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Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice

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Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice Published OnlineFirst April 15, 2011; DOI: 10.1158/0008-5472.CAN-10-4184 Cancer Therapeutics, Targets, and Chemical Biology Research Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice Krystyna M. Wozniak1, Kenichi Nomoto3, Rena G. Lapidus2, Ying Wu1, Valentina Carozzi5, Guido Cavaletti5, Kazuhiro Hayakawa6, Satoru Hosokawa6, Murray J. Towle3, Bruce A. Littlefield4, and Barbara S. Slusher1 Abstract 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 Â MTD, 0.5 Â MTD, 0.75 Â 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. Cancer Res; 71(11); 1–11. Ó2011 AACR. Introduction Breast cancer is the most common cause of cancer-related death among women in the Unites States. Many patients Peripheral neuropathy is a common dose-limiting toxicity progress from early-stage breast cancer to metastatic disease of many chemotherapeutic regimens. Chemotherapy-induced within short periods of time. Although several chemothera- peripheral neuropathy (CIPN) causes numerous debilitating peutic agents exist for metastatic disease, the overall prognosis symptoms, impairs functional capacity, and results in dose remains poor, with the 5-year survival rate approximating to reductions or possible cessation of chemotherapy. As a con- only 23% (1). sequence, effective chemotherapeutic regimens with a lower Paclitaxel is often administered as first-line therapy in propensity to induce neuropathy would be favored. breast cancer patients with metastatic disease, achieving overall response rates in the range of 30% to 60%, or 20% to 40% when used as second-line or salvage therapy (2). Taxanes are among the most effective antineoplastic agents Authors' Affiliations: 1Johns Hopkins Brain Science Institute; 2University of Maryland Greenebaum Cancer Center, Baltimore, Maryland; 3Eisai Inc., against many cancers, but their side effect of peripheral Andover, Massachusetts; 4Department of Biological Chemistry and Mole- neurotoxicity has limited their use (3, 4). Chronic neuropathic cular Pharmacology, Harvard Medical School, Boston, Massachusetts; pain affects between 20% and 50% of women after their breast 5University of Milan-Bicocca, Italy; and 6Eisai Co., Ltd., Tsukuba, Japan cancer treatment (5). Another chemotherapeutic agent admi- Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). nistered to metastatic breast cancer patients whose cancer is resistant or no longer responding to paclitaxel is the recently Corresponding Author: Krystyna M. Wozniak, Johns Hopkins Brain Science Institute, NeuroTranslational Drug Discovery Program, 855 North approved ixabepilone, which is a semisynthetic analogue of Wolfe Street, Baltimore, MD 21205. Phone: 443-287-0178; Fax: 410-614- epothilone B with antineoplastic activity against taxane-resis- 0659. E-mail: [email protected] or Barbara S. Slusher, Johns Hopkins – Brain Science Institute, NeuroTranslational Drug Discovery Program, 855 tant cell lines (6 8). Although ixabepilone may be useful for North Wolfe Street, Baltimore, MD 21205. Phone: 410-614-0662; E-mail: the treatment of locally advanced or metastatic breast cancer, [email protected] it induces neuropathy in up to 72% of patients (9). Both doi: 10.1158/0008-5472.CAN-10-4184 ixabepilone and paclitaxel are microtubule-stabilizing agents Ó2011 American Association for Cancer Research. that promote polymerization of microtubules (10). However, www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst April 15, 2011; DOI: 10.1158/0008-5472.CAN-10-4184 Wozniak et al. the precise mechanisms of paclitaxel- and ixabepilone- a final volume (as 80% of final) and the solution was main- induced neurotoxicities are not yet completely understood tained on ice during dosing. Dosing solutions were made (11–13). One of the reasons for this is the incomplete char- freshly every day and dosed in an administration volume of acterization of function and pathology of peripheral nerves in 10 mL/kg. chemotherapy-treated subjects, either from patients or pre- Ixabepilone was purchased as part of an IXEMPRA kit clinically from animals. Further studies in this area are, thus, (Bristol-Myers Squibb) for clinical administration. The ixabe- warranted. pilone solution was prepared according to instructions pro- Eribulin mesylate (previously E7389), another promising vided in the package insert. Basically, the kit consists of 2 vials, microtubule-targeting agent, is currently undergoing Food 1 containing 47 mg ixabepilone powder and the other contain- and Drug Administration (FDA) fast-track review. Recently, ing 23.5 mL diluent, which were stored in the refrigerator at positive results from randomized phase II and III trials of 4C. The total volume of the diluent was added to the total eribulin mesylate in patients with advanced metastatic breast amount of powder; therefore, after reconstitution, the con- cancer have been reported (14, 15). Eribulin mesylate is a centration of ixabepilone in the solution was 2 mg/mL. [The structurally simplified, macrocyclic, ketone analogue of hali- diluent supplied consists of a sterile nonpyrogenic solution of chondrin B, and it inhibits microtubule dynamics through a 52.8% (w/v) purified polyoxyethylated castor oil and 39.8% novel mechanism relative to other tubulin-targeting agents, (w/v) dehydrated alcohol.] The formulated ixabepilone stock including the taxanes, Vinca alkaloids, and epothilones. It solution (2 mg/mL) was immediately aliquoted and stored at binds with high affinity and specificity to positively charged À80C until use. On each experimental day, the stock solution ends of microtubules, thereby suppressing microtubule was diluted by adding 50% ethanol/50% cremophor with dynamics (16). Preclinically, eribulin mesylate has shown subsequent vortexing to yield a resultant solution that potent anticancer activity in vitro and in vivo (17). Preliminary was 5 times the required dosing concentration. Finally, reports from clinical observations of therapy with eribulin 4Â volumes of PBS were added, while vortexing, to achieve mesylate suggest that, at efficacious exposures, there is rela- a final dosing concentration of 10 mL/kg. tively low incidence and severity of neuropathy (18). Based on this finding, preclinical studies were conducted to directly Animals compare maximum tolerated dose (MTD) regimens (and Female BALB/c mice (approximately 7–8 weeks of age at equivalent fractions thereof) of paclitaxel, eribulin mesylate, onset of dosing) were used for all experiments. Mice were and ixabepilone for neuropathy induction in mice, which was obtained from the Harlan Laboratories Inc. and maintained evaluated by parameters including nerve conduction velocity with ad libitum access to water and a standardized synthetic (NCV), amplitude, and sciatic nerve and dorsal root ganglia diet (Harlan Teklab), both before and during the course of the (DRG) morphologic endpoints. In this article, we describe our study. findings from this study. Animal housing and procedure Materials and Methods Room temperature and humidity were maintained at 20 Æ 2C and 55 Æ 10%, respectively. Artificial lighting provided a Test materials 12-hour light/12-hour dark cycle (light 7 AM–7 PM). All The following chemicals were used in this study: eribulin experimental protocols were approved by the Institutional mesylate (synthesized at Eisai Research Institute, Andover, Animal Care and Use Committee of Eisai, Baltimore, MD, and MA) was stored at À80 C in the dark. Paclitaxel (C47H51NO14) conformed to all of the applicable institutional and govern- was purchased from LC Laboratories and stored at À20Cin mental guidelines for the humane treatment
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