Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)like mechanism, Although structurally dissimil ar, both classes of molecules lead to the arrest of cell division and event ual cell death by stabilizing cellular microtubule assemblies. The epothilo nes differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails. In the current account, we focus on the relationship between epothilone and paclitaxel in the cont ext of tumors with multiple drug resistance. The epothilone analogue Z-12,1 3-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulation s, routes, and schedules of i.v. administration of dEpoB have been tested i n nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be th e most beneficial in increasing efficacy and decreasing toxicity. Although dEpoB performed similarly to paclitaxel in sensitive tumors xenografts (MX- 1 human mammary and HT-29 colon tumor), its effects were clearly superior a gainst MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstra ted a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cell s refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy dru gs such as adriamycin, vinblastine, and etoposide in beneficial effects.