Differences and Similarities of Epothilones

Werner      Krause; Ulrich      Klar

doi:10.2174/157339411794474155

Abstract

Epothilones are a novel class of natural cytotoxic compounds, originally isolated from the myxobacterium Sorangium cellulosum in the early 1990s. They induce hyperstabilization of microtubules similar to the taxanes leading to cell cycle arrest and finally to apoptosis. The natural epothilones are characterized by the letters A – F. Their chemical structure consists of a 16-membered macrocyclic ring system with a common side chain that differs in its oxydation status. Currently, natural epothilones, such as epothilone B (patupilone) and D (KOS-862), semisynthetic (ixabepilone, BMS-310705) and fully synthetic epothilones (sagopilone and KOS-1584) are in clinical development. Whereas paclitaxel and docetaxel provide significant clinical benefit in the treatment of a number of tumor types, their use is often limited by the development of multidrug resistance. Preclinical results indicate that natural epothilones are not subject to multidrug resistance to the same extent as the taxanes. Whether this translates into additional clinical benefit is currently the objective of extensive investigations. Ixabepilone, like the taxanes a substrate for PgP, has recently been approved for the treatment of metastatic breast cancer in the USA. However, the European agency CHMP declined a positive opinion due to an insufficient benefit /risk ratio. Other epothilones are in different stages of development, the most advanced being patupilone in Phase III in ovarian cancer and sagopilone in Phase II in a number of different tumor types. Although their mechanism of action is identical and their chemical structures are very similar, epothilones exhibit a highly differentiated picture of activity, safety and tolerability profiles. For ixabepilone, the major adverse event is hematological toxicity followed by peripheral sensory neuropathy. Patupilone, on the other hand, is mainly characterized by gastrointestinal side effects, which require pretreatment and concomitant therapy. In the case of sagopilone, peripheral sensory neuropathy is the major clinically relevant side effect. This review summarizes both preclinical and clinical results for the epothilones currently in clinical development.

Keywords: Epothilones, cytotoxic drugs, oncology, microtubular inhibitors, multidrug resistance, clinical development, Microtubules, equilibrium, ovarian cancer, -tubulin, paclitaxel, potency, anti-cancer drugs, neurotoxicity, lactone ring system, bioavailability, ixabepilone, sagopilone, benzene ring, ketone, lipophilicity, water-soluble, heterozygous impairment, pancreatic tumor, brain tumor growth, infusion, single-agent studies, neutropenia, fatigue, sensory neuropathy, nausea, vomiting, dose, mucositis, ileus, diarrhea, ovarian, primary fallopian, ataxia, neuropathy, hyponatremia, chest pain, half-life, plasma level, urine, metabolites, germ cell, sarcoma, melanoma, thrombocytopenia, breast cancer, doxorubicin