epothilone-a and Lung-Neoplasms

Progress in the treatment of non-small-cell lung cancer (NSCLC) will require the introduction of new agents as well as better use of existing therapies. Targeted therapies are likely to have a profound effect on the treatment of NSCLC after identification of patients who are most likely to benefit. The epothilones are novel anti-tubulin agents derived from Sorangium cellulosum. β III tubulin overexpression has been implicated as a mechanism of anti-tubulin resistance that can be overcome by epothilones. Several epothilones have advanced to clinical trials; ixabepilone (BMS247550, aza-epothilone B, Bristol-Myers Squibb, New York, NY), patupilone (EPO906, Novartis, Basel, Switzerland) and sagopilone (ZK-EPO, ZK-219477, Schering AG, Berlin-Wedding, Germany) are currently in active development. Several of the epothilones, most notably ixabepilone, have demonstrated activity in lung cancer in phase I and II trials, including taxane-resistant patients. Although a phase II study failed to show superior outcome in patients with β III tubulin overexpression, other aspects of the epothilones argue for their continued development.

Topics: Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Drug Discovery; Drug Resistance, Neoplasm; Epothilones; Humans; Lung Neoplasms; Taxoids; Tubulin Modulators

Lung cancer is a leading cause of death among adults. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. For more than half of all patients diagnosis does not occur until the disease has metastasised. At this advanced stage, the 5-year survival rate is just 15%. Platinum-based chemotherapy forms the backbone of treatment for patients with advanced NSCLC and forms an important component of the therapeutic regimen for many patients with earlier stage disease. However, although a number of agents are available to partner the platinum-based compounds, treatment selection is largely empiric, and chemoresistance is a considerable barrier to improving outcomes. The identification of biologic and other markers to guide treatment selection, thus ensuring patients receive the most effective regimen for their individual tumour and avoid exposure to toxic agents from which they are unlikely to benefit, will be critical to improve outcomes for patients with NSCLC. The development of alternative agents for those patients who express predictors of a negative clinical response is of vital importance. A variety of biomarkers are emerging, including expression of DNA repair enzymes, ribonucleotide subunits and betaIII tubulin. Treatment algorithms based on elucidation of such markers to guide treatment selection can already be envisaged. For example, those patients with high betaIII tubulin expression should be considered for epothilone therapy as an alternative to taxane-based regimens. The epothilones may be preferred option as the evidence suggests that these agents retain activity versus taxane-resistant cancers. This paper reviews the evidence base for betaIII tubulin expression as a prognostic and predictive biomarker in NSCLC and briefly explores the implications for clinical decision making of this and other emerging biomarkers.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Humans; Lung Neoplasms; Prognosis; Taxoids; Tubulin

Breast cancer consists of a heterogeneous group of diseases, with a number of tumor-specific and patient-specific factors, which influence response to therapy and survival. Ixabepilone is a member of a novel class of antineoplastic agents, the epothilones, that has demonstrated activity in a number of human solid tumor types and is the first agent in this class to be approved by the Food and Drug Administration (FDA) for the treatment of metastatic or locally advanced breast cancer, that is resistant/refractory to anthracyclines, taxanes, and/or capecitabine. Both retrospective and prospective studies have been conducted to evaluate the efficacy of ixabepilone in various populations. The role of ixabepilone in poor prognosis subgroups of the metastatic breast cancer population is reviewed in this article.

Topics: Adult; Aged; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Drug Approval; Drug Delivery Systems; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Treatment Outcome; United States; United States Food and Drug Administration

Patients with metastatic breast cancer (MBC) have poor prognoses and 5-year survival rates of approximately 20%. The site(s) and degree of metastatic dissemination are among the principal prognostic factors for patients with MBC. Patients with visceral metastases to the liver and/or lung have a very poor prognosis. Although good performance status, restricted disease dissemination, and limited extent of metastatic infiltration are associated with higher responses to chemotherapy, responses are generally short lived, with rapid disease progression after treatment failure. Thus, novel strategies for the management of patients with MBC with visceral disease are urgently needed. We have analyzed outcomes of trials that evaluated various chemotherapeutic agents as monotherapy or in combination with capecitabine in patients with MBC with primary visceral disease involvement. Treatment with microtubule inhibitors such as paclitaxel, docetaxel, and albumin-bound paclitaxel, generally administered in earlier lines of treatment, resulted in comparable responses. Lower response rates (RRs) were reported with other agents such as capecitabine, vinorelbine, and gemcitabine. Adverse events consistent with known toxicities of each agent were observed in the selected trials and related to dose and administration schedule. The epothilone B analogue ixabepilone has demonstrated clinical efficacy and manageable safety in populations of heavily pretreated patients with MBC with high visceral disease burdens to liver and/or lung (61%-86% of patients). Objective RRs ranging from 12% to 57% have been reported for ixabepilone, as monotherapy and in combination with capecitabine, depending on degree of pretreatment. Responses to ixabepilone in patients with visceral metastases were comparable to those observed in overall study patient populations.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Epothilones; Female; Humans; Liver Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Viscera

Antitubulin agents are among the most active drugs for the treatment of non-small-cell lung cancer. The taxanes paclitaxel and docetaxel are highly active and frequently used for adjuvant therapy after resection of localized disease and in combination with radiation for locally advanced disease and treatment of patients with advanced disease. Despite their benefits, these drugs have significant problems, including toxicity and limited efficacy. Recently, new taxane formulations and novel antitubulin agents have been developed. In some cases, these drugs have reduced toxicity with preserved efficacy. In other cases, these agents have potentially unique activity and have now advanced to late-stage trials. This review evaluates 2 novel paclitaxel formulations, albumin-bound paclitaxel and paclitaxel poliglumex. New antimicrotubulin agents, including the epothilones, colchicine-binding antivascular agents, and vinca alkaloids, are also discussed.

Topics: Antineoplastic Agents; Bibenzyls; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Humans; Lung Neoplasms; Paclitaxel; Polyglutamic Acid; Tubulin Modulators; Vinblastine; Vinorelbine

Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment.. This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design.. Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin.. The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Epothilones; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Lymphoma, Non-Hodgkin; Male; Neoplasms; Ovarian Neoplasms; Tubulin Modulators

The treatment of patients with advanced non-small cell lung cancer has changed considerably in the past decade. This paper reviews the most significant changes seen in chemotherapy and the most promising new agents in development for this disease.. Chemotherapy prolongs survival and improves quality of life in patients with a good performance status and appears to alleviate disease-related symptoms in patients with a lower performance status. Platinum-based regimens became standard; none of the third-generation drug combinations seemed to be superior to the others. Nonplatinum combinations are reasonable alternatives now and offer a better toxicity profile in certain populations. Attempts to add molecular-targeted therapy to combination chemotherapy have failed except for bevacizumab. New compounds such as pemetrexed, bortezomib, TLK286, bevacizumab, and the epothilones are currently being evaluated in non-small cell lung cancer.. Management of non-small cell lung cancer has improved considerably in the past decade. The overall benefit of chemotherapy over supportive care has been shown, platinum-based doublets have been established, nonplatinum regimens have been developed, chemotherapy has been used more broadly in subgroups of patients who have been previously neglected, and a shorter chemotherapy duration has been shown to be equally effective. After hitting a plateau in the benefit of chemotherapy, new drugs with novel action mechanisms such as the ones described here offer hope to improve therapy for this disease.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Epothilones; Glutamates; Glutathione; Guanine; Humans; Lung Neoplasms; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pemetrexed; Pyrazines

Epothilones are cytotoxic macrolides with a similar mechanism of action to paclitaxel but with the potential advantage of activity in taxane-resistant settings in preclinical models. The epothilones ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO are in early clinical trials for cancer treatment. 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. Neuropathy induced by ixabepilone may be schedule dependent. Over 20 Phase II studies of epothilones in cancer treatment have been reported, and significant activity in taxane-sensitive tumour types (such as breast, lung and prostate cancers) has been noted. Response rates in taxane-refractory metastatic breast cancer are relatively modest, but ixabepilone and patupilone have shown promising efficacy in hormone-refractory metastatic prostate cancer and in taxane-refractory ovarian cancer.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Male; Prostatic Neoplasms; Tubulin Modulators

Cytotoxic agents have unequivocal activity in non-small cell lung cancer. Currently available agents have demonstrated the ability to prolong life and improve quality of life in advanced disease, and to increase the rate of cure when used in stage I and II disease in the adjuvant setting and as part of chemoradiotherapy in stage III disease. These agents have served as the core regimen to which agents effecting newly discovered molecular targets are added. However, there is little question that there is much room for improvement. A number of new agents have been identified that either derive from older drugs or affect their targets in novel ways. In particular, tubulin has been an attractive target since the dawn of medical oncology. A number of new antitubulin agents are currently in development. Epothilones are novel agents that bind to the same site as taxanes, yet are structurally distinct. Xyotax and abraxane are agents in which paclitaxel is delivered in a novel fashion that may both reduce toxicity and enhance activity. ABT 751 is an agent that targets the colchicine site of tubulin. Another approach is to enhance the activity of currently available agents by targeting detoxification and resistance pathways. TLK-286 is a novel agent that may enhance the activity of previously available agents by inhibiting GST-pi, a detoxifying mechanism that may be of particular relevance to platinum agents. It has also demonstrated some single-agent cytotoxic activity.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cytotoxins; Drug Delivery Systems; Epothilones; Glutathione; Humans; Lung Neoplasms; Taxoids; Tubulin Modulators

The treatment of lung cancer--small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC)--is a significant challenge in oncology. The best reported median survival remains near 1 year in advanced NSCLC despite several decades of steady improvement and extensive research with traditional chemotherapy drugs and novel compounds targeted to different aspects of tumor cell growth and function (such as the epidermal growth factor receptor). Extensive-stage SCLC survival is only slightly better. Novel "targeted" therapeutic agents hold promise, but cytotoxic therapy remains the backbone of treatment. Many new cytotoxic agents are currently in development. In this review, we will focus on 2 classes of cytotoxins: epothilones and topoisomerase I inhibitors. Epothilones are microtubule stabilizers with a mechanism of action similar to that of the taxanes, with preclinical activity superior to that of the taxanes. Phase I trials have been completed for patupilone and ixabepilone, and there are encouraging phase II data with ixabepilone in NSCLC. A phase II trial of patupilone is ongoing. The camptothecins, which are topoisomerase I inhibitors, have a long history in the treatment of lung cancer, but the currently available drugs, topotecan and irinotecan, have limitations. Gimatecan and other novel camptothecins have superior preclinical activity and promising phase I/II data in NSCLC and SCLC.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Clinical Trials as Topic; Enzyme Inhibitors; Epothilones; Humans; Lung Neoplasms; Prognosis; Topoisomerase I Inhibitors

There are several new cytostatic agents under investigation for the treatment of advanced non-small cell lung cancer either as first or second-line. In this review we will present the current information about oxaliplatin, epothilones, irinotecan and alimta.

Topics: Antineoplastic Agents; Camptothecin; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Epothilones; Glutamates; Guanine; Humans; Irinotecan; Lung Neoplasms; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Thymidylate Synthase

Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL.. HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m. Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of -9.4 and -10.8 points, respectively.. There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression.. NCT01492101.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Albumins; Anorexia; Antineoplastic Agents; Body Image; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Cancer Pain; Deoxycytidine; Docetaxel; Dyspnea; Epothilones; Fatigue; Female; Furans; Gemcitabine; Health Status; Heterocyclic Compounds, 4 or More Rings; Humans; Ketones; Liver Neoplasms; Lung Neoplasms; Middle Aged; Nausea; Paclitaxel; Polyethylene Glycols; Quality of Life; Reproductive Health; Sleep Initiation and Maintenance Disorders; Taxoids; Vinblastine; Vinorelbine; Vomiting

Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.. Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity.. Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively.. This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.

Topics: Administration, Intravenous; Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Administration Schedule; Epothilones; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Survival Analysis; Treatment Outcome

Sagopilone is the first fully synthetic epothilone in clinical development and has proven preclinical activity in tumor models. This multicenter, randomized, open-label, phase II study examined the efficacy and safety of three regimens with two doses and two infusion durations of second-line sagopilone in pretreated patients with stage IIIB or IV non-small-cell lung cancer.. Eligibility criteria included: at least one measurable lesion by modified response evaluation criteria in solid tumors; World Health Organization performance status of 0 or 1; and failure of previous platinum-based chemotherapy. Patients were randomized to receive: 16 mg/m2 sagopilone over 3 h (treatment arm A); 22 mg/m(2) sagopilone over 0.5 h (treatment arm B); or 22 mg/m2 sagopilone over 3h (treatment arm C). Treatment duration was two to six courses every 3 weeks; more than six treatment courses were permitted if there was sustained clinical benefit. The primary efficacy endpoint was best overall response after six courses; at least five confirmed responders per arm indicated a successful outcome.. In total, 128 patients (44, arm A; 41, arm B; 43, arm C) were randomized; 127 received at least one infusion of sagopilone. Baseline demographic data were similar across all arms. Eight patients across all arms had a confirmed partial response; the primary endpoint was not achieved. The most frequently reported adverse event (AE) was peripheral sensory neuropathy (75%). Most hematologic AEs were grade 1 or 2.. As fewer than five patients per arm responded after six treatment courses, the primary endpoint was not met. Sagopilone was only moderately tolerated. Most AEs, including peripheral neuropathy, were grade 1 or 2; hematologic toxicities were rare.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Epothilones; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Treatment Outcome

Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) isoform is an unfavorable prognostic factor in non-small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including β3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for β3T expression.. Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup.. Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies.. There was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biomarkers, Tumor; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug Administration Schedule; Epothilones; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Predictive Value of Tests; Prospective Studies; Treatment Outcome; Tubulin; Tubulin Modulators

Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in several solid tumours like ovarian cancer and melanoma. Data about clinical efficacy of sagopilone in small-cell lung cancer are lacking. Here we report the first phase-I trial of sagopilone in combination with cisplatin in previously untreated metastatic small-cell lung cancer patients.. Chemonaive patients with metastatic small-cell lung cancer (SCLC) received sagopilone in four different dosing schedules ranging from 12 to 22 mg/m(2) (on day 1 as 3-h infusion) followed by a fixed dose of cisplatin of 75 mg/m(2) as 1-h infusion on day 1. Chemotherapy was administered every 3 weeks to a maximum of six cycles. The primary objective was determination of dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in this setting. Secondary objectives were assessment of objective response rates (ORR) as well as investigation of sagopilone pharmacokinetics.. Twenty-six patients received a total of 107 treatment cycles of the platinum-sagopilone doublet. The recommended phase-II dose (RD) and schedule was found to be 19 mg/m(2) sagopilone followed by 75 mg/m(2) cisplatin. Peripheral neuropathy turned out as dose-limiting toxicity when the combination was administered over a median of four cycles. Objective responses were observed in six out of seven SCLC patients (85.7%) treated with the RD.. Sagopilone and cisplatin can be safely combined in the first-line treatment of metastasised SCLC. This combination demonstrated preliminary efficacy and should be further evaluated within phase-II trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Epothilones; Female; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prospective Studies

Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC.. Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0-1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30 mg/m2 and carboplatin AUC=6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15 mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles.. Eighty-two patients (median age, 63 years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5 months (A) and 15.7 months (B), median progression free survivals were A-5.3 months (95% CI 2.8-8.6) and B-6.7 months (95% CI 5.1-8.4), with median overall survivals of 9.3 months (95% CI 6.4-16.6) 13.2 months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B-23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology.. Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum-doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Carcinoma, Non-Small-Cell Lung; Epothilones; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Treatment Outcome

Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epidemiologic Methods; Epothilones; ErbB Receptors; Female; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome

Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [14C]-levels (100 microCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [14C]-labeling and an ultra-sensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0-2) received an intravenous dose of 70 mg, 80 nCi of [14C]ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities.

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chromatography, Liquid; Colonic Neoplasms; Epothilones; Feces; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Sigmoid Neoplasms; Tandem Mass Spectrometry

The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cohort Studies; Deoxycytidine; Dose-Response Relationship, Drug; Epothilones; Female; Gemcitabine; Humans; Kidney Neoplasms; Leukopenia; Lung Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Sarcoma; Urinary Bladder Neoplasms; Uterine Neoplasms; Water-Electrolyte Imbalance

Ixabepilone is the first in a new class of antineoplastic agents, the epothilones and their analogs. This international, randomized, phase II trial assessed two administration schedules of ixabepilone as second-line therapy in patients with non-small-cell lung cancer (NSCLC).. Patients had experienced disease progression after one prior cisplatin- or carboplatin-based chemotherapy regimen. Ixabepilone was administered as a single 32 mg/m(2) 3-hour infusion (77 patients; arm A) or a 6 mg/m(2) 1-hour infusion daily for 5 consecutive days (69 patients; arm B) in a 3-week cycle.. The intent-to-treat objective response rate was 14.3% in arm A and 11.6% in arm B. Median duration of response was 8.7 months (95% CI, 5.3 to 9.5 months) in arm A and 9.6 months (95% CI, 6.1 to 19.7 months) in arm B. Median time to progression was 2.1 months (95% CI, 1.4 to 2.8 months) for arm A and 1.5 months (95% CI, 1.4 to 2.8 months) for arm B. Median survival was 8.3 months (95% CI, 5.8 to 11.5 months) for arm A, and 7.3 months (95% CI, 5.7 to 11.7 months) for arm B; the 1-year survival rate (both cohorts) was 38%. Responses occurred in patients with taxane-pretreated and platinum-refractory tumors. Both regimens had an acceptable toxicity profile. Myelosuppression was manageable, manifesting primarily as neutropenia and leukopenia. Neuropathy was primarily sensory, generally mild to moderate in severity, and mostly reversible (both regimens).. Single-agent ixabepilone had clinically relevant activity and an acceptable safety profile in patients with advanced NSCLC whose tumors had failed one prior platinum-based chemotherapy regimen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Progression; Epothilones; Female; Humans; Lung Neoplasms; Male; Middle Aged; Platinum Compounds; Treatment Outcome

Resistance to microtubule-stabilizing agents is a major hurdle for successful cancer therapy. We investigated combined treatment of microtubule-stabilizing agents (MSAs) with inhibitors of angiogenesis to overcome MSA resistance.. Treatment regimens of clinically relevant MSAs (patupilone and paclitaxel) and antiangiogenic agents (everolimus and bevacizumab) were investigated in genetically defined MSA-resistant lung (A549EpoB40) and colon adenocarcinoma (SW480) tumor xenografts in nude mice (CD1-Foxn1, ICRnu; 5-14 per group). Tumor growth delays were calculated by Kaplan-Meier analysis with Holm-Sidak tests. All statistical tests were two-sided.. Inhibition of mTOR-kinase by everolimus only minimally reduced the proliferative activity of β tubulin-mutated lung adenocarcinoma cells alone and in combination with the MSA patupilone, but everolimus inhibited expression and secretion of vascular endothelial growth factor (VEGF) from these cells. mTOR-kinase inhibition strongly sensitized tumor xenografts derived from these otherwise MSA-resistant tumor cells to patupilone. Tumors treated with the combined modality of everolimus and patupilone had statistically significantly reduced tumor volume and stronger tumor growth delay (16.2 ± 1.01 days) than control- (7.7 ± 0.3 days, P = .004), patupilone- (10 ± 0.97 days, P = .009), and everolimus-treated (10.6 ± 1.4 days, P = .014) tumors. A combined treatment modality with bevacizumab also resensitized this MSA-refractory tumor model to patupilone. Treatment combination also strongly reduced microvessel density, corroborating the relevance of VEGF targeting for the known antivasculature-directed potency of MSA alone in MSA-sensitive tumor models. Resensitization to MSAs was also probed in P glycoprotein-overexpressing SW480-derived tumor xenografts. Different bevacizumab regimens also sensitized this otherwise-resistant tumor model to clinically relevant MSA paclitaxel.. A treatment combination of MSAs with antiangiogenic agents is potent to overcome tumor cell-linked MSA resistance and should be considered as strategy for MSA-refractory tumor entities.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Resistance, Neoplasm; Epothilones; Everolimus; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Mice; Mice, Nude; Microtubules; Paclitaxel; Real-Time Polymerase Chain Reaction; RNA, Neoplasm; Sirolimus; TOR Serine-Threonine Kinases; Tubulin Modulators; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

To evaluate the effect of Ixabepilone on quiescent or hypoxic cells response to ionizing radiation.. NCI-H460 and A549, two human NSCLC cell lines, were employed in this experiment. Quiescent cells (QC) or hypoxic cells (HC) were induced as mentioned previously and untreated cells as control. A colony forming assay was applied to compare cellular radio-sensitivity with or without Ixabepilone. Flow cytometry and Western blot analysis were used to detect cell cycle distribution and apoptosis.. Along with an increased population of G1 cell (NCI-H46 P=0.001 3; A549 P=0.006), both HC and QC were exhibited radio-resistance compared to untreated cells (survival fraction: NCI-H460 P=0.003; A549 P=0.000 1). Moreover, it was found that Ixabepilone, which induced apoptosis in both IR-treated or untreated NSCLC cells, significantly enhanced cells death under hypoxia (decrease of survival fraction: NCI-H460 P=0.000 2; A549 P<0.01).. The existence of quiescent or hypoxic cells in solid tumors poses a critical therapeutic problem since they were resistant to IR. Ixabepilone, which induces apoptosis in NSCLC, showed great radio-sensitization effect on hypoxic cells. Following work will focus on whether Ixabepilone could increase hypoxic tumor cells radio-sensitivity in vivo, which could provide useful data for the application of Ixabepilone in clinical practice.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Hypoxia; Cell Line, Tumor; Epothilones; Humans; Lung Neoplasms; Radiation Tolerance; Radiation, Ionizing

Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown.. We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors.. Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines.. Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Blotting, Western; Cell Cycle Proteins; Cell Line, Tumor; Cluster Analysis; DNA Mutational Analysis; Epothilones; Gene Expression Profiling; Humans; Immunohistochemistry; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Mesothelioma; Mesothelioma, Malignant; Microtubules; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Pleural Neoplasms; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Tissue Array Analysis; Transcriptome; Tubulin Modulators

Epothilones are a novel group of microtubule (mt) targeting cancer drugs that bind to the β-subunit of the αβ-tubulin dimer. Epothilones inhibit cell proliferation and induce cell death by interfering with the normal mt function. In this study, we examined the consequences of altered expression of human β-tubulin isotypes in terms of the epothilone drug response in human lung and breast cancer cell lines.. The β-tubulin isotypes TUBB2A-C, TUBB3 and TUBB were silenced or overexpressed in A549, A549EpoB40 and MCF7 cell lines in the presence or absence of epothilones. The drug effects on cell proliferation, mitosis and mt dynamics were determined using live cell microscopy and immunofluorescence assays.. Loss of TUBB3 enhanced the action of epothilones. TUBB3 knockdown increased the severity of drug-induced mitotic defects and resulted in stabilisation of the mt dynamics in cells. Moreover, exogenous expression of TUBB3 in the epothilone resistant cell line conferred the response to drug treatments. In contrast, reduced levels of TUBB2A-C or TUBB had not apparent effect on the cells' response to epothilones.. Our results show that the expression of TUBB3 contributes to the cellular response to epothilones, putatively by having an impact on the mt dynamics.

Topics: Antineoplastic Agents; Cell Line, Tumor; Epothilones; Female; Gene Silencing; Humans; Lung Neoplasms; MCF-7 Cells; Mitosis; Neoplasms; Spindle Apparatus; Transfection; Tubulin; Tubulin Modulators

The use of microtubule stabilizing agents (MSAs) is a promising strategy for anti-cancer therapy alone and as part of combined treatment modalities with ionizing radiation. However MSA-provoked molecular and cellular processes including the regulation of intercellular, paracrine signaling pathways are far from clear. Here we investigated the interference of the novel, clinically relevant MSA patupilone (epothilone B) with the tumor-cell derived vascular endothelial growth factor (VEGF), which is most relevant for tumor angiogenesis. Low-dose, sub-nanomolar concentrations of patupilone specifically reduced hypoxia-driven stabilization of the transcription factor HIF-1α in the patupilone-sensitive lung adenocarcinoma cell line A549, but not in the mutant derivative cell line A549.EpoB40. Patupilone further reduced hypoxia-induced VEGF expression and secretion but only in the A549 wildtype cell line. In the wildtype cell line, ionizing radiation alone induced hypoxia-dependent VEGF-expression but a strong dominant counteracting effect of patupilone was always observed when ionizing radiation was combined with patupilone, on the level of HIF-1α protein stability, VEGF-expression and VEGF-secretion. These results demonstrate that patupilone and ionizing radiation dysregulate hypoxia-induced stress responses, which might contribute to the potency of this promising, combined treatment modality.

Topics: Adenocarcinoma; Cell Line, Tumor; Combined Modality Therapy; Epothilones; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Neovascularization, Pathologic; Paracrine Communication; Protein Stability; Radiation, Ionizing; Tubulin Modulators; Vascular Endothelial Growth Factor A

Sagopilone, an optimized fully synthetic epothilone, is a microtubule-stabilizing compound that has shown high in vitro and in vivo activity against a broad range of human tumor models. We analyzed the differential mechanism of action of sagopilone in non-small cell lung cancer cell lines in vitro. Sagopilone inhibited proliferation of non-small cell lung cancer cell lines at lower nanomolar concentration. The treatment with sagopilone caused strong disturbances of cellular cytoskeletal organization. Two concentration-dependent phenotypes were observed. At 2.5 nM sagopilone or 4 nM paclitaxel an aneuploid phenotype occur whereas a mitotic arrest phenotype was induced by 40 nM sagopilone or paclitaxel. Interestingly, treatment with 2.5 nM of sagopilone effectively inhibited cell proliferation, but--compared to high concentrations (40 nM)--only marginally induced apoptosis. Treatment with a high versus a low concentration of sagopilone or paclitaxel regulates a non-overlapping set of genes, indicating that both phenotypes substantially differ from each other. Genes involved in G2/M phase transition and the spindle assembly checkpoint, like Cyclin B1 and BUBR1 were upregulated by treatment with 40 nM sagopilone. Unexpectedly, also genes involved in DNA damage response were upregulated under that treatment. In contrast, treatment of A549 cells with a low concentration of sagopilone revealed an upregulation of direct transcriptional target genes of TP53, like CDKN1A, MDM2, GADD45A, FAS. Knockdown of TP53, which inhibited the transcriptional induction of TP53 target genes, led to a significant increase in apoptosis induction in A549 cells when treated with a low concentration of sagopilone. The results indicate that activation of TP53 and its downstream effectors like CDKN1A by low concentrations of sagopilone is responsible for the relative apoptosis resistance of A549 cells and might represent a mechanism of resistance to sagopilone.

Topics: Antineoplastic Agents; Apoptosis; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cytoskeleton; DNA Damage; Epothilones; Humans; In Vitro Techniques; Lung Neoplasms; Oligonucleotide Array Sequence Analysis; Paclitaxel; Phenotype; Tumor Suppressor Protein p53; Up-Regulation

The metabolic switch to aerobic glycolysis (Warburg effect) and enhanced lactate production is characteristic for aggressive tumor cells and is a co-determining factor for tumor response and treatment outcome. Thus analysis of the metabolic status under treatment is important to understand and improve treatment modalities.. Metabolite concentrations were determined by the immersion of tumor sections in an ATP, lactate or glucose-depending luciferase-containing buffer system. Integrated light output is detected in a bioluminescent detection system.. Mice carrying tumor xenografts derived from A549 lung cancer cells were treated with the microtubule stabilizing agent patupilone, ionizing radiation or in combination. Lactate levels were significantly reduced and glucose levels drastically increased in comparison to untreated tumors. Interestingly, these changes were only minimal in tumors derived from patupilone-resistant but otherwise isogenic A549EpoB40 cells. ATP levels of all tumors tested did not change under any treatment. When compared with histological endpoints, basal and treatment-dependent changes of lactate levels in the different tumors mainly correlated with the proliferative activity and the tumor growth response to treatment.. This study shows that the tumor metabolism is responsive to different treatment modalities and could eventually be used as an early surrogate marker for treatment response.

Topics: Adenosine Triphosphate; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Epothilones; Glycolysis; Humans; Lactic Acid; Luciferases; Luminescent Measurements; Lung Neoplasms; Mice; Mice, Nude; Transplantation, Heterologous; Tumor Microenvironment

The optimal duration of ixabepilone and capecitabine chemotherapy combination is currently not known and will most likely be patient-specific based on efficacy, toxicity, quality of life, and patient preference.. We report an extremely long duration of chemotherapy with ixabepilone and capecitabine (42 cycles) in a patient with triple-negative metastatic breast cancer previously treated with anthracyclines and taxanes. Partial remission was achieved, and acceptable toxicity was observed.. This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer regimen, especially with respect to the optimal duration of its use.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Capecitabine; Carcinoma, Ductal; Carcinoma, Papillary; Combined Modality Therapy; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Epothilones; Female; Fluorouracil; Follow-Up Studies; Humans; Long-Term Care; Lung Neoplasms; Middle Aged; Neoplasms, Second Primary; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

Characterization of new anticancer drugs in a few xenograft models derived from established human cancer cell lines frequently results in the discrepancy between preclinical and clinical results. To take the heterogeneity of tumors into consideration more thoroughly, we describe here a preclinical approach that may allow a more rational clinical development of new anticancer drugs.. We tested Sagopilone, an optimized fully synthetic epothilone, in 22 well-characterized patient-derived non-small cell lung cancer models and correlated results with mutational and genome-wide gene expression analysis.. Response analysis according to clinical trial criteria revealed that Sagopilone induced overall responses in 64% of the xenograft models (14 of 22), with 3 models showing stable disease and 11 models showing partial response. A comparison with response rates for established drugs showed the strong efficacy of Sagopilone in non-small cell lung cancer. In gene expression analyses, Sagopilone induced tubulin isoforms in all tumor samples, but genes related to mitotic arrest only in responder models. Moreover, tumors with high expression of genes involved in cell adhesion/angiogenesis as well as of wild-type TP53 were more likely to be resistant to Sagopilone therapy. As suggested by these findings, Sagopilone was combined with Bevacizumab and Sorafenib, drugs targeting vascular endothelial growth factor signaling, in Sagopilone-resistant models and, indeed, antitumor activity could be restored.. Analyses provided here show how preclinical studies can provide hypotheses for the identification of patients who more likely will benefit from new drugs as well as a rationale for combination therapies to be tested in clinical trials.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Benzothiazoles; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Epothilones; Gene Expression Profiling; Humans; Lung Neoplasms; Mice; Niacinamide; Phenylurea Compounds; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Sorafenib; Xenograft Model Antitumor Assays

Topics: Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Epothilones; Humans; Lung Neoplasms; Taxoids; Tubulin Modulators

The combined treatment modality of ionizing radiation (IR) and the clinically relevant microtubule-stabilizing compound patupilone (epothilone B, EPO906) is a promising approach for anticancer therapy. Here, we investigated the role of the tumor microenvironment for the supra-additive in vivo response in tumor xenografts derived from patupilone-sensitive and patupilone-resistant non-small cell lung cancer cells.. The treatment response to a combined regimen of patupilone and IR was investigated in vitro and in tumor xenografts derived from wild-type A549 and A549.EpoB40 cells, which are resistant to patupilone due to a beta-tubulin mutation.. In both A549 and A549.EpoB40 cells, proliferative activity and clonogenicity were reduced in response to IR, whereas patupilone, as expected, inhibited proliferation of the mutant cell line with reduced potency. 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. A supra-additive tumor growth delay was induced by combined treatment in xenografts derived from A549 cells but not in xenografts derived from A549.EpoB40 cells. Histologic analysis revealed a significant decrease in tumor cell proliferation (Ki-67) and microvessel density and a treatment-dependent change of tumor hypoxia in A549 but not A549.EpoB40 xenografts.. Using a genetically defined patupilone-sensitive and patupilone-resistant tumor model, we here showed that the major cytotoxic effect of the combined treatment modality of IR and patupilone is directed against the tumor cell compartment. The induced antiangiogenic effect derives indirectly from the tumor cell.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Epothilones; Humans; Lung Neoplasms; Mice; Neovascularization, Pathologic; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Design; Epothilones; Female; Humans; Lung Neoplasms; Neoplasms; Tubulin

We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells. Here we present two lines of evidence indicating a central role for the lysosomal protease cathepsin B in mediating cell death. First, inhibition of cathepsin B, and not of caspases or other proteases, such as cathepsin D or calpains, results in a strong protection against drug-induced cell death in several NSCLC cells. Second, MSAs trigger disruption of lysosomes and release and activation of cathepsin B. Interestingly, inhibition of cathepsin B prevents the appearance of multinucleated cells, an early characteristic of MSA-induced cell death, pointing to a central, proximal role for cathepsin B in this novel cell death pathway.

Topics: Alkanes; Antineoplastic Agents; Apoptosis; Base Sequence; Carbamates; Carcinoma, Non-Small-Cell Lung; Caspases; Cathepsin B; Cell Death; DNA Primers; Epothilones; Humans; Lactones; Lung Neoplasms; Lysosomes; Microscopy, Fluorescence; Microtubules; Paclitaxel; Pyrones; Transfection; Tumor Cells, Cultured

Desoxyepothilone B (dEpoB), currently in clinical trials, is a novel microtubule inhibitor with similar mode-of-action to paclitaxel (Taxol). Intriguingly, it is effective in some cell lines and tumor xenografts refractory to Taxol. The purpose of this study is to compare signaling induced by the two drugs and identify a molecular basis for increased efficacy of dEpoB in resistant lines. The importance of ERK signaling, already established for Taxol, was shown for dEpoB and other G2-blocking agents. However, a role in differential sensitivity was not observed. Affymetrix analysis shows similar gene modulation by either agent, alone or in combination with MEK inhibitor. Differential sensitivity in a set of Taxol-resistant lines correlated to the expression of P-glycoprotein (P-gp), and its importance was demonstrated directly. These results suggest that Taxol and dEpoB elicit similar cell death pathways, and the increased efficacy of dEpoB in resistant tumor lines lies in differential susceptibility to P-gp.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Death; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Lung Neoplasms; Paclitaxel; Signal Transduction; Tumor Cells, Cultured

The incidence of recurrent cervical adenocarcinoma is rising relative to the squamous subtype. There are limited therapeutic options for women with advanced cervical adenocarcinoma. Only a few chemotherapy agents have demonstrated activity in this disease. This report describes results with BMS-247550, an epothilone B analog that stabilizes microtubules, with activity in previously treated adenocarcinoma of the cervix.. We present two women with recurrent cervical adenocarcinoma with metastases to the lung. Both women were treated previously with paclitaxel and were enrolled in a phase I study with BMS-247550. Both women had partial responses to BMS-247550 with a decrease in tumor size and CA-125 levels.. The demonstration of a response to BMS-247550, especially after additional chemotherapy had been administered, is encouraging, albeit preliminary. The ultimate role of BMS-247550 and multiagent chemotherapy in the treatment of adenocarcinoma of the cervix should be further investigated.

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Epothilones; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Uterine Cervical Neoplasms

To evaluate a semisynthetic epothilone B, BMS-247550, as a potential radiosensitizer in vitro and in vivo.. Human NCI-H460 lung cancer cells were treated with either BMS-247550 or paclitaxel and in combination with radiation at multiple doses for different time periods. Surviving fractions were then analyzed using a clonogenic assay. Cell cycle redistribution by BMS-247550 was measured with propidium iodide and flow cytometry. Percent apoptosis was also measured using 7-amino-actinomycin D staining with flow cytometry. For in vivo studies, the H460 xenograft model was used in athymic nude mice. Tumors were treated with BMS-247550 (5 mg/kg) i.p. injection on days 0, 2, and 4 and/or radiation (2 Gy/day, days 0-4).. The in vitro radiation dose enhancement ratios (DER) of 1-h BMS-247550 and paclitaxel were 2.03 and 1.34, respectively. Treatment with BMS-247550 enhanced the G2/M block and induced apoptosis; whereas in combination with radiation, the induction of apoptosis was additive. BMS-247550 in combination with radiation in vivo enhanced the tumor growth delay when compared with either drug or radiation alone.. These results demonstrated that BMS-247550 could enhance the effects of radiation in human lung cancer cells both in vitro and in vivo and that a G2/M block and increased apoptosis might be possible explanations for the enhancement.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Large Cell; Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Epothilones; Female; Flow Cytometry; Humans; Indicators and Reagents; Lung Neoplasms; Mice; Mice, Nude; Paclitaxel; Propidium; Radiation-Sensitizing Agents; Transplantation, Heterologous

To explore the molecular mechanisms underlying the actions of Taxol and the functionally related molecule epothilone B (EpoB), we have analyzed the gene expression profiles in A549 cells in response to increasing concentrations of these microtubule-stabilizing drugs. An almost identical expression pattern was observed in cells treated with either Taxol or EpoB. Low concentrations of the drugs induced aberrant mitosis including asymmetric and multipolar cell divisions. At drug concentrations that triggered G(2)-M arrest, cells escaped from a prolonged mitotic arrest without cell division, resulting in tetraploid G(1) cells. This mitotic slippage is correlated with diminished expression of cdc2 kinase, topoisomerase IIalpha, BUB3, and BUB2-like protein 1, as well as with an increased expression of 14-3-3-sigma. Poly(ADP-ribose) polymerase cleavage, an early indicator of apoptosis, occurred in cells undergoing mitotic slippage and in aneuploid cells resulting from aberrant mitosis. In contrast, cells arrested in mitosis demonstrated no signal for apoptosis but had an increased expression of survivin, an inhibitor of apoptosis. Induction of aneuploid or tetraploid G(1) cells was accompanied by increased expression of CD95, p21, and BTG2 that may contribute to cell death because their expression was diminished in an EpoB-resistant cell line. In contrast, expression of GADD45 and PTGF-beta could promote cell survival. We conclude that abnormal mitotic exit is required for apoptotic cell death induced by microtubule-stabilizing drugs.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Epothilones; Gene Expression; Gene Expression Profiling; Humans; Lung Neoplasms; Microtubules; Mitosis; Oligonucleotide Array Sequence Analysis; Paclitaxel; Polyploidy; RNA, Messenger

Discodermolide and epothilone B are promising novel chemotherapeutic agentsthat induce cell death through potent stabilization of microtubules. In this study, we investigated the cellular and molecular events underlying the cytotoxicity of these drugs in non-small cell lung carcinoma (NSCLC) cell lines, focusing on apoptotic characteristics. IC80 concentrations of either drug effectively disrupted the microtubule cytoskeleton of H460 cells and induced cell cycle disturbances with early accumulation in the G2-M phase and development of a hypodiploid cell population in both H460 and SW1573 cells. These events were followed by abnormal chromosome segregation during mitosis and subsequent appearance of multinucleated cells. At later time points, the cells displayed several apoptotic features, such as nuclear condensation and fragmentation as well as Annexin V staining, cleavage of poly(ADP-ribose) polymerase and the activation of caspases. To examine the contribution of apoptotic pathways to the cytotoxic effects of these agents, the involvement of the mitochondria and death receptor routes was studied. At 48 h after treatment, both agents disrupted mitochondria of H460 cells, as indicated by cytochrome c release. Nonetheless, H460 cells stably overexpressing antiapoptotic Bcl-2 or Bcl-xL did not show any protective effect from cell death induced by either drug. Possible death receptor dependency was investigated in H460 cells stably overexpressing dominant-negative FADD, which failed to reduce the cytotoxic effects of discodermolide and epothilone B. To study the role of caspases more directly, the effect of stable overexpression of the caspase-8 inhibitor cytokine response modifier A was studied in H460 cells. Furthermore, the effect of the pancaspase inhibitor z-Val-Ala-Asp-fluoromethyl ketone was investigated in a panel of lung carcinoma cell lines. Interestingly, caspase inhibition did not rescue cells from discodermolide or epothilone B-induced cell death. In conclusion, these results demonstrate that despite several apoptotic features detected at relatively late time points after drug exposure, apoptosis is not the dominant mode of cell death and induced low but efficacious concentrations of discodermolide and epothilone B.

Topics: Alkanes; Antineoplastic Agents; Apoptosis; Carbamates; Carcinoma, Non-Small-Cell Lung; Caspase Inhibitors; Caspases; Epothilones; Humans; Inhibitory Concentration 50; Jurkat Cells; Lactones; Lung Neoplasms; Macrolides; Mitochondria; Pyrones; Receptors, Tumor Necrosis Factor; Tumor Cells, Cultured

A new epothilone, 10,11-didehydroepothilone D (5), was isolated from a strain of the heterologous host Myxococcus xanthus genetically engineered to produce epothilone D (4). The structure of 5 was determined from NMR and MS data. The epothilone polyketide synthase was further modified in a recombinant M. xanthus strain to produce 5 as the major epothilone-related metabolite. The cytotoxicity of 5 against a panel of tumor cell lines, including several with multidrug resistance, and its effect on tubulin polymerization were comparable to epothilone D (4).

Topics: Antineoplastic Agents; Base Sequence; Binding Sites; Breast Neoplasms; Drug Screening Assays, Antitumor; Epothilones; Epoxy Compounds; Female; Genetic Engineering; Glioma; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia, Promyelocytic, Acute; Leukemia, T-Cell; Lung Neoplasms; Mass Spectrometry; Molecular Sequence Data; Molecular Structure; Multienzyme Complexes; Myxococcus xanthus; Nuclear Magnetic Resonance, Biomolecular; Thiazoles; Tubulin; Tumor Cells, Cultured

Although microtubule interacting agents inhibit spindle dynamics, thereby leading to a block in mitosis, we report that low concentrations of these drugs result in differential mitotic effects. Microtubule-stabilizing agents including Taxol, epothilone B, and discodermolide produce aneuploid populations of A549 cells in the absence of a mitotic block. Such aneuploid populations are diminished in an epothilone B-resistant cell line. In contrast, microtubule-destabilizing agents like colchicine, nocodazole, and vinblastine are unable to initiate aneuploidy. The aneuploid cells result from aberrant mitosis as multipolar spindles are induced by the stabilizing drugs, but not by destabilizing agents. The results suggest that the mechanism underlying aberrant mitosis may not be the same as that responsible for mitotic block, and that the former determines the sensitivity of cells to Taxol-like drugs.

Topics: Alkanes; Aneuploidy; Antineoplastic Agents; Carbamates; Carcinoma, Non-Small-Cell Lung; Epothilones; Humans; Lactones; Lung Neoplasms; Macrolides; Microtubules; Mitosis; Paclitaxel; Pyrones; Spindle Apparatus; Tumor Cells, Cultured

Peloruside A is a novel secondary metabolite isolated from a New Zealand marine sponge, Mycale hentscheli, that has potent paclitaxel-like microtubule-stabilizing activity and is cytotoxic at nanomolar concentrations. Its 16-membered macrolide ring is similar to that of epothilone, a drug currently under clinical investigation as an anticancer agent. Like paclitaxel, peloruside A arrests cells in the G(2)-M phase of the cell cycle and induces apoptosis. The relatively simple structure of peloruside makes it suitable for the design and synthesis of analogues with improved tumor targeting and reduced tumor cross-resistance.

Topics: Actins; Adenocarcinoma; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Epothilones; Humans; Lactones; Lung Neoplasms; Macrolides; Microtubules; Paclitaxel; Taxoids; Tubulin

Recently, three natural products have been identified, the epothilones, eleutherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitotic phase of the cell cycle. In this report, we have compared and contrasted the effects of these new agents in Taxol-sensitive and -resistant cell lines. We also have taken advantage of a human lung carcinoma cell line, A549-T12, that was isolated as a Taxol-resistant cell line and found to require low concentrations of Taxol (2-6 nM) for normal cell division. This study then examined the ability of these new compounds to substitute for Taxol in sustaining the growth of A549-T12 cells. Immunofluorescence and flow cytometry have both indicated that the epothilones and eleutherobin, but not discodermolide, can substitute for Taxol in this Taxol-dependent cell line. In A549-T12 cells, the presence of Taxol significantly amplified the cytotoxicity of discodermolide, and this phenomenon was not observed in combinations of Taxol with either the epothilones or eleutherobin. Median effect analysis using the combination index method revealed a schedule-independent synergistic interaction between Taxol and discodermolide in four human carcinoma cell lines, an effect that was not observed between Taxol and epothilone B. Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increase in the hypodiploid population, thereby indicating that a possible mechanism for the observed synergy is the potentiation of apoptosis. Our results suggest that Taxol and discodermolide may constitute a promising chemotherapeutic combination.

Topics: Alkaloids; Alkanes; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Carbamates; Cell Count; Cell Division; Cell Line; Cytoskeleton; Diterpenes; Dose-Response Relationship, Drug; Drug Synergism; Epothilones; Epoxy Compounds; Flow Cytometry; Humans; Lactones; Lung Neoplasms; Microtubules; Mitosis; Paclitaxel; Pyrones; Thiazoles; Tumor Cells, Cultured