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

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

^*Molecular Pharmacology and Therapeutics Program, and ^‡Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021; and ^†Cornell University Graduate School of Medical Sciences, 1275 York Avenue, New York, NY 10021

Contributed by Samuel J. Danishefsky

Abstract

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones 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 context of tumors with multiple drug resistance. The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulations, routes, and schedules of i.v. administration of dEpoB have been tested in nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be the 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 against MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstrated a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cells refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy drugs such as adriamycin, vinblastine, and etoposide in beneficial effects.

Footnotes

↵ § Present address: Bristol-Myers Squibb Company, Princeton, NJ 08543.
↵ ¶ Present address: Eli Lilly Corporate Research Center, Indianapolis, IN 46285.
↵ ‖ To whom reprint requests should be addressed. e-mail: dshfsky{at}ski.mskcc.org.
↵ ** Taxol is a trademark of Bristol-Myers Squibb.
↵ ‡‡ Desoxyepothilone B (Epothilone D) has been encountered as a very minor fermentation product in mixtures where epothilone A and epothilone B were the principle products.
ABBREVIATIONS:

dEpoB,

Z-12,13-desoxyepothilone B (NSC-703147);

VBL,

vinblastine;

DX,

doxorubicin (Adriamycin or Adr);

DMSO,

dimethyl sulfoxide;

MDR,

multidrug-resistant