Desoxyepothilone B: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B

Abstract

A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. Recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. The present study examined cell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed as much as 1, 970-fold cross-resistance to the sublines resistant to paclitaxel, adriamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance. In multidrug-resistant CCRF-CEM/VBL100 cells, IC50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEpoA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0.017, and 4.14 microM, respectively. In vivo studies, using i.p. administration, indicated that the parent, EpoB, was highly toxic to mice and showed little therapeutic effect when compared with a lead compound, dEpoB. More significantly, dEpoB (25-40 mg/kg, Q2Dx5, i.p.) showed far superior therapeutic effects and lower toxicity than paclitaxel, doxorubicin, camptothecin, or vinblastine (at maximal tolerated doses) in parallel experiments. For mammary adenocarcinoma xenografts resistant to adriamycin, MCF-7/Adr, superior therapeutic effects were obtained with dEpoB compared with paclitaxel when i.p. regimens were used. For ovarian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxel (i. v.) gave similar therapeutic effects. In nude mice bearing a human mammary carcinoma xenograft (MX-1), marked tumor regression and cures were obtained with dEpoB.

Figure 1

Chemical structures of paclitaxel, epothilones A and B, and desoxyepothilones A and B.

Figure 2

Therapeutic effect of dEpoB, paclitaxel, and Adriamycin in nude mice bearing the human mammary carcinoma MX-1 xenograft. MX-1 tissue preparation, 100 μl per mouse, was implanted s.c. on day 0. Every other day i.p. treatments were given on days 8, 10, 12, 14, and 16 with 35 mg/kg dEpoB (■), 5 mg/kg paclitaxel (▴), 2 mg/kg Adriamycin (X), and vehicle (DMSO, 30 μl)-treated control (♦). For paclitaxel, 2 of 10 mice died of toxicity on day 18. For Adriamycin, 1 of 10 mice died of toxicity on day 22. For dEpoB, 10 of 10 mice survived and were subjected to the second cycle of treatment at 40 mg/kg on days 18, 20, 22, 24, and 26. This led to 3 of 10 mice tumor-free up to day 80, whereas 7 of 10 mice were with markedly suppressed tumors and were sacrificed on day 50.