Disease relevance of Epothilone B

• In this study, we investigated the in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule stabilizing agent, in treatment of multiple myeloma (MM) [1].
• RESULTS: In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 +/- 5% decrease (P < 0.001) in tumor blood volume and a 32 +/- 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P < or = 0.014) [2].
• EXPERIMENTAL DESIGN: Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively) [2].
• Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts [3].
• CONCLUSIONS: These data suggest that patupilone holds promise for prostate cancer treatment [4].

High impact information on Epothilone B

• Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by patupilone and was paralleled by down-regulation of vascular endothelial growth factor (VEGF) secretion [1].
• Importantly, stimulation of cells from patients with MM, either with IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone [1].
• Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump [1].
• Patupilone induced G2M arrest of MM cells, with subsequent apoptosis [1].
• PURPOSE: To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors [5].

Chemical compound and disease context of Epothilone B

• Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment [6].
• Activity of epothilone B analogues ixabepilone and patupilone in hormone-refractory prostate cancer [7].
• Phase I studies have shown that dose-limiting toxicities of epothilones are generally neurotoxicity and neutropoenia although initial studies with patupilone indicated that diarrhoea was dose limiting [8].

Biological context of Epothilone B

• One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 +/- 4%), tumor blood volume (50 +/- 6%), and vessel diameter (40 +/- 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged [2].

Anatomical context of Epothilone B

• Patupilone induced vascular disruption in orthotopic rodent tumor models detected by magnetic resonance imaging and interstitial fluid pressure [2].

Associations of Epothilone B with other chemical compounds

• The epothilones ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancer treatment [8].
• Combined treatment with patupilone and IR induced a cytotoxic effect in vitro in an additive way in A549 cells but not in the tubulin-mutated, patupilone-resistant A549.EpoB40 cells [9].

Gene context of Epothilone B

• Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range [3].

Analytical, diagnostic and therapeutic context of Epothilone B

• Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel [1].
• In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 x 2 mg/kg plus 4 x 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest [3].
• Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (-21% to -70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume [2].
• Analysis by flow cytometry in vitro revealed an apoptosis- and G(2)-M-independent mode of radiosensitization by patupilone [3].

References