EPO906 (epothilone B): A promising novel microtubule stabilizer

Rothermel, J. D.; Wartmann, Markus; Chen, Tianling; Hohneker, John

doi:10.1016/s0093-7754(03)70025-6

Cited by 39 publications

(29 citation statements)

References 8 publications

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“…Interestingly, these two melanoma cell lines were also sensitive to epothilone B (IC 50 0.3 and 0.5 nM). In a Phase I study of epothilone B, plasma concentrations exceeded 1 nM for approximately 8 h (Rothermel et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…As they have different mechanisms of action, nonoverlapping toxicities and differing mechanisms of resistance, the combination of paclitaxel and temozolomide has been investigated in a Phase I study in melanoma patients. In addition to the clinical trial, in vitro growth inhibition studies were performed with the combination of temozolomide and either paclitaxel or epothilone B, a novel antimicrotubule compound (Rothermel et al, 2003).…”

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

et al. 2005

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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 À2 day À1 temozolomide and 225 mg m À2 day À1 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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2005

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“…bolus on a weekly schedule (4,14). The drug displays a rapid t 1/2 a, is eliminated from plasma with a terminal half-life of f6 hours, and shows a large volume of distribution to all tissues, including the tumor xenografts and brain from which tissues it is eliminated more slowly (15).…”

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confidence: 99%

“…In summary, the pharmacokinetic profile and activity of patupilone in experimental tumor models suggest that it could be an effective treatment for a range of solid tumors in the clinic. Patupilone is currently in clinical development and early phase II data indicate promising activity in several different solid tumor indications (12,14). However, a convenient and predictive surrogate biomarker of patupilone is currently not available because the pharmacokinetic profile limits the possibility of using drug levels in the plasma to obtain an effective pharmacokinetic/pharmacodynamic relationship.…”

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confidence: 99%

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Ferretti

Allegrini

O’Reilly

et al. 2005

Clinical Cancer Research

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Purpose: Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone. 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). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response.Results: In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 F 5% decrease (P < 0.001) in tumor blood volume and a 32 F 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P V 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (À21% to À70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 F 4%), tumor blood volume (50 F 6%), and vessel diameter (40 F 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged.Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005). Conclusions: Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy.

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“…31 This class of agent is particularly interesting since several analogs have demonstrable antitumor activity to paclitaxel-resistant models. Our data provide the first report of the relative sensitivity of RCC lines to the natural epothilone patupilone, with the RCC cell lines examined here clearly showing a far greater sensitivity to this drug than the other agents examined.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic chemotherapy resistance to the tubulin‐binding antimitotic agents in renal cell carcinoma

Ferguson

Jackson

Stanley

et al. 2005

Intl Journal of Cancer

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EPO906 (epothilone B): A promising novel microtubule stabilizer

Cited by 39 publications

References 8 publications

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

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

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Intrinsic chemotherapy resistance to the tubulin‐binding antimitotic agents in renal cell carcinoma

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