epothilone-a and Body-Weight

Obesity and inactivity are associated with increased risk of cancer-related and overall mortality in breast cancer, but there are few data in metastatic disease.. Cancer and Leukemia Group B 40502 was a randomized trial of first-line taxane-based chemotherapy for patients with metastatic breast cancer. Height and weight were collected at enrollment. After 299 patients enrolled, the study was amended to assess recreational physical activity (PA) at enrollment using the Nurses' Health Study Exercise Questionnaire. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using stratified Cox modeling (strata included hormone receptor status, prior taxane, bevacizumab use, and treatment arm). All statistical tests were 2-sided.. A total of 799 patients were enrolled, and at the time of data lock, median follow-up was 60 months. At enrollment, median age was 56.7 years, 73.1% of participants had hormone receptor-positive cancers, 42.6% had obesity, and 47.6% engaged in less than 3 metabolic equivalents of task (MET) hours of PA per week (<1 hour of moderate PA). Neither baseline body mass index nor PA was statistically significantly associated with PFS or OS, although there was a marginally statistically significant increase in PFS (hazard ratio = 0.83, 95% confidence interval = 0.79 to 1.02;. In a trial of first-line chemotherapy for metastatic breast cancer, rates of obesity and inactivity were high. There was no statistically significant relationship between body mass index and outcomes. More information is needed regarding the relationship between PA and outcomes.

Topics: Adult; Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Body Height; Body Mass Index; Body Weight; Breast Neoplasms; Epothilones; Exercise; Female; Humans; Middle Aged; Obesity; Paclitaxel; Progression-Free Survival; Proportional Hazards Models; Treatment Outcome; Young Adult

Patupilone (EPO906) is a microtubule stabilizer with a potent antitumor effect. Integrin αVβ3-binding (RGD) liposomes were loaded with EPO906, and their antitumor efficacy was evaluated in two pediatric tumor models, ie, neuroblastoma and rhabdomyosarcoma.. Integrin αVβ3 gene expression, RGD-liposome cellular association, and the effect of EPO906 and liposomal formulations of EPO906 on cell viability were assessed in vitro in human umbilical vein endothelial cells (HUVEC), in the RH-30 rhabdomyosarcoma cell line, and in the Kelly neuroblastoma cell line. In vivo, mice bearing neuroblastoma or rhabdomyosarcoma tumors were treated with EPO906, EPO906-liposomes, or EPO906-RGD-liposomes. Tumor growth, cumulative survival, and toxicity were monitored.. Integrin αVβ3 was highly expressed in HUVEC and RH-30, but not in Kelly cells. Accordingly, RGD-liposomes were highly associated with HUVEC and RH-30 cells in vitro, but not with the Kelly cells. EPO906 and its liposomal formulations inhibited HUVEC, RH-30, and Kelly cell viability to the same extent. In vivo, EPO906 1.5 mg/kg and liposomal EPO906 potently inhibited tumor growth in both xenograft models without triggering major toxicity. At this dose, liposomal EPO906 did not enhance the antitumor effect of EPO906 in neuroblastoma, but tended to have an increased antitumor effect in rhabdomyosarcoma. Using a lower dose of EPO906-RGD-liposomes significantly enhanced cumulative survival in rhabdomyosarcoma compared with EPO906 alone.. EPO906 shows a strong antitumor effect in neuroblastoma and rhabdomyosarcoma, without triggering major side effects. Its liposomal encapsulation does not alter its activity, and enhances cumulative survival when EPO906-RGD-liposomes are used at low dose in rhabdomyosarcoma.

Topics: Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Cell Survival; Drug Carriers; Epothilones; Female; Human Umbilical Vein Endothelial Cells; Humans; Integrin alphaVbeta3; Kaplan-Meier Estimate; Liposomes; Mice; Mice, SCID; Neuroblastoma; Oligopeptides; Rhabdomyosarcoma; Xenograft Model Antitumor Assays

Since peripheral sensory neuropathy is the major, clinically relevant side effect of sagopilone we investigated the general and peripheral neurotoxicity of sagopilone administered intravenously with different doses (1.2 and 2.4 mg/kg) and schedules in 48 Wistar rats and we performed in parallel a pharmacokinetic/pharmacodynamic (PK/PD) study. A trend toward a different peripheral neurotoxicity could be assessed after 2 weeks of treatment (bolus > 30-min infusion > 3-h infusion) with both doses of sagopilone. Although sagopilone concentrations in peripheral nerve tissue above 100 ng/g were associated with a reduction in nerve conduction velocity (NCV), a clear dose-dependence of this reduction on the level of systemic exposure to sagopilone was not observed. The PK/PD evaluation revealed no consistent effect of the infusion duration on serum PK parameters or the PD read-out NCV. Sagopilone concentrations in brain, sciatic nerve, liver, and kidney were higher after bolus compared to infusion, but there were no influence of infusion duration on these concentrations. No correlation between sagopilone concentrations in any organ/tissue with NCV changes was detected. This study evidences that the PD of sagopilone is not the main determinant of the onset and severity of sagopilone-induced peripheral neurotoxicity in the investigated clinically-relevant dose range, thus indicating that further investigation might identify neuronal-specific mechanisms of action able to drive a focused strategy to prevent peripheral neurotoxicity without reducing the anticancer effectiveness of the epothilones.

Topics: Animals; Area Under Curve; Benzothiazoles; Blood Cell Count; Blood Chemical Analysis; Body Weight; Data Interpretation, Statistical; Epothilones; Female; Infusions, Intravenous; Kidney; Liver; Neural Conduction; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Sciatic Nerve

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.

Topics: Animals; Antineoplastic Agents, Phytogenic; Body Weight; Dose-Response Relationship, Drug; Epothilones; Female; Furans; Ganglia, Spinal; Ketones; Mesylates; Mice; Mice, Inbred BALB C; Neural Conduction; Paclitaxel; Polyneuropathies; Rats; Sciatic Nerve; Tubulin Modulators

Epothilones are a novel class of microtubule-targeting anticancer agents that are neurotoxic. In this study, we investigated the epothilone B toxic effect in vitro and we characterized in vivo the general and neurological side effects of epothilone B administration in Wistar and Fischer rats. The in vitro experiments made it possible to explore a wide concentration range (0.1 nM-1 muM) and evidenced a dose-dependent effect of epothilone B exposure on neuron neurite elongation. This dose-dependent neurotoxic effect was confirmed in both in vivo studies performed on two different rat strains at the neurophysiological, behavioral and pathological levels in the dose range 0.25-1.5 mg/kg iv weekly x 4 weeks and tubulin hyper-polymerization was demonstrated in sciatic nerve specimens. These are the first studies of the neurological effects of epothilone B and they can provide a basis for extending pre-clinical investigation to other members of the epothilone family.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Epothilones; Female; Ganglia, Spinal; In Vitro Techniques; Myelin Sheath; Neural Conduction; Neurites; Neurons; Neurotoxins; Pain Threshold; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger; Sciatic Nerve; Skin; Tubulin

Microtubule agents appear promising for the treatment of prostate cancer. Patupilone (epothilone B), a highly potent non-taxane microtubule stabilizing agent, was evaluated in models of androgen-independent prostate cancer.. Patupilone was administered to athymic mice bearing human prostate cancer xenografts (subcutaneous DU 145 and PC-3M, orthotopic PC-3M).. One 4 mg/kg patupilone administration produced transient regression of DU 145 tumors, while two weekly administrations of 2.5 mg/kg produced stable disease followed by protracted regression, however with more pronounced body weight loss. Taxol (15 mg/kg every other day) weakly inhibited tumor growth, but with less body weight loss. Patupilone (5 mg/kg) produced protracted growth inhibition of subcutaneous PC-3M tumors, with transient body weight loss. In mice with orthotopic PC-3M tumors, 4 or 5 mg/kg/week patupilone impaired primary tumor growth, abrogated metastases and enhanced survival, with only transient body weight loss.. These data suggest that patupilone holds promise for prostate cancer treatment.

Topics: Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Epothilones; Humans; Lymphatic Metastasis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Paclitaxel; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Body Weight; Drug Screening Assays, Antitumor; Epothilones; Humans; Mice; Mice, Nude; Models, Chemical; Neoplasm Transplantation; Neoplasms; Paclitaxel; Structure-Activity Relationship; Tumor Cells, Cultured