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Introduction The tubulin poison paclitaxel is among the most widely used drugs in the treatment of a variety of solid tumors, including early-stage and metastatic breast cancer (MBC). Paclitaxel induces [...], Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.

Author(s): Mitsuhiro Matsuo [sup.1] , Hisakatsu Ito [sup.1] , Yoshinori Takemura [sup.1] , Mizuki Hattori [sup.1] , Masaaki Kawakami [sup.1] , Norimasa Takahashi [sup.2] , Mitsuaki Yamazaki [sup.1] Author Affiliations: [...], Paclitaxel-induced peripheral neuropathy (PIPN) is one of the serious adverse events associated with paclitaxel-based cancer treatments. A recent case study showed that the antiplatelet agent clopidogrel inhibits paclitaxel metabolism via cytochrome P450 (CYP) 2C8, resulting in severe PIPN. The aim of this study was to determine the impact of clopidogrel as a risk factor for the development of PIPN, using a retrospective cohort study. Data from paclitaxel-treated patients with or without clopidogrel and low-dose aspirin treatment were retrieved from medical charts. A total of 161 adult patients were included in this study: 135 were controls, 9 were clopidogrel-treated and 17 were aspirin-treated. The clopidogrel group had a greater proportion of males and a higher rate of comorbidities, such as diabetes mellitus and dyslipidemia, than the control group. However, patient characteristics were similar between the clopidogrel and aspirin groups. Severe PIPN was diagnosed in 3 (2.2%) and 2 (22.2%) patients in the control and clopidogrel groups, respectively (odds ratio: 12.0; p = 0.031). No patients in the aspirin group presented with severe neuropathy. These pilot data suggest that concomitant treatment with clopidogrel leads to a greater risk of PIPN. The avoidance of concomitant clopidogrel use may be effective in reducing clopidogrel-associated PIPN.

ABSTRACT Paclitaxel (Taxol[R]) 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 [...]

A study to compare the effectiveness of the drug paclitaxel and the combination paclitaxel plus bevacizumab in the initial treatment for metastatic breast cancer is conduced. Results show that the combination drug extends progression-free survival compared to paclitaxel alone but showed no significant change in the overall survival rate.

Byline: Jaffer A. Ajani (1,2), Yixing Jiang (1,2,3), Josephine Faust (1,2), Baochong B. Chang (1,2), Linus Ho (1,2), James C. Yao (1,2), Steven Rousey (1,2), Shaker Dakhil (1,2), Richard C. Cherny (1,2), Catherine Craig (1,2), Archie Bleyer (1,2) Keywords: Bryostatin-1; Protein Kinase C; gastric or gastroesophageal adenocarcinoma Abstract: Purpose: Protein Kinase C (PKC), involved in transmembrane signaling of cell surface receptors, promotes carcinogenesis and tumor progression. Bryostatin-1 competes with PKC for phorbol esters (tumor promoters), thus inhibiting tumor progression. Bryostatin-1 also increases cytotoxicity of paclitaxel in a sequential fashion. We studied sequential paclitaxel and bryostatin-1 in patients with untreated, advanced gastric adenocarcinoma. Methods: Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with advanced, measurable cancers were eligible. Patients were required to have near normal organ function and ECOG performance status of 0 or 1. All patients gave an informed consent. Patients received paclitaxel 80 mg/m.sup.2 in 2 h intravenously on day 1 and bryostatin-1 40 mcg/m.sup.2 in 1 h intravenously on day 2 each week for 3 consecutive weeks out of 4. Primary objective was to assess the objective response rate. Results: In a multi-center setting, 37 patients were enrolled and 35 were assessable for response. A confirmed partial response rate was 29%. The median time-to-progression was 4.25 months and the median survival time was 8 months. Grade 3 cumulative myalgias occurred in 55% of patients. Twelve patients discontinued therapy due to myalgias, including 6 patients who had not progressed after achieving a partial response. Other toxic effects were uncommon. Conclusions: Sequential paclitaxel plus bryostatin-1 resulted in a superior response rate than would be expected of paclitaxel alone in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Further development of this combination is warranted once an effective method to ameliorate or prevent myalgias can be established. Author Affiliation: (1) Department of GI Medical Oncology, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030 (2) UT M. D. Anderson Community Clinical Oncology Program (CCOP), Houston, TX (3) Milton S. Hershey Medical Center, Hershey, PA Article History: Registration Date: 01/01/2006 Online Date: 05/04/2006 Article note: Supported in part by the NCI phase II contract no. N01-CM-1703 and CCOP contract no. 5 U10 CA 045809-15

Byline: Jorge E. Romaguera (1), M. Alma Rodriguez (1), Fredrick B. Hagemeister (1), Peter McLaughlin (1), Jose Rodriguez (1), Alejandro Preti (1), Anas Younes (1), Andreas H. Sarris (1), Fernando Cabanillas (1) Keywords: relapsed NHL; paclitaxel; MINT chemotherapy Abstract: Purpose: Evaluate response, duration of response, and toxicity of paclitaxel in combination with other drugs known to be effective in non-Hodgkin's lymphoma (NHL). Methods: Thirty-eight patients with relapsed/refractory NHL who had been exposed to doxorubicin as well as the cytarabine-cisplatin combinations received Mesna 1.33 gm/M.sup.2/D daily days 1, 2, 3 IV over 1 hour ifosfamide 1.33 gm/M.sup.2/D daily days 1, 2, 3 IV over 1 hour (same bag) Novantrone 8 mg/M.sup.2/D IV day 1 and Taxol 27.5 mg/M.sup.2/D daily days 1, 2, 3, 4 by continuous 24-hour intravenous infusion. Premedication for Taxol included dexamethasone, diphenhydramine, and cimetidine on day 1. Results: Of 35 evaluable patients, 9 (26%) achieved a complete response and 7 (20%) a partial response for a total response rate of 46%. The median failure-free and overall survival times were 2 and 10 months, respectively. Major toxicity was hematologic with a median absolute neutrophil nadir of 196/mm.sup.3. Only 10% of the cycles were associated with a grade 3-4 infection. Conclusion: MINT is an active and safe regimen for relapsed/refractory NHL that have failed both an Adriamycin-containing regimen and a cytarabine/cisplatin-containing regimen. Author Affiliation: (1) Department of Lymphoma, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Article History: Registration Date: 03/10/2004

Byline: Danny Rischin (1), Lorraine K. Webster (2), Michael J. Millward (1), Guy C. Toner (1), Sumith Nawaratne (3), Vinod Ganju (1), Prudence Francis (1), James F. Bishop (1) Keywords: taxanes; anthracyclines; pharmacology Abstract: The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0--2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m.sup.2 without G-CSF and 175/90 mg/m.sup.2 with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m.sup.2 paclitaxel and 90 mg/m.sup.2 epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m.sup.2 and epirubicin 75 mg/m.sup.2 is recommended for phase II and III studies. Author Affiliation: (1) Division of Haematology and Medical Oncology, USA (2) Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Australia (3) Victorian College of Pharmacy, Monash University, Melbourne, Australia Article History: Registration Date: 14/10/2004

Byline: T.A. Dunn (1), H.J. Schmoll (2), V. Gruunwald (1), J. Casper (3), C. Bokemeyer (4) Keywords: human germ cell cancer; cytotoxic drugs; taxol; drug resistance Abstract: Taxol (Paclitaxel) is a novel anti-cancer drug which has shown excellent clinical activity in a variety of solid tumors, particularly in metastatic breast and ovarian cancer. 70-80% of patients with metastatic non-seminomatous germ cell tumor (NSGCT) attain disease free status with standard cisplatin-based combination chemotherapy but the emergence of drug resistance still prevents a small proportion of these patients from achieving long-term remission. Here we report the results of pre-clinical studies investigating whether taxol exhibits cross-resistance to cisplatin or ifosfamide in human NSGCT cell lines and in a cisplatin refractory xenograft model of human NSGCT. Following 96h drug exposure in a 5-day sulphohodamine B (SRB) in vitro assay, taxol demonstrated potent cytotoxicity in cell lines which were cisplatin sensitive (577 LM, H32, H12.1 mean IC50s 1.5-3.0 nM) or those with acquired or intrinsic cisplatin resistance (H12DDP, H23 mean IC50s 2.5 nM). Compared to the drug sensitive cell line, H12.1, the IC50 values of taxol were increased in cell line 1777NRp Cl-A with intermediate level resistance to cisplatin and ifosfamide (4.7 nM p &gt 0.05) and significantly elevated in cell line 1411HP, with a high level of cisplatin resistance (6.9 nM p &gt 0.01). The latter 2 cell lines may represent models corresponding to patients relapsing after high-dose platinum-based chemotherapy who seem to be resistant to taxol therapy. The IC50s of taxol in H32 and H12DDP were approximately 100 fold lower following drug exposure times exceeding 24 hours compared with short exposure times (1-6h). Dose dependent anti-tumor activity was observed with taxol in a cisplatin-refractory xenograft model of NSGCT (H23), with significant anti-tumor activity observed at a dose of 15 mg/kg/d injected intra-venously on days 1 through 5. The results of this study are in accordance with the most recent clinical data which showed that taxol is a useful drug in relapsed or cisplatin-refractory testicular germ cell cancer, with significant anti-tumor activity being observed in 25% of patients, but poor activity in patients previously treated with high-dose therapy. Further pre-clinical research, especially using models such as 1411HP and 1777NRp Cl-A, on the combinations of taxol with other regimens are required to enable successful treatment of the most drug resistant relapsed germ cell tumors. Author Affiliation: (1) Department of Hematology and Oncology, Hannover Medical University, Konstanty-Gutschow Strasse 8, 30623 (2) Department of Hematology and Oncology, Martin-Luther University of Halle-Wittenberg, Ernst-Grube Strasse 40, 06120, Halle/Saale, Germany (3) Department of Hematology and Oncology, University of Rostock, 18055, Rostock (4) Department of Hematology and Oncology, Eberhard-Karls-Universitat, Otfried-Muller Strasse 10, 72076, Tubingen Article History: Registration Date: 29/09/2004