新型抗肿瘤药埃坡霉素的临床研究进展

埃坡霉素（epothilones）是一类非紫杉烷类促微管蛋白聚合剂,其作用机制与紫杉醇相似,但结构完全不同,临床前研究结果显示其细胞毒活性较紫杉醇强,对紫杉类耐药的细胞株和小鼠肿瘤移植模型显示出较强的抗肿瘤活性。近来合成或半合成了很多埃坡霉素类似物,目前已进入临床抗肿瘤治疗研究的埃坡霉素类似物主要有ixabepilone、patupilone、BMS-310705、ZK—EPO、KOS-862及KOS-1584。现有的临床研究结果提示部分接受过紫杉类药物治疗的晚期乳腺癌、卵巢癌、膀胱癌或非小细胞肺癌患者埃坡霉素治疗有效。本文就埃坡霉素的化学结构,作用机制、药理活性及毒副作用等临床研究的进展进行了回顾和综述。     

Epothilones: clinical update and future directions

Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death. However, their mechanism of microtubule binding is different from that of paclitaxel, which makes epothilones an attractive drug class for patients with taxane-resistant malignancies. As taxane resistance remains a significant barrier in the treatment of a variety of cancers, it is important to understand epothilones and their indications. Several epothilone compounds, including ixabepilone (BMS-247550, aza-epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxyepothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), nd KOS-1584, have been testedf or the treatment of a variety of solid tumor types. Recently, ixabepilone became the first epothilone to be approved by the US Food and Drug Administration, for the treatment of metastatic or locally advanced breast cancer as monotherapy or in combination with capecitabine (Xeloda) after other treatments have failed. This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.     

Epothilones: mechanism of action and biologic activity.

Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.     

Targeting the microtubules in breast cancer beyond taxanes: the epothilones

Microtubule-targeting agents such as the taxanes are highly active against breast cancer and have become a cornerstone in the treatment of patients with early and advanced breast cancer. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic cell death. Among this family of compounds, patupilone, ixabepilone, BMS-310705, ZK-EPO, and KOS-862 are in clinical development. Extensive preclinical studies have shown that epothilones are working through partially nonoverlapping mechanisms of action with taxanes. In the clinic, epothilones have been found in a series of phase I and phase II studies to be active even in patients who had recently progressed to taxanes. The toxicity profile of these agents consists mostly of sensory neuropathy, sometimes reversible. Neoadjuvant studies with epothilones have been conducted and a number of phase III studies in advanced breast cancer are either under way or have been recently completed. The results of these studies are eagerly awaited and it is anticipated that epothilones may become an important treatment option in patients with breast cancer.     

Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms

Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the betaIII-tubulin isoform. Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.     

Clinical experience with epothilones in patients with breast cancer

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.     

Pharmacodynamics of tubulin and tubulin-binding agents: extending their potential beyond taxanes

Chemotherapeutic agents that disrupt the assembly or disassembly of microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapy is limited principally by problems with formulation, slow administration, cumulative neurotoxicity, and resistance in part through induction of P-glycoprotein. The broad-spectrum anticancer activity of taxane therapy has encouraged investigators to identify a class of structurally novel microtubulin-stabilizing agents that could produce comparable outcomes with fewer problems. Preclinical studies indicate that epothilones have a broad spectrum activity in paclitaxel-resistant breast cancer models. Several epothilone analogues have displayed promising antitumor activity in initial clinical trials. Ixabepilone, an epothilone derivative in the later stages of clinical development, has exhibited antitumor activity in breast cancers, with or without previous taxane therapy. The most common adverse events associated with ixabepilone are reversible sensory neuropathy and neutropenia. This review briefly outlines the basic science behind microtubule-targeting agents and examines the preclinical studies of several of these agents in breast cancer models. Also discussed are results from clinical trials of epothilones alone and in combination in patients with breast cancer.     

The epothilones: new therapeutic agents for castration-resistant prostate cancer

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.     

Efficacy and safety of ixabepilone, a novel epothilone analogue

The epothilones and their analogues are a new class of anticancer agents derived from the fermentation of myxobacterium Sorangium cellulosum. These compounds have some similarities to taxanes in targeting and stabilizing microtubules, but they also have important differences. Among the epothilone family, ixabepilone has emerged to be a semisynthetic epothilone analogue of interest. Ixabepilone has demonstrated consistent preclinical activity and seems active against various taxane-sensible and taxane-resistant cell lines, including those with overexpression of multidrug resistance and with mutations in the beta-tubulin gene. The interest of this ixabepilone has been confirmed clinically. Phase II clinical studies have demonstrated high activity in patients with taxane-resistant metastatic breast cancer and in patients with other chemotherapy-resistant tumor types.     

A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days

BACKGROUND: The epothilones are a novel class of microtubule-stabilizing agents. Ixabepilone (BMS-247550; NSC 710428) is a semisynthetic analog of the natural product epothilone B. The authors conducted a Phase I study by administering ixabepilone to patients as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. METHODS: Twenty-six patients were enrolled and received ixabepilone at a starting dose of 8 or 10 mg/m(2) per day for 3 consecutive days. RESULTS: One hundred and nineteen cycles were administered to 26 patients. The maximum-tolerated dose was 8 mg/m(2) per day of ixabepilone administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. The dose-limiting toxicity (DLT) was neutropenia. Other nonhematologic Grade 3 toxicities included fatigue (3 cycles), hyponatremia (1 cycle), anorexia (1 cycle), ileus (1 cycle), stomatitis (1 cycle), and emesis (1 cycle). Prolonged disease stabilization was observed in patients with mesothelioma, ovarian carcinoma, and renal cell carcinoma. CONCLUSIONS: The recommended Phase II dose of ixabepilone on the daily schedule for 3 days was 8-10 mg/m(2) per day. Neutropenia was the DLT. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra?, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.     

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane‐resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy‐sensitive and chemotherapy‐resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single‐agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline‐ and taxane‐resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy‐naïve and taxane‐resistant hormone‐refractory prostate cancer and platinum‐resistant non‐small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.     

Optimizing ixabepilone treatment schedules in patients with advanced or metastatic breast cancer

The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m(2) every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m(2) on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.     

Epothilones in development for non--small-cell lung cancer: novel anti-tubulin agents with the potential to overcome taxane resistance

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.     

Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule.

BACKGROUND: BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication. PATIENTS AND METHODS: Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule. RESULTS: The dose was escalated from 5-30 mg/m(2)/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m(2) were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported. CONCLUSIONS: Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.     

Predictive value of preclinical toxicology studies for platinum anticancer drugs.

Rodent and nonrodent toxicology studies are currently expected to support Phase I trials of antineoplastic drugs in the United States. To determine the predictive value of these studies, we initiated a project to compare preclinical and clinical toxicity data within various drug classes. The first class analyzed was the platinum anticancer drugs. Twelve platinum analogues that had both preclinical (mice, rats and/or dogs) and clinical data from matching drug administration schedules were identified. The rodent LD10 (the dose that causes lethality in 10% of treated animals) or dog toxic dose high (a dose that when doubled causes lethality in dogs) correlated well with the human maximally tolerated dose on a mg/m2 basis. For every platinum analogue investigated, one-third the rodent LD10 or one-third the dog toxic dose high in mg/m2 gave a starting dose and a first escalation dose that did not exceed the clinical maximally tolerated dose. The dose-limiting toxicities in patients were previously observed in 7 of 7, 7 of 8, and 9 of 11 mouse, rat, and dog studies, respectively. Our data indicate that mice, rats, and dogs all had value in predicting a safe starting dose and the qualitative toxicities in humans for platinum anticancer compounds. The efficiency of Phase 1 trials could have been improved without sacrificing patient safety by allowing higher starting doses for this drug class than conventionally permitted.     

Efficacy and safety of ixabepilone (BMS-247550), a novel epothilone B analogue

The epothilones are a new class of non-taxane tubulin polymerization agents obtained by natural fermentation of the myxobacteria Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilization of microtubules, but they also have important differences. Among the epothilone family, ixabepilone (BMS247550) is a semisynthetic derivative of the natural product epothilone B. Ixabepilone was evaluated in vivo in a panel of human and rodent tumour models, the majority of which were chosen because of their known, well-characterized resistance to paclitaxel, and seems able to overcome the over-expression of multidrug resistance and to be unaffected by mutations in the beta tubulin gene. The interest of ixabepilone was clinically confirmed in clinical studies of phase II which demonstrated a strong activity at the patients with metastatic breast cancer resistant to taxanes and in patients suffering of other types of chemoresistant tumors.     

Preclinical discovery of ixabepilone, a highly active antineoplastic agent

The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum. These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.     

Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice

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.