymeric microparticles: Quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics  

PubMed Central

Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi-phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5–6 vs. 50–60 ?m). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r2>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both temporal and spatial factors that were determined by the characteristics of the drug delivery system. A combination of fast- and slow-releasing microparticles with 5–6 ?m diameter provided favorable spatial distribution and optimal drug release for IP therapy. PMID:24056144

Tsai, Max; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

2013-01-01

282

[A case of paclitaxel-resistant cancerous ascites secondary to gastric carcinoma responding well to TS-1 therapy].  

PubMed

Paclitaxel was used as the first-line drug for treatment of a case with peritoneal recurrence of gastric cancer, accompanied by cancerous ascites. Because paclitaxel was ineffective, TS-1 was used as the second-line drug, resulting in disappearance of cancerous ascites on diagnostic imaging. This case was an 81-year-old male patient. In February 2004, he underwent resection of the pyloric side of the stomach (D 2) based on a diagnosis of advanced gastric cancer. CT scans, conducted in February 2005, revealed ascites, and a diagnosis of cancerous peritonitis was made on the basis of subsequent cyto-diagnostic findings. He was later hospitalized because of anorexia and difficulty with oral ingestion, and received paclitaxel therapy (60 mg/m(2)). Abdominal CT scans in May of the same year showed the disappearance of ascites. Thereafter, he was managed as an outpatient. In June of the same year, relapse of ascites was detected by CT scans, and exacerbation of ascites was seen in August. In October, paclitaxel was switched to TS-1 (80 mg/m(2)). CT scans, obtained at the end of two cycles of TS-1 therapy, revealed complete disappearance of ascites. This therapy was administered for 4 cycles in total. CT scans, performed at the end of each cycle of TS-1 therapy, confirmed the absence of ascites. At present (July 2006), the patient is managed on an outpatient basis. Our experience with this case suggests that if paclitaxel therapy fails to exert satisfactory efficacy, switching to second-line TS-1 therapy is a promising means of treating gastric cancer complicated by cancerous peritonitis. PMID:17197755

Hara, Akinori; Tsunemi, Soichiro; Yamamoto, Masashi; Izumi, Nobuyuki; Iwamoto, Shinji

2006-12-01

283

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101  

PubMed Central

Purpose Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for development of this toxicity. Experimental Design A prospective pharmacogenetic analysis of primary breast cancer patients randomized to the paclitaxel arm of CALGB 40101 was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was performed and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. Results A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort (rs10771973; HR, 1.57; 95% CI, 1.30–1.91; P = 2.6 × 10?6) and in a European (HR, 1.72; 95% CI, 1.06–2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10?3) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. Conclusions A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. PMID:22843789

Baldwin, R. Michael; Owzar, Kouros; Zembutsu, Hitoshi; Chhibber, Aparna; Kubo, Michiaki; Jiang, Chen; Watson, Dorothy; Eclov, Rachel J.; Mefford, Joel; McLeod, Howard L.; Friedman, Paula N.; Hudis, Clifford A.; Winer, Eric P.; Jorgenson, Eric M.; Witte, John S.; Shulman, Lawrence N.; Nakamura, Yusuke; Ratain, Mark J.; Kroetz, Deanna L.

2012-01-01

284

Knockdown of vascular endothelial cell growth factor expression sensitizes U251 glioma cells to liposomal paclitaxel and radiation treatment in vitro.  

PubMed

Glioblastoma is the most aggressive malignancy of the human brain, accounting for 40% of all primary malignant brain tumors. However, there is no effective treatment for this disease. This study was designed to develop anti-vascular endothelial growth factor (VEGF) as a novel adjuvant therapy for glioblastoma. A VEGF shRNA vector was constructed to silence VEGF expression in U251 glioma cells and these cells were treated with various concentrations of liposomal paclitaxel, 6 Gy radiation or liposomal paclitaxel plus radiation. The data demonstrated that the VEGF shRNA vector significantly knocked down VEGF expression, which synergistically sensitized U251 glioma cells to liposomal paclitaxel, radiation or liposomal paclitaxel plus radiation treatment in terms of cell viability, apoptosis, colony formation and morphological changes. Future studies are required to evaluate these effects in vivo. PMID:22969865

Yu, Yang; Feng, Jianguo; Zong, Xiangyun; Yang, Hongjian; Zou, Dehong; He, Xiangming

2012-02-01

285

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

286

Paclitaxel loaded poly( l-lactic acid) microspheres for the prevention of intraperitoneal carcinomatosis after a surgical repair and tumor cell spill  

Microsoft Academic Search

A controlled release delivery system for paclitaxel was developed using poly(l-lactic acid) to provide local delivery to the peritoneal cavity. Microspheres were made in 1–40 and 30–120?m size ranges. In an in vitro release study, 30–120?m microspheres loaded with 10, 20 and 30% paclitaxel exhibited a burst phase of release for 3 days followed by an apparently zero-order phase of

R. T Liggins; S D'Amours; J. S Demetrick; L. S Machan; H. M Burt

2000-01-01

287

Nonvascular drug-eluting stent coated with sodium caprate-incorporated polyurethane for the efficient penetration of paclitaxel into tumor tissue.  

PubMed

To increase the therapeutic potency of nonvascular drug-eluting stents, sodium caprate was employed as a drug-penetration enhancer. A polytetrafluoroethylene-covered drug-eluting stent was coated with a mixture containing sodium caprate, paclitaxel, and polyurethane via the rolling coating technique. The coated stent has a smooth membrane surface with a 40-µm membrane thickness. Paclitaxel was released from the coated stent for two months. In the multilayered cell sheet model, sodium caprate in the polyurethane membrane (PUSC10) showed the possibility of enhancing the paclitaxel tissue penetration. The amount of penetrated paclitaxel for the sodium caprate-containing polyurethane membrane (PUSC10) was two times higher than that of sodium caprate-free polyurethane membrane. Additionally, the potential of sodium caprate was confirmed by a tumor-bearing small animal model. PUSC10 incorporated with Nile red (as a model fluorescence dye for visualization of drug penetration; PUSC10-Nile red) or PUSC10 incorporated with paclitaxel (PUSC10-paclitaxel) membrane was implanted at tumor sites in Balb/c mice. In the case of PUSC10-Nile red, the tissue penetration depth of Nile red was significantly increased from 30?µm (without sodium caprate) to 1060?µm (with sodium caprate). After seven days, an almost four times higher therapeutic area of PUSC10-paclitaxel was observed compared to that of polyurethane-paclitaxel (without sodium caprate) by a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results indicate that sodium caprate improves the penetration and therapeutic efficiencies of drugs in drug-eluting stents, and thus, it has potential for local stent therapy. PMID:25252589

Jeong, Dooyong; Lee, Don Haeng; Lee, Dong Ki; Na, Kun

2014-09-24

288

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer  

Microsoft Academic Search

Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between

S Gori; M Colozza; A M Mosconi; E Franceschi; C Basurto; R Cherubini; A Sidoni; A Rulli; C Bisacci; V De Angelis; L Crinò; M Tonato

2004-01-01

289

A Phase II Trial of Paclitaxel in Patients with Advanced or Recurrent Adenocarcinoma of the Endometrium: A Gynecologic Oncology Group Study  

Microsoft Academic Search

Objective: To determine the efficacy and toxicity of paclitaxel in advanced or recurrent adenocarcinoma of the endometrium. Methods: Thirty patients with advanced or recurrent endometrial cancer with measurable disease not previously treated with chemotherapy were treated with paclitaxel, 250 mg\\/m2, over 24 hr with G-CSF, 5 mcg\\/kg\\/day, from Days 2 to 12. The cycle was repeated every 21 days. Patients

Harrison G. Ball; John A. Blessing; Samuel S. Lentz; David G. Mutch

1996-01-01

290

Liquid-Liquid Extraction for Recovery of Paclitaxel from Plant Cell Culture: Solvent Evaluation and Use of Extractants for Partitioning and Selectivity  

PubMed Central

A major challenge in the production of metabolites by plant cells is the separation and purification of a desired product from a number of impurities. An important application of plant cell culture is the biosynthesis of the anti-cancer agent paclitaxel. Liquid-liquid extraction plays a critical role in the recovery of paclitaxel and other valuable plant-derived products from culture broth. In this study, the extraction of paclitaxel and a major unwanted by-product, cephalomannine, from plant cell culture broth into organic solvents is quantified. Potential solvent mixtures show varying affinity and selectivity for paclitaxel over cephalomannine. The partition coefficient of paclitaxel is highest in ethyl acetate and dichloromethane, with measured values of 28 and 25, respectively; however selectivity coefficients are less than 1 for paclitaxel over cephalomannine for both solvents. Selectivity coefficient increases to 1.7 with extraction in n-hexane but the partition coefficient decreases to 1.9. Altering the pH of the aqueous phase results in an increase in both recovery and selectivity using n-hexane, but does not change the results for other solvents significantly. The addition of extractants trioctyl amine (TOA) or tributyl phosphate (TBP) to n-hexane gives significantly higher partition coefficients for paclitaxel (8.6 and 23.7, respectively), but no selectivity. Interestingly, when 20% hexafluorobenzene (HFB) is added to n-hexane, the partition coefficient remains approximately constant but the selectivity coefficient for paclitaxel over cephalomannine improves to 4.5. This significant increase in selectivity early in the purification process has the potential to simplify downstream processing steps and significantly reduce overall purification costs. PMID:22581674

McPartland, Timothy J.; Patil, Rohan A.; Malone, Michael F.; Roberts, Susan C.

2012-01-01

291

Determination of paclitaxel in human plasma using single solvent extraction prior to isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection  

Microsoft Academic Search

An isocratic reversed-phase high-performance liquid chromatographic method with ultraviolet detection at 230 nm has been developed for the determination of paclitaxel in human plasma. Plasma samples were prepared by a selective one-step liquid–liquid extraction involving a mixture of acetonitrile–n-butyl chloride (1:4, v\\/v). Paclitaxel and the internal standard docetaxel were separated using a column packed with ODS-80A material, and a mobile

Alex Sparreboom; Peter de Bruijn; Kees Nooter; Walter J Loos; Gerrit Stoter; Jaap Verweij

1998-01-01

292

Poly(ethylene oxide)-block-polyphosphester-based Paclitaxel Conjugates as a Platform for Ultra-high Paclitaxel-loaded Multifunctional Nanoparticles†  

PubMed Central

A new type of degradable, nanoscopic polymer assembly containing ultra-high levels of drug loading via covalent attachment within amphiphilic core-shell nanoparticle morphology has been generated as a potentially effective and safe anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-based paclitaxel drug conjugates (PEO-b-PPE-g-PTX) were synthesized by rapid, scalable and versatile approach that involves only two steps: organocatalyst-promoted ring-opening-polymerization followed by click reaction-based conjugation of a PTX prodrug. Variations in the polymer-to-PTX stoichiometries allowed for optimization of the conjugation efficiency, the PTX drug loading and the resulting water solubilities of the entire polymer and the PTX content. The PEO-b-PPE-g-PTX formed well-defined micelles in aqueous solution, with a PTX loading capacity as high as 65 wt%, and a maximum PTX concentration of 6.2 mg/mL in water, which is 25000-fold higher than the aqueous solubility of free PTX. The positive cell-killing activity of PEO-b-PPE-g-PTX against several cancer cell lines is demonstrated, and the presence of pendant reactive functionality provides a powerful platform for future work to involve conjugation of multiple drugs and imaging agents to achieve chemotherapy and bioimaging. PMID:25152808

Zhang, Shiyi; Zou, Jiong; Elsabahy, Mahmoud; Karwa, Amolkumar; Li, Ang; Moore, Dennis A.; Dorshow, Richard B.; Wooley, Karen L.

2013-01-01

293

Gemcitabine and paclitaxel suppress the production of vascular endothelial growth factor induced by deferoxamine in human non-small cell lung cancer A549 cells  

PubMed Central

Vascular endothelial growth factor (VEGF) plays an important role in the process of angiogenesis in many types of cancer, including non-small cell lung cancer (NSCLC), and angiogenesis inhibitors and standard chemotherapy exhibit synergy though an unknown mechanism. We therefore hypothesized that cytotoxic chemotherapy influences VEGF production and analyzed VEGF production in an NSCLC A549 cell line after treatment with standard chemotherapy. Paclitaxel inhibited the production of VEGF in A549 cells, while cisplatin and erlotinib did not. Paclitaxel and gemcitabine inhibited deferoxamine (DFX) (known to mimic hypoxia)-induced VEGF production in A549 cells. Erlotinib also inhibited DFX-induced VEGF production in A549 cells slightly, while cisplatin did not. We subsequently examined the effect of the interaction between paclitaxel or gemcitabine and VEGF protein. Paclitaxel and gemcitabine did not directly affect the binding of VEGF. Since VEGF is known as one of the HIF-1 target genes, we examined the effect of paclitaxel and gemcitabine on HIF-1? levels induced by DFX in A549 cells. Paclitaxel and gemcitabine inhibited DFX-induced HIF-1? in A549 cells. These findings may be useful for future treatment schedules, including anti-cancer agents in NSCLC. PMID:22993609

IKEDA, RYUJI; VERMEULEN, LEE C.; JIANG, ZHISHENG; LAU, ELIM; KOLESAR, JILL M.

2010-01-01

294

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

295

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

296

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

297

Toward Biosynthetic Design and Implementation of Escherichia coli-Derived Paclitaxel and Other Heterologous Polyisoprene Compounds  

PubMed Central

Escherichia coli offers unparalleled engineering capacity in the context of heterologous natural product biosynthesis. However, as with other heterologous hosts, cellular metabolism must be designed or redesigned to support final compound formation. This task is at once complicated and aided by the fact that the cell does not natively produce an abundance of natural products. As a result, the metabolic engineer avoids complicated interactions with native pathways closely associated with the outcome of interest, but this convenience is tempered by the need to implement the required metabolism to allow functional biosynthesis. This review focuses on engineering E. coli for the purpose of polyisoprene formation, as it is related to isoprenoid compounds currently being pursued through a heterologous approach. In particular, the review features the compound paclitaxel and early efforts to design and overproduce intermediates through E. coli. PMID:22287010

Jiang, Ming; Stephanopoulos, Gregory

2012-01-01

298

Conjugation of paclitaxel to iron oxide nanoparticles for tumor imaging and therapy  

NASA Astrophysics Data System (ADS)

A strategy for conjugating an antitumor agent to superparamagnetic iron oxide nanoparticles (SPIONs) via a biocleavable ester binding is reported. Paclitaxel (PTX) was selected as a model drug. Both the in vitro and in vivo performance of the conjugates of SPION-PTX was investigated respectively. PTX can be released slowly through the hydrolysis of the ester bond in a pH-dependent manner and the SPION-PTX has near equal cytotoxity to the clinical PTX injection (Taxol) at the equivalent dose of PTX. Furthermore, the SPION-PTX can accumulate in tumor tissues as demonstrated by MRI and exhibit better tumor suppression effect than Taxol in vivo. The above good performance of the SPION-PTX together with the good biocompatibility of the SPIONs would promote greatly the application of the SPIONs in the biomedicine field.

Liu, Dongfang; Wu, Wei; Chen, Xi; Wen, Song; Zhang, Xizhi; Ding, Qi; Teng, Gaojun; Gu, Ning

2012-03-01

299

Folate-mediated targeting of albumin conjugates of paclitaxel obtained through a heterogeneous phase system.  

PubMed

The study developed cytotoxic macromolecular conjugates that specifically target the folate receptor and deliver the drug into cell cytoplasm. The anticancer agent paclitaxel was conjugated to human serum albumin (HSA) and this drug-albumin conjugate was further equipped with folic acid, linked via an extended poly(ethylene glycol) spacer. Preparation was carried out in a heterogeneous phase system exploiting the binding ability of Cibacron Blue dye to HSA. Unreacted reagents were easily removed and, after purification by gel filtration, the conjugate was fully characterized. Binding and in vitro cytotoxicity studies on human nasopharyngeal epidermal carcinoma KB and colorectal carcinoma HT-29 cells (as negative control) demonstrated increased selectivity and anti-tumoral activity. PMID:19712735

Dosio, Franco; Arpicco, Silvia; Stella, Barbara; Brusa, Paola; Cattel, Luigi

2009-12-01

300

Use of cholesterol-rich nanoparticles that bind to lipoprotein receptors as a vehicle to paclitaxel in the treatment of breast cancer: pharmacokinetics, tumor uptake and a pilot clinical study  

Microsoft Academic Search

Purpose  In animal experiments paclitaxel oleate associated with a cholesterol-rich nanoemulsion concentrated in the neoplastic tissues\\u000a and showed reduced toxicity and increased antitumor activity compared with paclitaxel-Cremophor EL. Here, a clinical study\\u000a was performed in breast cancer patients to evaluate the tumoral uptake, pharmacokinetics and toxicity of paclitaxel associated\\u000a to nanoemulsions.\\u000a \\u000a \\u000a \\u000a Methods  Twenty-four hours before mastectomy [3H]-paclitaxel oleate associated with [14C]-cholesteryl oleate-nanoemulsion

Luís A. Pires; Roberto Hegg; Claudete J. Valduga; Sílvia R. Graziani; Débora G. Rodrigues; Raul C. Maranhão

2009-01-01

301

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

302

TLR4 is a novel determinant of the response to paclitaxel in breast cancer  

PubMed Central

Overexpression of Toll-like Receptor-4 (TLR4) in human tumors often correlates with chemoresistance and metastasis. We found that TLR4 is overexpressed in the majority of clinical breast cancer (BC) samples and in 68% of the examined BC lines. TLR4 is activated by lipopolysaccharide (LPS) and other ligands including the widely-used drug paclitaxel (PXL). LPS is frequently used to show a tumor-promoting role of TLR4 although this bacterial component is unlikely to be found in BC environment. We reasoned that PXL-dependent activation of TLR4 is more relevant to BC chemoresistance that could be mediated by activation of the NF-?B pathway leading to upregulation of pro-survival genes. To test this hypothesis, we correlated TLR4 expression with resistance to PXL in two modified BC lines with either depleted or overexpressed TLR4 protein. Depletion of TLR4 in naturally overexpressing MDA-MB-231 cells downregulated pro-survival genes concomitant with 2–3 fold reduced IC50 to PXL in vitro and a 6-fold decrease in recurrence rate in vivo. Conversely, TLR4 overexpression in a negative cell line HCC1806 significantly increased expression of inflammatory and pro-survival genes along with a 3-fold increase of IC50 to PXL in vitro and enhanced tumor resistance to PXL therapy in vivo. Importantly, both tumor models showed that many PXL-upregulated inflammatory cytokines were co-induced with their receptors suggesting that this therapy induces autocrine tumor-promoting loops. Collectively, these results demonstrate that paclitaxel not only kills tumor cells but also enhances their survival by activating TLR4 pathway. These findings suggest that blocking TLR4 could significantly improve response to PXL therapy. PMID:23720768

Rajput, Sandeep; Volk-Draper, Lisa D.; Ran, Sophia

2013-01-01

303

Synergistic effects of IAP inhibitor LCL161 and paclitaxel on hepatocellular carcinoma cells.  

PubMed

Inhibitor of Apoptosis Proteins (IAPs) are key regulators of apoptosis in hepatocellular carcinoma (HCC) and their expression is negatively correlated with patient survival. LCL161 is a small molecule inhibitor of IAPs that has potent antitumour activity in a range of solid tumours. In HCC, response to LCL161 therapy has shown to be mediated by Bcl-2 expression. In this study, we aim to determine whether LCL161 has any therapeutic potential in HCC. Protein expression was determined by Western blot. Cell proliferation was determined by Cell Proliferation ELISA and BrdU colorimetric assays. Apoptosis was determined by Annexin V assay. Cell cycle analysis was performed by staining cells with propidium iodide and analysed in a FACScan. Automated Cell Counter and phase contrast microscopy were used to determine the cell viability. We have found that LCL161 targets (cIAP1, cIAP2 and XIAP) were up-regulated in HCC tumours. Both high Bcl-2 expressing HuH7 cells and low Bcl-2 expressing SNU423 cells showed strong resistance to LCL161 therapy with significant effects on both apoptosis and cell viability only evident at LCL161 concentrations of ?100?M. At these doses there was significant inhibition of IAP targets, however there was also significant inhibition of off-target proteins including pERK and pJNK suggesting apoptosis caused by drug toxicity. However, when used in combination with paclitaxel in HuH7 and SNU423 cells, LCL161 had significant antiproliferative effects at doses as low as 2?M and this was independent of Bcl-2 expression. Thus, LCL161 may be a useful agent in combination with paclitaxel to treat liver tumours. PMID:24976294

Tian, Aiping; Wilson, George S; Lie, Stefanus; Wu, Guang; Hu, Zenan; Hebbard, Lionel; Duan, Wei; George, Jacob; Qiao, Liang

2014-09-01

304

Hyperthermic intraperitoneal chemotherapy with cisplatin and paclitaxel in advanced ovarian cancer: a multicenter prospective observational study  

PubMed Central

Objective Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been recently reported with favorable oncological outcomes as treatment of advanced epithelial ovarian cancer (EOC). The aim of this study was to demonstrate the feasibility of CRS+HIPEC with cisplatin and paclitaxel for the treatment of advanced EOC. Methods This is a prospective observational study of 54 patients, from April 2007 to October 2013, with primary or recurrent peritoneal carcinomatosis due to EOC. The mean age was 54.51±9.34. Thirty patients (59%) had primary EOC, and 24 patients (41%) had recurrent disease. Results Mean peritoneal cancer index was 10.11 (range, 0 to 28), complete cytoreduction (CC0) was achieved for 47 patients (87%), CC1 for seven patients (13%). Patients with suboptimal cytoreduction (CC2 and CC3) were not included in the study. The mean stay in intensive care unit was 4.73±5.51 days and the mean hospitalization time was 24.0±10.03 days. We did not observe any intraoperative death. Seven patients (13%) required additional operations. Three patients (5.6%) died within 30 days from the procedure. Severe complications were seen in 19 patients (35.2%). During the follow-up period, disease recurred in 33 patients (61.1%); the median disease-free survival time was 12.46 months and the median overall survival time was 32.91 months. Conclusion CRS+HIPEC with cisplatin and paclitaxel for advanced EOC is feasible with acceptable morbidity and mortality. Additional follow-up and further studies are needed to determine the effects of HIPEC on long term survival. PMID:25376916

Coccolini, Federico; Campanati, Luca; Catena, Fausto; Ceni, Valentina; Jimenez Cruz, Jorge; Lotti, Marco; Magnone, Stefano; Napoli, Josephine; Rossetti, Diego; De Iaco, Pierandrea; Frigerio, Luigi; Pinna, Antonio; Runnebaum, Ingo; Ansaloni, Luca

2015-01-01

305

Systems Pharmacological Analysis of Paclitaxel-Mediated Tumor Priming That Enhances Nanocarrier Deposition and Efficacy  

PubMed Central

Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with sterically stabilized liposome (SSL)-DXR. Using data extracted from diverse literature sources, Cremophor-paclitaxel (Taxol®) PK was described by a carrier-mediated dispositional model and SSL-DXR PK was described by a two-compartment model with first-order drug release. A hybrid-physiologic, well-stirred model with partition coefficients (Kp) captured intratumor concentrations. Apoptotic responses driving tumor priming were modeled using nonlinear, time-dependent transduction functions. The tumor growth model used net first-order growth and death rate constants, and two transit compartments that captured the temporal displacement of tumor exposure versus effect, and apoptotic signals from each agent were used to drive cytotoxic effects of the combination. The final model captured plasma and intratumor PK data, apoptosis induction profiles, and tumor growth for all treatments/sequences. A feedback loop representing PAC-induced apoptosis effects on Kp_DXR enabled the model to capture tumor-priming effects. Simulations to explore time- and sequence-dependent effects of priming indicated that PAC priming increased Kp_DXR 3-fold. The intratumor concentrations producing maximal and half-maximal effects were 18 and 7.2 ?g/ml for PAC, and 17.6 and 14.3 ?g/ml for SSL-DXR. The duration of drug-induced apoptosis was 27.4 h for PAC and 15.8 h for SSL-DXR. Simulations suggested that PAC administered 24 h before peak priming could increase efficacy 2.5-fold over experimentally reported results. The quantitative approach developed in this article is applicable for evaluating tumor-priming strategies using diverse agents. PMID:23115220

Straubinger, Robert M.; Mager, Donald E.

2013-01-01

306

Role of Focal Adhesion Kinase in Regulating YB–1–Mediated Paclitaxel Resistance in Ovarian Cancer  

PubMed Central

Background We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood. Methods We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test. Results We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (? 2 = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006). Conclusions We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1–mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK. PMID:24062525

2013-01-01

307

Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy.  

PubMed

Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with sterically stabilized liposome (SSL)-DXR. Using data extracted from diverse literature sources, Cremophor-paclitaxel (Taxol(®)) PK was described by a carrier-mediated dispositional model and SSL-DXR PK was described by a two-compartment model with first-order drug release. A hybrid-physiologic, well-stirred model with partition coefficients (Kp) captured intratumor concentrations. Apoptotic responses driving tumor priming were modeled using nonlinear, time-dependent transduction functions. The tumor growth model used net first-order growth and death rate constants, and two transit compartments that captured the temporal displacement of tumor exposure versus effect, and apoptotic signals from each agent were used to drive cytotoxic effects of the combination. The final model captured plasma and intratumor PK data, apoptosis induction profiles, and tumor growth for all treatments/sequences. A feedback loop representing PAC-induced apoptosis effects on Kp(_DXR) enabled the model to capture tumor-priming effects. Simulations to explore time- and sequence-dependent effects of priming indicated that PAC priming increased K(p_DXR) 3-fold. The intratumor concentrations producing maximal and half-maximal effects were 18 and 7.2 ?g/ml for PAC, and 17.6 and 14.3 ?g/ml for SSL-DXR. The duration of drug-induced apoptosis was 27.4 h for PAC and 15.8 h for SSL-DXR. Simulations suggested that PAC administered 24 h before peak priming could increase efficacy 2.5-fold over experimentally reported results. The quantitative approach developed in this article is applicable for evaluating tumor-priming strategies using diverse agents. PMID:23115220

Ait-Oudhia, Sihem; Straubinger, Robert M; Mager, Donald E

2013-01-01

308

Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel  

PubMed Central

Purpose Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters prior to 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. Experimental Design 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 wildtype and Oatp1b2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Results Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and Oatp1b2, and these transport processes were strongly reduced in the presence of clinically-relevant concentrations of PS80 and CrEL. In the absence of solubilizers, deficiency of Oatp1b2 in mice was associated with a significantly decreased taxane clearance due to a liver distribution defect (P<0.00001), but these kinetic changes were masked in the presence of PS80 or CrEL (P>0.05). Conclusions Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes, and 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; Hagenbuch, Bruno; Moghaddam-Helmantel, Inge Ghobadi; Gibson, Alice A.; de Bruijn, Peter; Mathijssen, Ron H. J.; Sparreboom, Alex

2014-01-01

309

The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer  

PubMed Central

Gastric cancer is the second most common cause of cancer-related deaths worldwide. Taxanes have shown therapeutic effects against gastric cancer while also activating the PI3K/mTOR signaling pathway. We investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, alone and in combination with nanoparticle albumin-bound (nab)-paclitaxel in experimental gastric cancer. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in murine xenografts. Phosphorylated mTOR and 4E-BP1 levels were elevated in gastric cancer cells and tumor tissues by nab-paclitaxel. BEZ235 effectively inhibited cell proliferation in vitro and provided additive effects in combination with nab-paclitaxel. Furthermore, BEZ235 blocked the activated PI3K/mTOR pathway either alone or in combination with nab-paclitaxel in gastric cancer cells. BEZ235 and nab-paclitaxel caused an increase in PARP-1 and caspase-3 cleavage. Net local tumor growth inhibition for the BEZ235, nab-paclitaxel and BEZ235+nab-paclitaxel groups was 45.1, 77.9 and 97% compared to controls. The effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BEZ235 also caused a decrease in phospho-mTOR and phospho-Akt in tumor tissue lysates. Median animal survival (controls, 23 days) was 26.5 days after BEZ235 (p=0.227), 90.5 days after nab-paclitaxel (p=0.001) and 97 days in the BEZ235+nab-paclitaxel combination treatment group (p=0.001). Our findings suggest that BEZ235 exerts some antitumor effects against gastric cancer and enhances effects of nab-paclitaxel through inhibition of cell proliferation and modulation of the PI3K/mTOR pathway. This approach may represent a promising combination targeted therapy for gastric cancer. PMID:24042258

ZHANG, CHANG-HUA; AWASTHI, NIRANJAN; SCHWARZ, MARGARET A.; SCHWARZ, RODERICH E.

2013-01-01

310

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

311

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

312

Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib.  

PubMed

Lapatinib, a dual kinase inhibitor against epidermal growth factor receptor (EGFR) and human epidermal receptor two (HER2) has shown efficacy in treating HER2 positive breast cancer. Nanoparticle albumin bound (nab) paclitaxel was developed to reduce toxicities from paclitaxel and improve its efficacy. Thirty patients with stage I-III HER2 positive breast cancer were treated in the neoadjuvant setting with lapatinib 1,000 mg/day and nab-paclitaxel 260 mg/m(2) every 3 weeks for four cycles. The primary end point of the trial was clinical response rate (cRR) with secondary end points including pathologic complete response rate (pCR), tolerability of the combination, and marker response. The cRR was 82.8% (24 patients) with six (20.7%) patients having complete clinical response, 18 (62.1%) having partial clinical response, and five (17.2%) stable disease. A pCR was observed in five of the 28 patients (17.9%). The most frequent grade 2 toxicities were neuropathy in nine patients (30%), fatigue in seven patients (23.3%), rash in 11 patients (36.7%), and bone pain in 10 patients (33.3%). There was no significant drop in the left ventricular ejection fraction (LVEF). Of the tissue markers examined, we were not able to find a predictor of response. The combination of lapatinib and nab-paclitaxel was well tolerated and provided good efficacy in women with HER2 positive breast cancer. This combination offers an alternative non-anthracycline-containing regimen for women with HER2 positive breast cancer. PMID:21359953

Kaklamani, Virginia G; Siziopikou, Kalliopi; Scholtens, Denise; Lacouture, Mario; Gordon, Jennifer; Uthe, Regina; Meservey, Caitlin; Hansen, Nora; Khan, Seema A; Jeruss, Jacqueline S; Bethke, Kevin; Cianfrocca, Mary; Rosen, Steven; Von Roenn, Jamie; Wayne, Jeffrey; Parimi, Vamsi; Jovanovic, Borko; Gradishar, William

2012-04-01

313

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

314

Chitosan-alginate composites blended with cloisite 30B as a novel drug delivery system for anticancer drug paclitaxel  

Microsoft Academic Search

In the present research program, polymer composites have been used as the drug carrier for delivery system of anticancer drug\\u000a Paclitaxel. Chitosan (CS) and sodium alginate (ALG) with different ratios were blended with different wt% of montmorillonite\\u000a (MMT) (Cloisite 30B) solution by solvent evaporation method. MMT was incorporated in the formulation as a matrix material\\u000a component which also plays the

P. L. Nayak; Debasish Sahoo

315

A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA–paclitaxel microspheres  

Microsoft Academic Search

A translymphatic drug delivery system which incorporates poly-lactide-co-glycolide–paclitaxel (PLGA–PTX) or PLGA–rhodamine microspheres into gelatin sponge matrix is described. The system combines the sustained release properties of PLGA–PTX with the structural advantages of gelatin matrix that can be implanted directly to the lymphatic site for both therapeutic and prophylactic purposes. The PLGA microspheres were prepared using spray drying technique. The particles

Jiang Liu; Dale Meisner; Elizabeth Kwong; Xiao Y. Wu; Michael R. Johnston

2007-01-01

316

Role of paclitaxel and cisplatin as the neoadjuvant treatment for locally advanced squamous cell carcinoma of the vulva  

PubMed Central

Objective The therapeutic outcomes of patients with advanced vulvar cancer are poor. Multi-modality treatments including concurrent chemoradiation or different regimens of neoadjuvant chemotherapy (NACT), and surgery have been explored to reduce the extent of surgery and morbidity. The present single-institution trial aimed to evaluate the efficacy and toxicity of paclitaxel and cisplatin in locally advanced vulvar cancer. Methods From 2002 to 2009, 10 patients with stage III-IV locally advanced squamous cell carcinoma of the vulva were prospectively treated with 3 courses of paclitaxel-ifosfamide-cisplatin or paclitaxel-cisplatin. Nine of them subsequently underwent radical local excision or radical partial vulvectomy and bilateral inguino-femoral lymphadenectomy. Results The clinical response rate of all enrolled patients was 80%, whereas the pathological responses included 1 case with complete remission, 2 with persistent carcinoma in situ, and 6 invasive cancer cases with tumor shrinkage of more than 50%. Four patients had positive nodes. Forty percent of patients experienced grade 3-4 bone marrow toxicity, which was successfully managed with granulocyte-colony stimulating factor, even in cases of elderly patients. Median progression-free survival after surgery was 14 months (range, 5 to 44 months). Six of the 7 recurrent cases were local, and 3 of them were treated with salvage surgery while the other 3 received radiation with or without chemotherapy. After a median follow-up period of 40 months (range, 5 to 112 months), 55.5% of patients remained alive with no evidence of disease, including 2 long-term survivors after recurrence at 5 and 9 years. Conclusion Based on the high response rate and manageable toxicity, NACT with paclitaxel and cisplatin with or without ifosfamide followed by surgery could be considered as a therapeutic option for locally advanced vulvar cancer. PMID:24459577

Zanaboni, Flavia; Martinelli, Fabio; Scasso, Santiago; Laufer, Joel; Ditto, Antonino

2014-01-01

317

Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel – a phase II study  

Microsoft Academic Search

Vinorelbine (VNB) shows high antitumoral activity in advanced breast cancer due to its high affinity for mitotic tubulin\\u000a and differs from the other vinca alkaloids with regard to its low degree of neurotoxicity because of its low affinity for\\u000a axonal tubulin. Preclinical data show the existence of different binding sites on tubulin for vinca alkaloids and paclitaxel\\u000a (P), suggesting a

Barbara Fazeny; Udo Zifko; Siegfried Meryn; Heinz Huber; Wolfgang Grisold; Christian Dittrich

1996-01-01

318

Development and validation of RP-HPLC method: scope of application in the determination of oil solubility of paclitaxel.  

PubMed

A simple, reproducible, feasible and innovative reversed-phase high-performance liquid chromatographic method was developed and validated for the quantitative determination of paclitaxel dissolved in various oils. The method was validated after extraction of the analyte from capryol 90, triacetin and olive oil. The method was conducted on a Hypersil BDS C18 column, 250 × 4.6 mm, 5 µm particle size, with a mobile phase composed of acetonitrile: 10 mM KH2PO4 buffer (pH 3.5) (55:45, v/v) and detection at 227 nm. The linearity, in the range of 5 to 50 µg/mL, presented determination coefficients of 0.9983, 0.9997 and 0.9990 in capryol 90, triacetin and olive oil, respectively, calculated by the least-squares regression method. Intra-day precision values for percentages recovered were 0.68 to 0.80, 0.83 to 1.13 and 0.97 to 1.88, and inter day precision values were 1.52 to 1.92, 1.43 to 1.83 and 1.26 to 2.06 for capryol 90, triacetin and olive oil, respectively. The recovery of paclitaxel from the capryol 90, triacetin and olive oil ranged from 97.94 to 103.55, 96.85 to 103.27 and 97.14 to 103.64%, respectively. This developed and validated method was successfully applied to quantitatively assess paclitaxel dissolved in various oils. The solubility of paclitaxel was found to be higher in triacetin than in other tested oils. PMID:23293041

Choudhury, Hira; Gorain, Bapi; Karmakar, Sanmoy; Pal, Tapan Kumar

2014-01-01

319

Self-assembled nanoparticles of cholesterol-modified O-carboxymethyl chitosan as a novel carrier for paclitaxel  

Microsoft Academic Search

Self-assembled nanoparticles of cholesterol-modified O-carboxymethyl chitosan (CCMC) were prepared to be used as a novel carrier for paclitaxel (PTX) in this study. CCMC-6.9 was synthesized by the covalent conjugation of cholesterol to O-carboxymethyl chitosan with the succinyl linkage and the degree of substitution (DS) of the cholesterol moiety was 6.9%. CCMC-6.9 formed self-assembled nanoparticles with a size of 209.5 nm

Yin-song Wang; Qian Jiang; Rong-shan Li; Ling-long Liu; Qi-qing Zhang; Yu-mei Wang; Jing Zhao

2008-01-01

320

Continuation of bevacizumab and addition of hormone therapy following weekly paclitaxel therapy in HER2-negative metastatic breast cancer  

PubMed Central

Background Bevacizumab plus taxane chemotherapy improves progression-free survival (PFS) versus taxane monotherapy in the first-line treatment of HER2-negative metastatic breast cancer (MBC) and appears promising in the second-line setting. This retrospective analysis evaluated the efficacy and safety of this combination in a real-world setting. Patients and methods Eligible patients received bevacizumab (10 mg/kg days 1 and 15, every 28 days) plus paclitaxel (80 mg/m2 days 1, 8, and 15, every 28 days) as first-line therapy for MBC, or as subsequent lines, including bevacizumab continuation therapy, at La Paz University Hospital between August 2007 and October 2012. End points included objective response rate (ORR), PFS, overall survival (OS), and safety. Results Seventy-eight patients were included. Median PFS was 12.8 months for patients receiving first-line treatment and 9.3 months for subsequent lines. Forty-five patients (57.7%) continued bevacizumab after stopping paclitaxel, and had significantly longer PFS and OS than those who did not (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.248–0.653, P<0.001; HR 0.39, 95% CI 0.218–0.710, P=0.002; respectively). In the continuation phase, estrogen receptor-positive patients had longer PFS and OS when receiving hormone therapy plus bevacizumab versus patients receiving only bevacizumab (HR 0.50, 95% CI 0.24–1.04, P=0.06; HR 0.43, 95% CI 0.16–1.16, P=0.09; respectively). Thirty-five patients (44.9%) reported grade 3–4 adverse events. Conclusion Bevacizumab plus paclitaxel was effective in HER2-negative MBC. Continuation of bevacizumab and addition of hormone therapy following paclitaxel therapy could be beneficial. PMID:25473300

Redondo, Andrés; Martínez, Virginia; Zamora, Pilar; Castelo, Beatriz; Pinto, Alvaro; Cruz, Patricia; Higuera, Oliver; Mendiola, Marta; Hardisson, David; Espinosa, Enrique

2014-01-01

321

miR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis.  

PubMed

Non-small cell lung cancer is one of the most aggressive cancers as per as the mortality and occurrence is concerned. Paclitaxel based chemotherapeutic regimes are now used as an important option for the treatment of lung cancer. However, resistance of lung cancer cells to paclitaxel continues to be a major clinical problem nowadays. Despite impressive initial clinical response, most of the patients eventually develop some degree of paclitaxel resistance in the course of treatment. Previously, utilizing miRNA arrays we reported that downregulation of miR-17 is at least partly involved in the development of paclitaxel resistance in lung cancer cells by modulating Beclin-1 expression [1]. In this study, we showed that miR-16 was also significantly downregulated in paclitaxel resistant lung cancer cells. We demonstrated that anti-apoptotic protein Bcl-2 was directly targeted miR-16 in paclitaxel resistant lung cancer cells. Moreover, in this report we showed that the combined overexpression of miR-16 and miR-17 and subsequent paclitaxel treatment greatly sensitized paclitaxel resistant lung cancer cells to paclitaxel by inducing apoptosis via caspase-3 mediated pathway. Combined overexpression of miR-16 and miR-17 greatly reduced Beclin-1 and Bcl-2 expressions respectively. Our results indicated that though miR-17 and miR-16 had no common target, both miR-16 and miR-17 jointly played roles in the development of paclitaxel resistance in lung cancer. miR-17 overexpression reduced cytoprotective autophagy by targeting Beclin-1, whereas overexpression of miR-16 potentiated paclitaxel induced apoptotic cell death by inhibiting anti-apoptotic protein Bcl-2. PMID:25435430

Chatterjee, Abhisek; Chattopadhyay, Dhrubajyoti; Chakrabarti, Gopal

2015-02-01

322

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

323

miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6.  

PubMed

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1. PMID:24510775

Zhu, Xiaolan; Li, Yuefeng; Xie, Chanjuan; Yin, Xinming; Liu, Yueqin; Cao, Yuan; Fang, Yue; Lin, Xin; Xu, Yao; Xu, Wenlin; Shen, Huiling; Wen, Jian

2014-09-15

324

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

325

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

PubMed

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

326

Dose-dense epirubicin and paclitaxel with G-CSF: a study of decreasing intervals in metastatic breast cancer  

PubMed Central

Anthracyclines and taxanes are very effective drugs in the treatment of advanced breast cancer. With G-CSF support, the dose-intensity of this combination can be increased by reducing the interval between chemotherapy cycles, the so-called ‘shortening of cycle time’. We treated 36 patients with advanced breast cancer in a multicentre phase I/II study. The treatment regimen consisted of epirubicin 75 mg m?2followed by paclitaxel 135 mg m?2(3 h) in combination with G-CSF. At least six patients were treated in each cohort and were evaluated over the first three cycles. Starting at an interval of 14 days, in subsequent cohorts of patients the interval could be shortened to 10 days. An 8-day interval was not feasible due mainly to incomplete neutrophil recovery at the day of the next scheduled cycle. In the 10-day interval cohort it was feasible to increase the paclitaxel dose to 175 mg m?2. The haematological and non-haematological toxicity was relatively mild. No cumulative myelosuppression was observed over at least three consecutive cycles. In combination with G-CSF, epirubicin 75 mg m?2and paclitaxel 175 mg m?2could be safely administered every 10 days over at least three cycles, enabling a dose intensity of 52 and 122 mg m?2per week, respectively. © 2000 Cancer Research Campaign PMID:10864197

Lalisang, R I; Voest, E E; Wils, J A; Nortier, J W; Erdkamp, F L; Hillen, H F; Wals, J; Schouten, H C; Blijham, G H

2000-01-01

327

A phase II study of sequential 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel in advanced breast cancer (Protocol PV BC 97/01)  

PubMed Central

Sequential administration of the association of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel could be better tolerated than the association of an anthracycline and paclitaxel while having a similar antitumour effect. 69 patients with advanced breast cancer previously untreated with anthracyclines or paclitaxel entered a phase II multicentre study in which FEC was followed by paclitaxel. Both regimens were administered 4 times every 21 days. The median follow-up is 20 months and 38/69 patients have died. Grade III–IV toxicity was acceptable. Leukopenia occurred in 26% of patients, thrombocytopenia in 2% and anaemia in 4%. One patient had reversible heart failure during FEC therapy. Peripheral neuropathy and arthralgia-myalgia occurred in 9% and 4% of patients, respectively and one patient had respiratory hypersensitivity during paclitaxel treatment. 9 patients did not complete therapy because of: treatment refusal (n= 1), cardiac toxicity (n= 1), early death during FEC chemotherapy (n= 1), major protocol violations (n= 4), hypersensitivity reaction (n= 1) and early death during paclitaxel chemotherapy (n= 1). The overall response rate was 65% (95% CI = 53–76), and 7% of patients had stable disease. Therapy was defined as having failed in 28% of patients because they were not evaluable (13%) or had progressive disease (15%). The median time to progression and survival are 13.2 and 23.5 months, respectively. Sequential FEC-paclitaxel is a suitable strategy for patients with metastatic breast cancer who have not been previously treated with anthracyclines and/or taxanes. In fact, it avoids major haematologic toxicity and has a good antitumour effect. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11461067

Riccardi, A; Pugliese, P; Danova, M; Brugnatelli, S; Grasso, D; Giordano, M; Bernardo, G; Giardina, G; Fava, S; Montanari, G; Pedrotti, C; Trotti, G; Rinaldi, E; Poli, M A; Tinelli, C

2001-01-01

328

STX140, but Not Paclitaxel, Inhibits Mammary Tumour Initiation and Progression in C3(1)/SV40 T/t-Antigen Transgenic Mice  

PubMed Central

Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer. PMID:24324595

Meyer-Losic, Florence; Newman, Simon P.; Day, Joanna M.; Kasprzyk, Philip G.; Purohit, Atul; Foster, Paul A.

2013-01-01

329

Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12.  

PubMed

Unresectable cancer of the pancreas was treated with the combination of weekly paclitaxel and external beam irradiation in an effort to improve palliation and extend life expectancy. One hundred twenty-two patients were entered in a multicentered protocol. Thirteen patients were either ineligible, cancelled, or had delinquent data, thus providing 109 for analysis. Unresectable cancer was based on imaging studies (computed tomography or magnetic resonance imaging), all had histologic proof of adenocarcinoma, and none had evidence of metastatic disease or peritoneal seeding. Image-guided radiotherapy treatment consisted of 50.4 Gy in 28 fractions over 5.5 weeks with coplanar anterior/posterior and lateral ports. An initial dose of 45 Gy was given to fields covering the primary tumor plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. A cone down field was used for the last three fractions to encompass the gross tumor volume with a 1- to 1.5-cm margin. Paclitaxel was administered weekly with irradiation in a dosage of 50 mg/m2 as a 3-hour infusion. The median age was 63 and 53% were female. The Karnofsky performance status was greater than or equal to 80 in 81%. Eighty percent were classified T3 or 4; 20% had N1 disease. The primary tumor was located in the pancreatic head in 65%. Eighty-five percent received all six cycles of paclitaxel per protocol, whereas 93% received irradiation with acceptable protocol variation. Field placement, total dose, fractionation, and overall treatment time were given per protocol in greater than or equal to 90%. Acute toxicity (worst per patient) occurred in 39% with grade III (35% of these were asymptomatic neutropenia), 5% with grade IV, and one patient died of infection during the fourth cycle of chemotherapy (grade V). The median follow-up time for alive patients is 20.6 months (range 5-30). The median survival is 11.2 months (95% CI 10.1, 12.3) with estimated 1- and 2-year survivals of 43% and 13%, respectively. External irradiation plus concurrent weekly paclitaxel is well tolerated when given with large-field radiotherapy. The median survival is better than historical results achieved with irradiation and fluoropyrimidines. These data provide the basis for a new Radiation Therapy Oncology Group trial using paclitaxel and irradiation combined with a second radiation sensitizer, gemcitabine, now under way. PMID:14758134

Rich, Tyvin; Harris, Jonathan; Abrams, R; Erickson, B; Doherty, M; Paradelo, J; Small, W; Safran, H; Wanebo, Harold J

2004-02-01

330

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

331

High Id1 expression, a generally negative prognostic factor, paradoxically predicts a favorable prognosis for adjuvant paclitaxel plus cisplatin therapy in surgically treated lung cancer patients  

PubMed Central

Adjuvant chemotherapy is commonly given to surgically treated non-small-cell lung cancer (NSCLC) patients. However, the prerequisite for chemotherapy needs to be scrutinized in order to maximize the benefits to patients. In this study, we observed that NSCLC cells with high Id1 protein expression were vulnerable to the treatment of paclitaxel and cisplatin. In addition, paclitaxel and cisplatin caused Id1 protein degradation through ubiquitination. In the nude mice xenograft model, the tumor growth was reduced to a large degree in the Id1-overexpressing group upon treatment with paclitaxel and cisplatin. Furthermore, immunohistochemical staining for Id1 followed by Kaplan-Meier survival analysis showed that surgically treated NSCLC patients with high Id1 expression in primary tumor tissues had better disease-free and overall survivals after adjuvant paclitaxel and cisplatin chemotherapy. In summary, our current data suggest that Id1, a generally negative prognostic factor, predicts a favorable prognosis in the case of surgically treated NSCLC patients receiving the definitive adjuvant chemotherapy. The distinct role of Id1 reported in this study may arise from the phenomenon of Id1 dependence of NSCLC cells for survival, which renders the cancer cells additionally susceptive to the adjuvant chemotherapy with paclitaxel and cisplatin. PMID:25344919

Cheng, Yu-Jen; Lee, Yi-Chen; Chiu, Wen-Chin; Tsai, Jen-Wei; Su, Yu-Han; Hung, Amos C.; Chang, Po-Chih; Huang, Chih-Jen; Chai, Chee-Yin; Yuan, Shyng-Shiou F.

2014-01-01

332

Pharmacokinetics and biodistribution study of paclitaxel liposome in Sprague-Dawley rats and Beagle dogs by liquid chromatography-tandem mass spectrometry.  

PubMed

Lipusu is the first paclitaxel liposome preparation approved in the world and has been widely used in China for the treatment of ovary, breast and non-small cell lung cancer. In present study we evaluated the pharmacokinetic and tissue distribution characteristics of paclitaxel liposome in Sprague-Dawley rats and Beagle dogs. A rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of paclitaxel in plasma and tissues. The plasma concentrations of paclitaxel in both rats and dogs initially declined steeply, followed by slow elimination after intravenous administration of Lipusu at 5?mg/kg and 1?mg/kg, respectively. The pharmacokinetic parameters calculated by a non-compartmental method in rats and dogs were as follows: AUC0-24: 3?566.5±1?366.1 and 443.2±165.7??g?·?h/L, CL: 1.5±0.5 and 2.1±0.6?L/h/kg, Vd: 20.0±7.8 and 38.4±12.5?L/kg, t1/2: 9.3±2.9 and 14.1±6.9?h, respectively. Biodistribution results in rats showed that except for brain and testis, liposomal paclitaxel was extensively distributed into various tissues, especially highly in liver and spleen. PMID:23842945

Wang, X; Song, L; Li, N; Qiu, Z; Zhou, S; Li, C; Zhao, J; Song, H; Chen, X

2013-11-01

333

Three-dimensional collagen type I matrix up-regulates nuclear isoforms of the microtubule associated protein tau implicated in resistance to Paclitaxel therapy in ovarian carcinoma.  

PubMed

Epithelial ovarian carcinoma is the deadliest gynecologic malignancy. One reason underlying treatment failure is resistance to paclitaxel. Expression of the microtubule associated protein tau has recently been proposed as a predictor of response to paclitaxel in ovarian carcinoma patients. Expression of tau was probed using immunohistochemistry in 312 specimens of primary, and 40 specimens of metastatic, ovarian carcinoma. Serous epithelial ovarian carcinoma cell line models were used to determine the expression of tau by Western blot and immunofluorescence staining. Subcellular fractionation and Western blot were employed to examine nuclear and cytoplasmic localization of tau. Gene silencing and clonogenic assays were used to evaluate paclitaxel response. Tau was expressed in 44% of all tested cases. Among the primary serous epithelial ovarian carcinoma cases, 46% were tau-positive. Among the metastatic serous epithelial ovarian carcinomas, 63% were tau-positive. Cell culture experiments demonstrated that tau was expressed in multiple isoforms. Three-dimensional collagen I matrix culture conditions resulted in up-regulation of tau protein. Silencing of tau with specific siRNAs in a combination with three-dimensional culture conditions led to a significant decrease of the clonogenic ability of cells treated with paclitaxel. The data suggest that reduction of tau expression may sensitize ovarian carcinoma to the paclitaxel treatment. PMID:25658796

Gurler, Hilal; Yu, Yi; Choi, Jacqueline; Kajdacsy-Balla, Andre A; Barbolina, Maria V

2015-01-01

334

Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study  

PubMed Central

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420?mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11237379

Doz, F; Gentet, J C; Pein, F; Frappaz, D; Chastagner, P; Moretti, S; Vassal, G; Arditti, J; Tellingen, O Van; Iliadis, A; Catalin, J

2001-01-01

335

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

336

Replacing Heme with Paclitaxel to Prepare Drug-Loaded Globin Nanoassembles for CD163 Targeting.  

PubMed

Protein-based nanoparticles hold great promises in both preclinical and clinical practices, such as oncology diagnosis and treatment, because of their high biocompatibility and biodegradability. However, the complicated preparation and lack of targeting specific cells or tissues may limit their further uses. To overcome these limitations, we developed a novel replacing method for preparing dual-functional protein nanocarrier, such that one function is capable of encapsulating small molecule into protein, whereas the other function is cable of recognizing CD163 receptor [hemoglobin (Hb) scavenger receptor]. In this study, Hb was chosen as the targeting drug carrier. First, the heme group in the Hb was removed and replaced by paclitaxel (PTX) to form nanoparticles (Gb-NPs-PTX). The resulted Gb-NPs-PTX showed spherical shape and their diameter could be controlled in the range of 120-160 nm by altering the ratio of PTX to Hb. The binding activity of Gb-NPs-PTX to CD163 was confirmed by cell uptake in CD163(+) Chinese hamster ovary cells. Results in vivo also showed a CD163-dependent tissue accumulation of Gb-NPs-PTX in mice. In summary, by using the novel replacing method, PTX could be easily encapsulated into Hb nanoparticles and the targeting effects of Hb could also be kept. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1045-1055, 2015. PMID:25640195

Meng, Zhengjie; Yang, Xiaoyan; Hu, Die; Wang, Kaikai; Zhi, Feng; Chen, Xi; Gong, Guangming; Wu, Jinhui; Hu, Yiqiao

2015-03-01

337

Solid-Nanoemulsion Preconcentrate for Oral Delivery of Paclitaxel: Formulation Design, Biodistribution, and ? Scintigraphy Imaging  

PubMed Central

Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC) using oil [propylene glycol monocaprylate/glycerol monooleate, 4?:?1?w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1?:?1?w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1?:?1?w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel), respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in ? scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC. PMID:25114933

Ahmad, Javed; Mir, Showkat R.; Kohli, Kanchan; Chuttani, Krishna; Mishra, Anil K.; Panda, A. K.

2014-01-01

338

Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases  

PubMed Central

Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01–0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis. PMID:25574399

Kisiel, Walter; Lu, Yang J.; Petersen, Lars C.; Ndungu, John M.; Moore, Terry W.; Parker, Ernest T.; Sun, Aiming; Liotta, Dennis C.; El-Rayes, Bassel F.; Brat, Daniel J.; Snyder, James P.; Shoji, Mamoru

2014-01-01

339

Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles.  

PubMed

Paclitaxel (PTX) is one of the most potent intravenous chemotherapeutic agents to date, yet an oral formulation has been problematic because of its low solubility and permeability. Using the recently discovered solubilizing properties of rubusoside (RUB), we investigated the unique PTX-RUB formulation. PTX was solubilized by RUB in water to levels of 1.6-6.3?mg/ml at 10-40% weight/volume. These nanomicellar PTX-RUB complexes were dried to a powder, which was subsequently reconstituted in physiologic solutions. After 2.5?h, 85-99% of PTX-RUB remained soluble in gastric fluid, whereas 79-96% remained soluble in intestinal fluid. The solubilization of PTX was mechanized by the formation of water-soluble spherical nanomicelles between PTX and RUB, with an average diameter of 6.6?nm. Compared with Taxol, PTX-RUB nanoparticles were nearly four times more permeable in Caco-2 cell monocultures. In a side-by-side comparison with dimethyl sulfoxide-solubilized PTX, PTX-RUB maintained the same level of cytotoxicity against three human cancer cell lines with IC50 values ranging from 4 to 20?nmol/l. In addition, tubule formation and migration of human umbilical vein endothelial cells were inhibited at levels as low as 5?nmol/l. These chemical and biological properties demonstrated by the PTX-RUB nanoparticles may improve oral bioavailability and enable further pharmacokinetic, toxicologic, and efficacy investigations. PMID:25243454

Liu, Zhijun; Zhang, Fang; Koh, Gar Yee; Dong, Xin; Hollingsworth, Javoris; Zhang, Jian; Russo, Paul S; Yang, Peiying; Stout, Rhett W

2015-02-01

340

Adduct formation in quantitative bioanalysis: effect of ionization conditions on paclitaxel.  

PubMed

Quantitative analysis of target compounds with liquid chromatography atmospheric pressure ionization mass spectrometry is sometimes hampered by adduct formation. In these situations, cationization with alkali metal ions instead of proton addition is often observed in the positive ion mode. This work studies the process of adduct formation and investigates potential strategies to control this phenomenon. Paclitaxel, a pharmaceutical chemotherapeutic agent, was used as a model compound. Electrospray (ESI), atmospheric pressure chemical ionization (APCI) and sonic spray ionization (SSI) are evaluated and compared. The work was performed on two different instruments, allowing the evaluation of different ionization behavior for different source design for electrospray, if any. Different mobile phase additives were compared, including acetic acid, formic acid, ammonium formate, and a range of primary amines. Continuous infusion was used for a fast screening, to detect optimal conditions. These were then further investigated in detail by LC-MS. The results indicate that electrospray is the more sensitive interface for this compound on the investigated apparatus. Unacceptable quantitative data were acquired without additives in the mobile phase. Generally, additives increased the reproducibility significantly. A response of mainly one ion was achieved with dodecylamine/acetic acid and acetic acid/sodium acetate. The data also point out the importance of evaluating adduct formation for compounds prone to this phenomenon during method development, especially in view of accurate quantitation. PMID:15047063

Mortier, Kjell A; Zhang, Guo-Fang; van Peteghem, Carlos H; Lambert, Willy E

2004-04-01

341

A polymer-free Paclitaxel eluting coronary stent: effects of solvents, drug concentrations and coating methods.  

PubMed

Some polymer coatings used in drug-eluting stents (DES) cause adverse reactions. Hence, the use of self-assembled monolayers (SAMs) as a polymer-free platform to deliver an anti-proliferative drug (paclitaxel-PAT) from 2D metal substrates was previously demonstrated. In this study, we optimized the PAT coating on SAMs coated 3D coronary stents. For the optimization process, we investigated the effects of solvents (ethanol, DMSO, and their mixtures), drug concentrations (2, 3, 4, 8, and 12 mg/mL) in the coating solution, and coating methods (dip and spray) on PAT deposition. A solvent mixture of 75:25 v/v Et-OH:DMSO was determined to be the best for obtaining smooth and homogenous PAT coating. PAT coated stents prepared using 8 mg/mL and 3 mg/mL concentrations of PAT by dip and spray coating methods, respectively, were optimal in terms of carrying adequate drug doses (0.35 µg/mm(2) for dipping and 0.76 µg/mm(2) for spraying) as well as negligible defects observed in the coating. PAT was successfully released from SAMs coated stents in a biphasic manner with an initial burst followed by a sustained release for up to 10 weeks. Thus, this study sheds light on the effects of solvents, drug concentrations, and coating methods on preparing a polymer-free DES. PMID:24705673

Lamichhane, Sujan; Gallo, Annemarie; Mani, Gopinath

2014-06-01

342

Blood viscosity as a sensitive indicator for paclitaxel induced oxidative stress in human whole blood  

PubMed Central

In this study, the in vitro effects of paclitaxel (PTX) and Cremophor-EL (CrEL) on blood viscosity and oxidative stress markers were investigated. Whole-blood samples were collected from healthy volunteers and co-incubated with PTX, CrEL or their combination then compared with control blood samples. After a 24 h incubation time, the whole-blood viscosity (WBV), erythrocyte sedimentation rate (ESR), levels of whole-blood malondialdehyde (MDA), protein carbonyl content (PCC) and reduced glutathione (GSH) were determined. Moreover, plasma nitrite and plasma sialic acid (SA) values were measured. The present results revealed that the incubation of blood samples with PTX, CrEL or PTX plus CrEL significantly increased the values of WBV, ESR, MDA and PCC compared to control samples. In contrast, a significant decrease in levels of GSH, SA and nitrite was observed after incubation of blood samples with tested agents compared to control. The effects of tested agents on the measured parameters were more pronounced in the case of blood samples treated with PTX plus CrEL. The present study demonstrates that PTX-induced oxidative stress is associated with an increase of WBV.

Harisa, Gamaleldin I.

2014-01-01

343

Overcoming paclitaxel resistance in lung cancer cells via dual inhibition of stathmin and Bcl-2.  

PubMed

Lung cancer is the leading cause of death from malignancy in people and over 85% of these patients eventually die from disseminated disease. Paclitaxel (TAX) is widely used as an antimicrotubule agent for the treatment of lung cancer. Unfortunately, the resistance to this antimicrotubule agent occurs frequently. Stathmin (STMN1) is a ubiquitous microtubule destabilizing protein linked to cancer and cell health and its expression level often correlates with cancer stage progression and prognosis for survival. Overexpression of the antiapoptotic protein Bcl-2 has been shown to prolong drug-induced growth arrest, potentially inducing resistance. In this study, we used a short hairpin RNA (shRNA) approach to evaluate the effect of STMN1 and Bcl-2 downregulation in the sensitivity to TAX in lung cancer cells. We achieved significant downregulation of STMN1 and Bcl-2 mRNA and protein expression by a combination of double shRNA treatment strategy. Our experimental data showed that inhibition of STMN1 and Bcl-2 expression with RNA interference can sensitize lung cancer cells to TAX. These findings suggest a novel approach to improve the efficacy of certain antimicrotubule agents against lung cancer by regulating the function of STMN1 and Bcl-2. PMID:23496232

Han, Zheng-Xiang; Wang, Hong-Mei; Jiang, Guan; Du, Xiu-Ping; Gao, Xiang-Yang; Pei, Dong-Sheng

2013-06-01

344

Paclitaxel-eluting balloon dilation of biliary anastomotic stricture after liver transplantation  

PubMed Central

AIM: To investigate the safety and effectiveness of endoscopic therapy with a paclitaxel-eluting balloon (PEB) for biliary anastomotic stricture (AS) after liver transplantation (LT). METHODS: This prospective pilot study enrolled 13 consecutive eligible patients treated for symptomatic AS after LT at the University Hospital of Münster between January 2011 and March 2014. The patients were treated by endoscopic therapy with a PEB and followed up every 8 wk by endoscopic retrograde cholangiopancreatography (ERCP). In cases of re-stenosis, further balloon dilation with a PEB was performed. Follow-up was continued until 24 mo after the last intervention. RESULTS: Initial technical feasibility, defined as successful balloon dilation with a PEB during the initial ERCP procedure, was achieved in 100% of cases. Long-term clinical success (LTCS), defined as no need for further endoscopic intervention for at least 24 mo, was achieved in 12 of the 13 patients (92.3%). The mean number of endoscopic interventions required to achieve LTCS was only 1.7 ± 1.1. Treatment failure, defined as the need for definitive alternative treatment, occurred in only one patient, who developed recurrent stenosis with increasing bile duct dilatation that required stent placement. CONCLUSION: Endoscopic therapy with a PEB is very effective for the treatment of AS after LT, and seems to significantly shorten the overall duration of endoscopic treatment by reducing the number of interventions needed to achieve LTCS.

Hüsing, Anna; Reinecke, Holger; Cicinnati, Vito R; Beckebaum, Susanne; Wilms, Christian; Schmidt, Hartmut H; Kabar, Iyad

2015-01-01

345

A New Hydrotropic Block Copolymer Micelle System for Aqueous Solubilization of Paclitaxel  

PubMed Central

Paclitaxel (PTX), a potent anti-cancer drug, is poorly soluble in water, and this has been a major limitation in developing patient friendly formulations for clinical applications. Recent studies on polymeric micelles, especially hydrotropic polymer micelles, have suggested an alternative formulation of PTX based on their high loading capacity and physical stability in aqueous media. The present study aims at aqueous solubilization of PTX in polymer micelles without using any organic solvents that is usually required for solubilization in polymer micelles. Poly(ethylene glycol) was used as a hydrophilic block and, as a hydrotropic block, poly(4-(2-vinylbenzyloxy-N-picolylnicotinamide)) (P(2-VBOPNA)) was synthesized by atom transfer radical polymerization. The hydrotropic block copolymers did not form a micellar structure at pH 2 or below due to protonation of PNA groups, but the aqueous solubility of PTX increased significantly by the hydrotropic activity of P(2-VBOPNA). At pH values higher than 2, the PTX solubility increased even further due to deprotonation of 2-VBOPNA, leading to effective polymer micellization. A longer hydrotropic block resulted in higher aqueous PTX solubility, and slightly slower release rate from the micelles. The hydrotropic block copolymers synthesized in this study are able to form PTX-loaded polymeric micelles in aqueous solution without using any organic solvents. PMID:18155795

Huh, Kang Moo; Min, Hyun Soo; Lee, Sang Cheon; Lee, Hong Jae; Kim, Sungwon; Park, Kinam

2008-01-01

346

Sulfatide-containing lipid perfluorooctylbromide nanoparticles as paclitaxel vehicles targeting breast carcinoma  

PubMed Central

Targeted nanoparticle (NP) delivery vehicles are emerging technologies, the full potential of which has yet to be realized. Sulfatide is known to bind to extracellular matrix glycoproteins that are highly expressed in breast tumors. In this study, we report for the first time the combination of sulfatide and lipid perfluorooctylbromide NPs as a targeted breast cancer delivery vehicle for paclitaxel (PTX). PTX-sulfatide-containing lipid perfluorooctylbromide NPs (PTX-SNPs) were prepared using the emulsion/solvent evaporation method. PTX-SNPs exhibited a spherical shape, small particle size, high encapsulation efficiency, and a biphasic release in phosphate-buffered solution. The cytotoxicity study and cell apoptosis assay revealed that blank sulfatide-containing lipid perfluorooctylbromide NPs (SNPs) had no cytotoxicity, whereas PTX-SNPs had greater EMT6 cytotoxicity levels than PTX-lipid perfluorooctylbromide NPs (PTX-NPs) and free PTX. An in vitro cellular uptake study revealed that SNPs can deliver greater amounts of drug with more efficient and immediate access to intracellular targets. In vivo biodistribution measured using high-performance liquid chromatography confirmed that the PTX-SNPs can target breast tumor tissues to increase the accumulation of PTX in these tissues. The in vivo tumor inhibition ability of PTX-SNPs was remarkably higher than PTX-NPs and free PTX. Furthermore, toxicity studies suggested that the blank SNPs had no systemic toxicity. All results suggested that SNPs may serve as efficient PTX delivery vehicles targeting breast carcinoma. PMID:25170267

Li, Xiao; Qin, Fei; Yang, Li; Mo, Liqian; Li, Lei; Hou, Lianbing

2014-01-01

347

[Two cases of effective weekly paclitaxel administration and concurrent radiation for metastatic breast cancer].  

PubMed

We report two cases in which weekly paclitaxel (TXL) administration and concurrent radiation was effective for metastatic breast cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication. Case 1: A 50-year-old woman was found to have atelectasis of the middle lobe after treatment for brain metastasis. She was diagnosed with hilar, mediastinal and supraclavicular lymph nodes metastases. She received weekly TXL administration and concurrent radiation to the mediastinum and supraclavicular fossa. The metastatic lymph nodes had disappeared one month after the treatment. Case 2: A 31-year-old woman was diagnosed with advanced breast cancer with lung, pleural, bone and orbital metastases. She received weekly TXL administration and concurrent radiation to the orbit. The lung and pleural metastases had disappeared and the orbital metastasis was decreased by 75% one month after the treatment, and the case was assessed as a partial response. Leukopenia and other major adverse effects were not observed in either of the two cases. PMID:12557714

Kokufu, Ikuo; Tanei, Tomonori; Taniguchi, Hirokazu; Kimura, Fumihiko; Fukuda, Kazuhiro; Yamamoto, Masayuki; Yano, Tokiharu; Yamada, Katsumi; Tamaoka, Koichi; Hosono, Masako

2003-01-01

348

Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma.  

PubMed

Tumor acidity is now considered an important determinant of drug-resistance and tumor progression, and anti-acidic approaches, such as Proton Pump inhibitors (PPIs), have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to evaluate the possible PPI-induced sensitization of human melanoma cells to Paclitaxel (PTX). Our results show that PTX and the PPI Lansoprazole (LAN) combination was extremely efficient against metastatic melanoma cells, as compared to the single treatments, both in vitro and in vivo. We also showed that acidity plays an important role on the anti-tumor activity of these drugs, being detrimental for PTX activity, while crucial for the synergistic effect of PTX following pretreatment with LAN, due to its nature of pro-drug needing protonation for a full activation. We obtained straightforward results in a human melanoma xenograft model combining well tolerated LAN doses with suboptimal and poorly toxic doses of PTX. With this study we provide a clear evidence that the PPI LAN may be included in new combined therapy of human melanoma together with low doses of PTX. PMID:25449440

Azzarito, Tommaso; Venturi, Giulietta; Cesolini, Albino; Fais, Stefano

2015-01-28

349

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

350

Solid-nanoemulsion preconcentrate for oral delivery of paclitaxel: formulation design, biodistribution, and ? scintigraphy imaging.  

PubMed

Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC) using oil [propylene glycol monocaprylate/glycerol monooleate, 4:1?w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1:1?w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1:1?w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel), respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in ? scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC. PMID:25114933

Ahmad, Javed; Mir, Showkat R; Kohli, Kanchan; Chuttani, Krishna; Mishra, Anil K; Panda, A K; Amin, Saima

2014-01-01

351

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

352

[Modification of the response to paclitaxel of human differentiated colon cancer line after long-term treatment at very low dose].  

PubMed

Taxoids (paclitaxel, Taxol and docetaxel, Taxotere), drugs which stabilize microtubules, demonstrate marked activity against ovarian, brain and lung cancer. We investigated, on the human colon adenocarcinoma HT29-D4 cell line, firstly the effects of taxoids in function of the differentiation state and secondly the effects of a low dose of paclitaxel on the differentiation process. The cellular parameters studied were microtubular network, cell cycle and cell tubulin content. Undifferentiated cells treated with paclitaxel or docetaxel (10-100 nM) classically induced bundles in interphasic cells and pseudoasters in mitotic cells, arrest in cell cycle in G2M and increase in tubulin content. Inversely, no modification was observed in differentiated cells after similar taxoid treatment. Long-term low-dose pretreatment of differentiated cells restitutes some sensitivity to taxoids since these cells become responsive to further taxoid treatment, as reflected by modifications of the microtubule network. PMID:8652907

Carles, G; Braguer, D; Rognoni, J B; Roccabianca, M; Marvaldi, J; Briand, C

1996-02-01

353

Ultrasonication assisted Layer-by-Layer technology for the preparation of multi-functional anticancer drugs paclitaxel and lapatinib  

NASA Astrophysics Data System (ADS)

In this dissertation, ultrasonication assisted Layer-by-Layer (LbL) technology for the preparation of multifunctional poorly water-soluble anticancer drug nanoparticles, paclitaxel and lapatinib, has been developed. Many FDA approved drugs are very low soluble in water; therefore, it is very difficult to load and control their release and targeting efficiently, which greatly confines their application. The development of this method will pave the way for the development and application of those low soluble anticancer drugs. In the first part of this dissertation, the first approach for powerful ultrasonication, the top-down approach (sonicating bulk drug crystals in polyelectrolyte solution), was successfully applied for the preparation of the nanoparticles of paclitaxel. For this approach, a 200 nm diameter was a kind of "magic" barrier for colloidal particles prepared. This diameter barrier may be related to the nucleation size of the solvent vapor microbubbles. Consequently, agents enhancing bubbling formation (such as NH4HCO3) were applied to decrease paclitaxel colloid particles to 100-120 nm. Those paclitaxel nanoparticles were Layer-by-Layer coated with a 10-20 nm polycation/polyanion shell to provide aqueous colloidal stability and slower particle dissolution. However, a large obstacle of these powerful ultrasonication methods was a necessity of long ca 45 minutes high power ultrasonication which resulted in TiO2 contamination from titanium electrode. The small amount of TiO2 contamination from ultrasonication did negatively affect the in vivo testing of this system in mice, and had to be removed before low toxicity of the Layer-by-Layer coated paclitaxel nanoparticles were observed. In the second part of the dissertation, the second approach for sonication, the bottom-up approach (sonicating drug in a water-miscible organic solvent followed by slow water add-in) was successfully applied for the preparation of the nanoparticles of lapatinib and paclitaxel with less powerful sonication. By using polymeric excipients combined with non-ionic and anionic surfactants along with regular sonication, the prepared particle sizes was uniform at around 140-150 nm. Less sonication time (ca 15 minutes) and lower sonication power avoided TiO2 contamination. The amphiphiles attached to the hydrophobic nanoparticles and served as anchors for LbL shell. The inner LbL layers and surfactants minimized the surface free energy, thereby preventing crystal form changes and nanoparticles coalescence, while the outermost layers enhanced colloidal stability. In the third part of the dissertation, LbL shells with PEGylation (using a block copolymer of poly-L-lysine (PLL) and PEG) for lapatinib were developed for enhanced colloidal stability in high molarity PBS buffer. In the above proposed paclitaxel and lapatinib formulation, we obtained 150-200 nm with high drug content of 80-90% due to very thin capsule walls (ca 10 nm). The drug release time from the LbL capsules was found to be between 10 and 20 hours depending on the shell thickness. Washless Layer-by-Layer assembly was used: 1) addition of polycation in the amount that is enough to reverse surface charge of the dispersion to a high positive (+30 mV) value; 2) addition of polyanion in the amount that is enough to reverse surface charge of the dispersion to a high negative (-30 mV) value. No intermediate washing of nanoparticles was done until the shell was complete. The washless method had the advantage of time and energy saving, preservation of the sample structure and no losses of sample. In the last part of the dissertation, we elaborated nanoformulation of two drugs in one nanocapsule locating paclitaxel in the core and lapatinib on the shell periphery. With this formulation, combining in one nanoparticle dual drugs, we reached the drugs' efficiency synergy. In a multidrug-resistant (MDR) ovarian cancer cell line, OVCAR-3, LbL lapatinib/paclitaxel nanocolloids mediated an enhanced cell growth inhibition in comparison with the LbL paclitaxel-only and LbL lapatinib-only

Zhang, Xingcai

354

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

355

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

356

Chemotherapy for endometrial carcinoma (GOGO-EM1 study): TEC (paclitaxel, epirubicin, and carboplatin) is an effective remission-induction and adjuvant therapy  

Microsoft Academic Search

Background  TAP chemotherapy (paclitaxel, doxorubicin, and cisplatin) is effective for advanced and recurrent endometrial carcinoma, but\\u000a has occasional severe toxicity. TEC chemotherapy (paclitaxel, epirubicin, and carboplatin) has been suggested to have less\\u000a toxicity; however, the optimal dosage has yet to be determined.\\u000a \\u000a \\u000a \\u000a \\u000a Patients and methods  Phase I\\/II prospective study for TEC therapy was performed. A retrospective comparison of the prognosis between adjuvant

Tomomi Egawa-Takata; Yutaka Ueda; Chie Kuragaki; Takahito Miyake; Takashi Miyatake; Masami Fujita; Kiyoshi Yoshino; Ryuichi Nakashima; Mika Okazawa; Tateki Tsutsui; Ken-Ichirou Morishige; Tadashi Kimura; Masato Yamasaki; Takamichi Nishizaki; Masaaki Nagamatsu; Kimihiko Ito; Masahiro Asada; Kazuhide Ogita; Akinori Wakimoto; Toshiya Yamamoto; Yukihiro Nishio; Takayuki Enomoto

357

[A case of triple-negative breast cancer achieved pCR by epirubicin and cyclophosphamide(EC)therapy followed by gemcitabine plus paclitaxel combination preoperative therapy].  

PubMed

A 59-year-old woman was diagnosed with triple-negative breast cancer(TNBC)(T2N0M0)and treated with primary systemic therapy. The patient was treated with 4 courses of epirubicin and cyclophosphamide(EC)therapy every 3 weeks, followed by weekly gemcitabine-paclitaxel combination therapy. As she was judged to have achieved a partial response(PR) by ultrasound and CT examination after eight courses, she underwent partial resection of the left breast. CR was revealed by the pathological examination of the resected specimen. Gemcitabine-paclitaxel combination therapy seems to be a one of the useful preoperative chemotherapies for TNBC. PMID:23863586

Saito, Motonobu; Fujita, Shotaro; Sakuma, Takeshi; Matsuzaki, Masami; Katagata, Naoto; Watanabe, Fumiaki; Takenoshita, Seiichi; Nomizu, Tadashi

2013-05-01

358

Pretreatment with turmeric modulates the inhibitory influence of cisplatin and paclitaxel on CYP2E1 and CYP3A1/2 in isolated rat hepatic microsomes.  

PubMed

Previous animal studies have shown that turmeric can significantly modulate the activity of several drug metabolizing enzymes, this may dramatically affect the bioavailability of several drugs resulting in over dose or less therapeutic effects. This study was directed to evaluate the inhibitory effects of cisplatin and paclitaxel on two CYP450 enzymes namely CYP2E1 and CYP3A1/2 in hepatic microsomes isolated from normal and turmeric pretreated rats. Cisplatin and paclitaxel were added by different concentrations to hepatic microsomes isolated from untreated and turmeric (100 mg/kg/day) pretreated rats for 15 days after receiving pyrazole or dexamethasone for induction of CYP2E1 and CYP3A1/2 respectively. The kinetic potency of these drugs as CYP inhibitors was determined by analysis of Lineweaver-Burk plot. Addition of cisplatin or paclitaxel by (10, 50 and 100 ?M) to hepatic microsomes from normal or turmeric pretreated rats caused a concentration dependent inhibition of CYP2E1, with an evidence of less inhibition in turmeric pretreated microsomes particularly at higher concentration. Both drugs at 100 ?M displayed a mixed type of inhibition of CYP2E1 in normal or turmeric pretreated microsomes where paclitaxel was the most potent inhibitor. Cisplatin (10, 50 and 100 ?M) caused a concentration dependant inhibition of CYP3A1/2 that was enhanced by turmeric pretreatment. The inhibition of CYP3A1/2 by cisplatin (100 ?M) was in non-competitive manner with a smaller Ki value in turmeric pretreated microsomes. The inhibitory influence of paclitaxel (10, 50 and 100 ?M) on CYP3A1/2 decreased with increasing the drug concentration and this inhibition was augmented by turmeric pretreatment. Interestingly, the inhibition of this enzyme by paclitaxel (10 ?M) was switched from mixed type in normal microsomes to competitive manner in turmeric pretreated ones with a marked reduction of Ki values reflecting greater inhibitory influence of paclitaxel on CYP3A1/2 by turmeric pretreatment. In conclusion, turmeric pretreatment attenuated the inhibitory influence of cisplatin and paclitaxel on CYP2E1 activity and magnified their inhibition on CYP3A1/2, thus the use of turmeric with drugs or other medications should raise concern for drugs-herb interactions. PMID:24882083

Ahmed, Enas M; EL-Maraghy, Shohda A; Teleb, Zakaria A; Shaheen, Amira A

2014-09-01

359

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

360

Long-Term Outcomes and Toxicity of Concurrent Paclitaxel and Radiotherapy for Locally Advanced Head-and-Neck Cancer  

SciTech Connect

Purpose: To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Patients and Methods: Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m{sup 2}/cycle, and the subsequent 19 patients received 120 mg/m{sup 2}/cycle. External beam radiotherapy was delivered to a dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. Results: The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). Conclusion: The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

Citrin, Deborah [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)], E-mail: citrind@mail.nih.gov; Mansueti, John; Likhacheva, Anna; Sciuto, Linda [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Albert, Paul S. [Biometric Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Rudy, Susan F. [Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD (United States); Cooley-Zgela, Theresa [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Cotrim, Ana [National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Solomon, Beth [Speech Language Pathology Section, Rehabilitation Medicine Department, National Institutes of Health, Bethesda, MD (United States); Colevas, A. Dimitrios [Head and Neck Oncology Program, Stanford Cancer Center, Stanford University, Stanford, CA (United States); Russo, Angelo [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Morris, John C. [Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Herscher, Laurie [Department of Radiation Oncology, Suburban Hospital, Bethesda, MD (United States); Smith, Sharon [Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)] (and others)

2009-07-15

361

Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients.  

PubMed

The vast majority of women with advanced ovarian cancer will ultimately relapse and develop a drug-resistant disease with an overall 5-year survival of <50%. Unfortunately, the mechanisms of drug resistance actually operating in patients are still unknown. To address this issue, in 41 patients affected by advanced ovarian cancer the three main mechanisms of paclitaxel resistance were investigated: overexpression of MDR-1 gene, point mutations at prominently expressed alpha-tubulin and beta-tubulin genes and selective alterations in the expression of beta-tubulin isotypes. MDR-1 and the beta-tubulin isotypes expression were evaluated by semiquantitative and real-time PCR. On the same specimens, quantitative immunohistochemistry was also done in the tumor area. No statistically significant changes of MDR-1 expression were noticed between the sensitive and resistant patients either at the mRNA or protein level. The tubulin mutations for the ubiquitous alpha-tubulin and beta-tubulin genes were evaluated by automated DNA sequencing, and in all patients, no mutations were detected in both resistant and sensitive cases. With regard to the expression of tubulin isoforms, a statistically significant up-regulation of class III beta-tubulin was found in the resistant subset. It is worth noting that this statistically significant increase of the expression of class III beta-tubulin was detectable at the mRNA and protein level. By a direct comparison of the three main known mechanisms of paclitaxel resistance, this study indicates that overexpression of class III beta-tubulin is the most prominent mechanism of paclitaxel resistance in ovarian cancer. PMID:15671559

Mozzetti, Simona; Ferlini, Cristiano; Concolino, Paola; Filippetti, Flavia; Raspaglio, Giuseppina; Prislei, Silvia; Gallo, Daniela; Martinelli, Enrica; Ranelletti, Franco Oreste; Ferrandina, Gabriella; Scambia, Giovanni

2005-01-01

362

Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: A randomized double-blind placebo controlled trial  

PubMed Central

Background Axonal sensory peripheral neuropathy is the major dose-limiting side effect of paclitaxel.Omega-3 fatty acids have beneficial effects on neurological disorders from their effects on neurons cells and inhibition of the formation of proinflammatory cytokines involved in peripheral neuropathy. Methods This study was a randomized double blind placebo controlled trial to investigate the efficacy of omega-3 fatty acids in reducing incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN). Eligible patients with breast cancer randomly assigned to take omega-3 fatty acid pearls, 640?mg?t.i.d during chemotherapy with paclitaxel and one month after the end of the treatment or placebo. Clinical and electrophysiological studies were performed before the onset of chemotherapy and one month after cessation of therapy to evaluate PIPN based on "reduced Total Neuropathy Score". Results Twenty one patients (70%) of the group taking omega-3 fatty acid supplement (n = 30) did not develop PN while it was 40.7%( 11 patients) in the placebo group(n = 27). A significant difference was seen in PN incidence (OR = 0.3, .95% CI = (0.10-0.88), p = 0.029). There was a non-significant trend for differences of PIPN severity between the two study groups but the frequencies of PN in all scoring categories were higher in the placebo group (0.95% CI = (?2.06 -0.02), p = 0.054). Conclusions Omega-3 fatty acids may be an efficient neuroprotective agent for prophylaxis against PIPN. Patients with breast cancer have a longer disease free survival rate with the aid of therapeutical agents. Finding a way to solve the disabling effects of PIPN would significantly improve the patients’ quality of life. Trial registration This trial was registered at ClinicalTrials.gov (NCT01049295) PMID:22894640

2012-01-01

363

A Phase II Trial of Neoadjuvant Chemotherapy with Genexol® (Paclitaxel) and Epirubicin for Locally Advanced Breast Cancer  

PubMed Central

Purpose Neoadjuvant chemotherapy (NC) is yet to be established as the definitive treatment regimen for locally advanced breast cancer (LABC). The aim of this study was to determine the efficacy and toxicity of NC with epirubicin and paclitaxel. Methods Between March 2007 and January 2009, 50 patients with LABC were enrolled in an open-label, phase II, multicenter study carried out at five distinct institutions. All patients were scheduled to receive four cycles of 60 mg/m2 epirubicin and 175 mg/m2 paclitaxel every 3 weeks, preoperatively, unless they developed profound side effects or disease progression. After curative surgery, two additional cycles of chemotherapy were administered to patients who had shown a positive response to NC. Results In all, 196 cycles of chemotherapy were administered preoperatively; 47 of the 50 patients (94%) underwent all four cycles of designated treatment. Complete disappearance of invasive foci of the primary tumor, and negative axillary lymph nodes were confirmed in eight patients (16.0%), post operation. The cumulative 5-year disease-free survival rate was 70.0% for patients with complete remission (CR) and partial remission (PR), and 33.3% for patients with stable disease (SD) and progressive disease (PD) (p=0.018). The cumulative 5-year overall survival was 90.0% for patients who achieved CR and PR and 55.6% for patients who had SD and PD (p=0.001). Neutropenia (42.0%) was the most common grade 3/4 toxicity. However, none of the toxicities resulted in cessation of the treatment. Conclusion The encouraging pathologic response observed in the patients treated with epirubicin plus paclitaxel NC in this study suggests that epirubicin could be a substitute for doxorubicin, which is the most cardiotoxic agent. PMID:25548582

Lee, Jinsun; Chang, Eilsung; Choi, Woonjung; Lee, Kwangman; Yoon, Hyunjo; Jung, Sunghoo; Park, Minho; Yoon, Junghan; Kim, Sungyong

2014-01-01

364

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

365

Chitosan\\/pshRNA plasmid nanoparticles targeting MDR1 gene reverse paclitaxel resistance in ovarian cancer cells  

Microsoft Academic Search

Summary  In order to investigate the effect of chitosan\\/pshRNA plasmid nanoparticles targeting MDR1 genes on the resistance of A2780\\/TS\\u000a cells to paclitaxel, chitosan\\/pshRNA plasmid nanoparticles were synthesized by means of a complex coacervation technique and\\u000a transfected into A2780\\/TS cells. The cells transfected with MDR1-targeted chitosan\\/pshRNA plasmid nanoparticles were experimental\\u000a cells and the cells transfected with chitosan\\/pGPU6\\/GFP\\/Neo no-load plasmid nanoparticles served as

Yan Yang; Zehua Wang; Minfang Li; Shi Lu

2009-01-01

366

DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate: a curcumin analog with a synergic effect in combination with paclitaxel in breast cancer treatment.  

PubMed

This paper describes a new method for the preparation of sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, DM-1, and 3-oxo-penta-1,4-dienyl-bis (2-methoxy-phenolate), DM-2. The aim of this work was to evaluate the antitumor effects of DM-1 in adjuvant chemotherapy for breast cancer treatment. Mice bearing mammary adenocarcinomas (Ehrlich ascites tumors) were treated with paclitaxel alone, DM-1 alone, and paclitaxel + DM-1. Tumor samples were used to perform cytological analysis by the Papanicolaou method and apoptosis analysis by annexin V and phosphorylated caspase 3. The paclitaxel + DM-1 group had decreased tumor areas and tumor volumes, and the frequency of metastasis was significantly reduced. This caused a decrease in cachexia, which is usually caused by the tumor. Furthermore, treatment with paclitaxel + DM-1 and DM-1 alone increased the occurrence of apoptosis up to 40% in tumor cells, which is 35% more than in the group treated with paclitaxel alone. This cell death was mainly caused through phosphorylated caspase 3 (11% increase in paclitaxel + DM-1 compared to the paclitaxel group), as confirmed by reduced malignancy criteria in the ascitic fluid. DM-1 emerges as a potential treatment for breast cancer and may act as an adjuvant in chemotherapy, enhancing antitumor drug activity with reduced side effects. PMID:22194218

Faião-Flores, Fernanda; Suarez, José Agustín Quincoces; Pardi, Paulo Celso; Maria, Durvanei Augusto

2012-06-01

367

Lactoferrin-appended solid lipid nanoparticles of paclitaxel for effective management of bronchogenic carcinoma.  

PubMed

Abstract Lung cancer is a dreadful disease which claims to be more life threatening as compared to total sum up of colon, prostate and breast cancers. Thus, there is an urgent need to develop an effective delivery approach for its management. Paclitaxel (PTX) is one of the well-known choice as antineoplasitic agent used for the treatment of different types of human cancers such as non-small-cell lung, head and neck cancers, leukemia, breast, ovarian and melanoma. Lactoferrin (Lf), a "multifunctional protein" is crucial for natural immunity which is secreted by exocrine glands. Lf receptors are expressed on the apical surface on bronchial epithelial cells. These over-expressed LF receptors can be utilized for the transportation of Lf-conjugated drug or nanocarrier devices. The present study was aimed to develop PTX-loaded Lf-coupled solid lipid nanoparticles (SLNs) for the treatment of lung cancer. PTX-loaded SLNs were prepared, characterized and then coupled with Lf using carbodiimide chemistry. The formulations were characterized by transmission electron microscopy, particle size, polydispersity index and zeta potential, whereas Lf conjugation was confirmed by FT-IR and (1)H NMR and efficiency of prepared system was evaluated by in vitro, ex vivo and in vivo evaluations. The ex vivo cytotoxicity studies on human bronchial epithelial cell lines, BEAS-2B, revealed superior anticancer activity of Lf-coupled SLNs than plain SLNs and free PTX. In vivo biodistribution studies showed higher concentrations of PTX accumulated in lungs via Lf-coupled SLNs than plain SLNs and free PTX. These studies suggested that Lf-coupled PTX-loaded SLNs could be used as potential targeting carrier for delivering anticancer drug to the lungs with the minimal side effects. PMID:24467582

Pandey, Vikas; Gajbhiye, Kavita Rai; Soni, Vandana

2015-02-01

368

Comparative study of sequential combinations of paclitaxel and methotrexate on a human bladder cancer cell line.  

PubMed

We investigated the cytotoxic effect of different sequential combinations of paclitaxel (Taxol, TX), an antimicrotuble agent, and methotrexate (MTX), a potent inhibitor of dihydrofolate reductase, on a human bladder cancer cell line (T24). The results obtained with a colony-forming assay 5 days after 24 hr of exposure to TX alone showed a strong decline in colony growth up to a concentration of 6 nM. There was a plateau phase at TX concentrations ranging from 6 to 10 nM. The IC50 values found with the different dosing sequences and 24-hr exposure to the drugs were 0.24 microM for MTX alone, 3.49 nM for TX alone, 3.84 nM for TX followed by MTX, 3.75 nM for TX and MTX simultaneously, and 2.10 nM for MTX followed by TX. The cytotoxic effect due to drug interactions in the different sequential combinations was evaluated by an algebraic method. All the combination sequences were found to be synergistic (combination index [CI] < 1) at low TX concentrations. An antagonistic effect (CI > 1) was obtained at higher TX concentrations. Our data demonstrate that the T24 cell line is sensitive to TX and that the cytotoxic effect is enhanced to different degrees depending on the treatment sequence when TX is combined with MTX. These findings could have implications in the design of appropriate administration schedules of these two drugs for the treatment of bladder cancer. PMID:10834027

Cos, J; Bellmunt, J; Soler, C; Ribas, A; Lluis, J M; Murio, J E; Margarit, C

2000-01-01

369

Efficacy of dual-functional liposomes containing paclitaxel for treatment of lung cancer.  

PubMed

This study was mainly focused on the development of a dual-ligand liposomal delivery system for targeting the delivery of paclitaxel (PTX) to lung cancer. The specific ligand peptide HAIYPRH (T7) and the cationic cell-penetrating peptide TAT were connected with phospholipid via a polyethylene glycol (PEG) spacer to prepare the dual-ligand liposomes (T7/TAT-LP-PTX). Physicochemical characterizations of T7/TAT-LP-PTX, such as particle size, ? potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. In the cellular uptake study, the T7/TAT-LP endocytosed by the A549 cells was 2.26-, 3.48- and 8.56-fold higher than TAT-LP, T7-LP and LP, respectively. The IC50 values of TAT-LP-PTX, T7-LP-PTX and LP-PTX were much higher than those of T7/TAT-LP-PTX, respectively. The homing specificity of T7/TAT-LP was evaluated on the tumor spheroids, which revealed that T7/TAT-LP was more efficaciously internalized in tumor cells than TAT-LP, T7-LP and LP, respectively. Compared to LP, TAT-LP and T7-LP, T7/TAT-LP showed the strongest cell uptake property, and the highest accumulation ability in tumor spheroids in vitro. In the in vivo study, the T7/TAT-LP-PTX exhibited the best inhibitory effect of tumor growth for A549-bearing mice. Collectively, these results suggested that T7/TAT-LP-PTX is a promising drug delivery system for the treatment of lung cancer. PMID:25482610

Wang, Rong-Hua; Cao, Hong-Mei; Tian, Zhi-Ju; Jin, Bo; Wang, Qing; Ma, Hong; Wu, Jing

2015-02-01

370

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

371

MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel  

PubMed Central

Paclitaxel (PTX) is the front-line chemotherapeutic agent against human non-small cell lung cancer (NSCLC). However, its therapeutic efficacy is restricted by the increasing frequency of chemotherapeutic resistance in NSCLC. Accumulating evidence has shown the potential role of microRNAs (miRNAs) in the chemotherapeutic sensitivity of cancer cells. Previously it was reported that microRNA-7 (miR-7) acts as an important tumor suppressor in NSCLC. Therefore, the present study was conducted to determine the regulatory role of miR-7 in PTX chemotherapy for NSCLC. Four NSCLC cell lines were used to analyze the correlation of the PTX-sensitivity and endogenoaus miR-7 expression. miR-7 expression was up- and downregulated using miR-7 mimics and inhibitors respectively, and the role of miR-7 in sensitizing NSCLC cells to PTX was assessed by cell viability and apoptosis assays. The molecular mechanism of PTX sensitivity was determined by quantitative polymerase chain reaction and western blotting. It was found that the sensitivity of NSCLC cells to PTX was dependent on endogenous miR-7. Upregulation of miR-7 enhanced the PTX-sensitivity of NSCLC cells by suppressing cell proliferation and promoting cell apoptosis, while the inhibition of miR-7 abrogated the antiproliferative proapoptotic effects of PTX. Pretreatment of miR-7 mimics enhanced the PTX-mediated downregulation of epidermal growth factor receptor (EGFR) in NSCLC cells. These results have identified miR-7 as a potential EGFR-targeting sensitizer in PTX therapy. These data may facilitate the development of novel chemotherapeutic approaches for NSCLC. PMID:25289099

LIU, RONGHUA; LIU, XIAOMING; ZHENG, YIJIE; GU, JIE; XIONG, SHUDAO; JIANG, PEI; JIANG, XUECHAO; HUANG, ENYU; YANG, YIXIAN; GE, DI; CHU, YIWEI

2014-01-01

372

Dissecting the Paclitaxel-Microtubule Association: Quantitative Assessment of the 2?-OH Group†  

PubMed Central

Paclitaxel (PTX) is a microtubule-stabilizing agent that is widely used in cancer chemotherapy. This structurally complex natural product acts by binding to ?-tubulin in assembled microtubules. The 2?-hydroxyl group in the flexible side chain of PTX is an absolute requirement for activity, but its precise role in the drug-receptor interaction has not been specifically investigated. The contribution of the 2?-OH group to the affinity and tubulin-assembly efficacy of PTX has been evaluated through quantitative analysis of PTX derivatives possessing side chain deletions: 2?-deoxy-PTX, N-debenzoyl-2?-deoxy-PTX and baccatin III. The affinity of 2?-deoxy-PTX for stabilized microtubules was more than 100-fold less than that of PTX and only about 3-fold greater than the microtubule affinity of baccatin III. No microtubule binding activity was detected for the analog N-debenzoyl-2?-deoxy-PTX. The tubulin-assembly efficacy of each ligand was in concordance with the microtubule binding affinity, as was the trend in cytotoxicities. Molecular dynamics simulations revealed that the 2?-OH group of PTX can form a persistent hydrogen bond with D26 within the microtubule binding site. The absence of this interaction between 2?-deoxy-PTX and the receptor can account for the difference in binding free energy. Computational analyses also provide a possible explanation for why N-debenzoyl-2?-deoxy-PTX is inactive, in spite of the fact that it is essentially a substituted baccatin III. We propose that the hydrogen bonding interaction between the 2?-OH group and D26 is the most important stabilizing interaction that PTX forms with tubulin in the region of the C-13 side chain. We further hypothesize that the substituents at the 3?-position function to orient the 2?-OH group for a productive hydrogen bonding interaction with the protein. PMID:23473345

Sharma, Shubhada; Lagisetti, Chandraiah; Poliks, Barbara; Coates, Robert M.; Kingston, David G. I.; Bane, Susan

2013-01-01

373

Paclitaxel-loaded PCL-TPGS nanoparticles: in vitro and in vivo performance compared with Abraxane®.  

PubMed

The purpose of this work was to develop Cremophor(®) EL-free nanoparticles (NPs) loaded with Paclitaxel (PTX) in order to improve the drug i.v. pharmacokinetic profile and to evaluate its activity against commercially available formulations such as Taxol(®) and Abraxane(®). PTX-loaded poly(?-caprolactone)-alpha tocopheryl polyethylene glycol 1000 succinate (PCL-TPGS) NPs were prepared using three different techniques: (i) by nanoprecipitation (NPr-method), (ii) by emulsion-solvent evaporation homogenized with an Ultra-Turrax(®) (UT-method) and (iii) by emulsion-solvent evaporation homogenized with an ultrasonicator (US-method). The NPs prepared by US-method showed the smallest size and the highest drug content. The NPs exhibited a slow and continuous release of PTX. The in vitro anti-tumoral activity was assessed using two human breast cancer cell lines (MCF-7 and MDA-MB-231) with the WTS assay. Cytotoxicity studies with both cell lines showed that PTX-loaded PCL-TPGS NPs exhibited better anti-cancer activity compared to PTX solution and the commercial formulation Abraxane(®) at different concentrations. Importantly, in the case of triple negative MDA-MB-231 breast cancer cells, the IC50 value for PTX-loaded PCL-TPGS NPs was 7.8 times lower than Abraxane(®). Finally, in vivo studies demonstrated that PTX-loaded PCL-TPGS NPs exhibited longer systemic circulation time and slower plasma elimination rate than Taxol(®) and Abraxane(®). Therefore, the novel NPs investigated might be an alternative nanotechnological platform for PTX delivery system in cancer chemotherapy. PMID:24060929

Bernabeu, Ezequiel; Helguera, Gustavo; Legaspi, Maria J; Gonzalez, Lorena; Hocht, Christian; Taira, Carlos; Chiappetta, Diego A

2014-01-01

374

Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields  

PubMed Central

The use of stents for vascular disease has resulted in a paradigm shift with significant improvement in therapeutic outcomes. Polymer-coated drug-eluting stents (DES) have also significantly reduced the incidence of reobstruction post stenting, a disorder termed in-stent restenosis. However, the current DESs lack the capacity for adjustment of the drug dose and release kinetics to the disease status of the treated vessel. We hypothesized that these limitations can be addressed by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of paclitaxel (PTX). Magnetic treatment of cultured arterial smooth muscle cells with PTX-loaded MNPs caused significant cell growth inhibition, which was not observed under nonmagnetic conditions. In agreement with the results of mathematical modeling, significantly higher localization rates of locally delivered MNPs to stented arteries were achieved with uniform-field–controlled targeting compared to nonmagnetic controls in the rat carotid stenting model. The arterial tissue levels of stent-targeted MNPs remained 4- to 10-fold higher in magnetically treated animals vs. control over 5 days post delivery. The enhanced retention of MNPs at target sites due to the uniform field-induced magnetization effect resulted in a significant inhibition of in-stent restenosis with a relatively low dose of MNP-encapsulated PTX (7.5 ?g PTX/stent). Thus, this study demonstrates the feasibility of site-specific drug delivery to implanted magnetizable stents by uniform field-controlled targeting of MNPs with efficacy for in-stent restenosis. PMID:20404175

Chorny, Michael; Fishbein, Ilia; Yellen, Benjamin B.; Alferiev, Ivan S.; Bakay, Marina; Ganta, Srinivas; Adamo, Richard; Amiji, Mansoor; Friedman, Gary; Levy, Robert J.

2010-01-01

375

Separation of paclitaxel and related taxanes by micellar electrokinetic capillary chromatography.  

PubMed

Micellar electrokinetic capillary chromatography is used to separate paclitaxel (trade name Taxol, Bristol-Myers Squibb) and 14 related taxanes in 11.5 min. An aqueous acetonitrile (ACN) buffer containing sodium dodecyl sulfate (SDS) surfactant allows resolution of the 15 taxanes from each other and from the principal matrix ingredient in the injectable dosage form of the drug, Cremophor EL (polyethoxylated castor oil). Although the precise effect of high concentrations of ACN on micelle size and structure is not clear, the separation achieved is not possible in the absence of the organic modifier. The migration order is apparently the of decreasing aqueous-phase solubility, which is related to the presence of a side chain at the carbon 13-position, to the addition of a xylosyl group at the 7-position, and to the number of acetylated hydroxyl groups; it is also related to the increasing affinity of the taxane side chain for the micellar phase. The retention factors, k', increase linearly with SDS concentration above the critical micelle concentration. With increasing concentration of ACN, k' values for the taxanes without side chain decrease; for the most hydrophobic taxanes, k' increases up to 20% (v/v) ACN and then decreases sharply at higher concentrations; for the others, k' varies little up to 10% ACN, and then decreases rapidly with added ACN. Similar behavior was observed with methanol, but the break in k' occurred between 30% and 40% (v/v). Resolution was unacceptably poor if the samples dissolved in methanol were injected; samples dissolved in buffer containing SDS were well-behaved, probably because of stacking of the micelles during injection. Van't Hoff plots (in k' vs 1/T) were linear and allowed calculation of the delta H degree of transfer of taxane from aqueous to micelle phase. However, similar to the situation in HPLC, uncertainty in the micelle/aqueous phase ratio precludes reliable determination of the corresponding delta S degree. PMID:9511466

Shao, L K; Locke, D C

1998-03-01

376

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

377

Improving Paclitaxel Delivery: In Vitro and In Vivo Characterization of PEGylated Polyphosphoester-Based Nanocarriers.  

PubMed

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 ?g/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma. PMID:25629952

Zhang, Fuwu; Zhang, Shiyi; Pollack, Stephanie F; Li, Richen; Gonzalez, Amelia M; Fan, Jingwei; Zou, Jiong; Leininger, Sarah E; Pavía-Sanders, Adriana; Johnson, Rachel; Nelson, Laura D; Raymond, Jeffery E; Elsabahy, Mahmoud; Hughes, Dennis M P; Lenox, Mark W; Gustafson, Tiffany P; Wooley, Karen L

2015-02-11

378

pH and glutathion-responsive hydrogel for localized delivery of paclitaxel.  

PubMed

pH and glutathion (GSH)- responsive nanogels (NGs) based on poly-N-isopropylacrilamide (NIPA), N-hydroxyethyl acrylamide (HEAA) and tert-butyl 2-acrylamidoethyl carbamate (2AAECM) were synthesized by a microemulsion polymerization method using N, N'-cystaminebisacrylamide (CBA) as a crosslinking agent and evaluated for passive targeting of paclitaxel (PTX). Physicochemical characterizations of unloaded and PTX-loaded NGs, such as particle size, morphology, encapsulation efficiency and in vitro PTX release were also assessed. Electron microscopy techniques (SEM and TEM) as well as dynamic light scattering (DLS) analysis showed nanosized spherical hydrogels. FTIR spectra confirmed the synthesis of nanogels by free radical polymerization among vinyl groups of monomers. In vitro release was analyzed by high-performance liquid chromatography (HPLC) and differences between two NG formulations were obtained. Nanogels released almost 64% of PTX after 50h at GSH concentrations equivalent to that in the cellular cytosol, whereas less PTX was released from NGs at pH and GSH levels similar to plasma. Cellular uptake and cytotoxicity were also demonstrated by using coumarin-6 and MTT assays, respectively, for three tumor cell lines (MCF7, HeLa and T47D). Cellular uptake assays revealed rapid uptake within 2h and intracellular accumulation of coumarin-6-loaded nanogels after 48 h incubation. MTT assays showed changes in cell viability at different concentrations of PTX formulations, as well as pure PTX (10 ?M, 20 ?M and 30 ?M). To investigate PTX effect on cell viability, changes in cell cycle were examined by flow cytometry and a G2/M cell arrest was demonstrated. Overall, synthesized nanogels may be used as potential carriers for hydrophobic anticancer drugs. PMID:24491841

Pérez, Elena; Fernández, Ana; Olmo, Rosa; Teijón, Jose M; Blanco, M Dolores

2014-04-01

379

Comparison of Therapeutic G-CSF Cycles and Prophylactic G-CSF Cycles in Patients Receiving Paclitaxel and Carboplatin Combination Chemotherapy for Ovarian Cancer: A Retrospective Study Report  

PubMed Central

Objective: The aim of the present study was to investigate the differences between therapeutic granulocyte-colony stimulating factor (G-CSF) cycles and prophylactic G-CSF cycles in patients receiving paclitaxel and carboplatin combination chemotherapy for ovarian cancer. Material and Method: Medical records of 15 women who received paclitaxel and carboplatin combination chemotherapy for ovarian cancer between January 2003 and December 2012 were analyzed retrospectively. All 15 patients completed 6 cycles of paclitaxel and carboplatin as the first-line chemotherapy. The complications were compared between therapeutic G-CSF cycles and prophylactic G-CSF cycles. Results: The number of chemotherapy cycles correlated with the ratio of prophylactic G-CSF cycles. It was considered that earlier prophylactic G-CSF injections were chosen due to a gradual decrease in WBC and neutrophil counts. The WBC and neutrophil counts were significantly higher in prophylactic G-CSF cycles than in therapeutic G-CSF cycles. However, there were no significant differences in the intervals of chemotherapy, delay of chemotherapy, and incidence of febrile neutropenia between the therapeutic G-CSF and prophylactic G-CSF cycles. Conclusion: Prophylactic G-CSF injections were not effective in preventing the incidence of febrile neutropenia in patients receiving paclitaxel and carboplatin combination chemotherapy for ovarian cancer. PMID:25648659

Kawashima, Masaaki; Kondo, Hajime

2014-01-01

380

Development and Evaluation a Novel TPGS-mediated Paclitaxel-Loaded PLGA-mPEG nanoparticle for the Treatment of Ovarian Cancer.  

PubMed

One of the major obstacles to successful paclitaxel (PTX) chemotherapy is toxic side effects, which are often due to the conventional surfactants used, such as Cremophor EL. PTX is characterized by its hydrophobicity and insolubility, which limit its application in ovarian cancer therapy. The aim of this study was to develop Cremophor EL-free PTX-loaded methoxy poly(ethylene glycol)-block-(lactic-co-glycolic acid) copolymers (PLGA-mPEG) nanoparticles (NPs) using d-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a novel emulsifier. The ability of nanoparticles loaded with paclitaxel (NP-PTX) to inhibit tumor growth was assessed in vitro and in vivo. The acute toxicity of NP-PTX was also evaluated in vivo. We found that paclitaxel was efficiently encapsulated into PLGA-mPEG NPs with a low concentration of TPGS as the emulsifier. The synthesized NP-PTX demonstrated the desired diameter of 80 nm as characterized by transmission electron microscopy. The NP-PTX also exhibited a sustained release of loaded PTX over 4 days with the same chemotherapeutic efficiency and reduced side effects. NP-PTX-treated cells showed slightly lower cytotoxic responses compared with those treated with free PTX at the same concentration. In vivo studies confirmed that NP-PTX significantly enhanced the median lethal dose of paclitaxel by 10-fold, and a similar effect on the inhibition of tumor growth was achieved in nude mice. PMID:25451039

Lv, Wen; Cheng, Lihua; Li, Baohua

2014-11-29

381

The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells.  

PubMed

Dysregulation of Na+/H+ exchanger isoform one (NHE1) activity is a hallmark of cells undergoing tumorigenesis and metastasis, the leading cause of patient mortality. The acidic tumor microenvironment is thought to facilitate the development of resistance to chemotherapy drugs and to promote extracellular matrix remodeling leading to metastasis. Here, we investigated NHE1 as a co-adjuvant target in paclitaxel chemotherapy of metastatic breast cancer. We generated a stable NHE1-knockout of the highly invasive, triple-negative, MDA-MB-231 breast cancer cells. The NHE1-knockout cells proliferated comparably to parental cells, but had markedly lower rates of migration and invasion in vitro. In vivo xenograft tumor growth in athymic nude mice was also dramatically decreased compared to parental MDA-MB-231 cells. Loss of NHE1 expression also increased the susceptibility of knockout cells to paclitaxel-mediated cell death. NHE1 inhibition, in combination with paclitaxel, resulted in a dramatic decrease in viability, and migratory and invasive potential of triple-negative breast cancer cells, but not in hormone receptor-positive, luminal MCF7 cells. Our data suggest that NHE1 is critical in triple-negative breast cancer metastasis, and its chemical inhibition boosts the efficacy of paclitaxel in vitro, highlighting NHE1 as a novel, potential co-adjuvant target in breast cancer chemotherapy. PMID:25514463

Amith, Schammim Ray; Wilkinson, Jodi Marie; Baksh, Shairaz; Fliegel, Larry

2015-01-20

382

Maximum Tolerated Dose and Early Response — Results of a Phase I Trial of Paclitaxel and Cisplatin with Radiation Therapy in Carcinoma of the Cervix 1  

Microsoft Academic Search

AimsCisplatin-based chemotherapy with radiotherapy is currently the standard treatment for locally advanced carcinoma of the cervix. Recent studies have shown a better response with the addition of newer chemotherapeutic agents. The aim of this phase I study was to establish the maximum tolerated dose (MTD) of paclitaxel in combination with cisplatin as a radiosensitiser along with radiation therapy in the

E. Prasad; P. N. Viswanathan; V. F. Rangad; S. Pavamani; T. S. Ram

2009-01-01