DESOXYEPOTHILONE-B - AN EFFICACIOUS MICROTUBULE-TARGETED ANTITUMOR AGENT WITH A PROMISING IN-VIVO PROFILE RELATIVE TO EPOTHILONE-B

A new class of 16-membered macrolides, the epothilones (Epos), has bee n synthesized and evaluated for antitumor potential in vitro and in vi vo. Recent studies in these and other laboratories showed that epothil ones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement s tudies, substitution for paclitaxel in paclitaxel-dependent cell growt h, and electron microscopic examinations. The present study examined c ell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed a s much as 1,970-fold cross-resistance to the sublines resistant to pac litaxel, adriamycin, vinblastine, or actinomycin IF, most epothilones exhibit little or no cross-resistance, In multidrug-resistant CCRF-CEM /VBL100 cells, IC50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEp oA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0 .017, and 4.14 mu M, respectively. In vivo studies, using i.p. adminis tration, 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, doxo rubicin, 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 w ith dEpoB compared with paclitaxel when i.p. regimens were used. For o varian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxe l (i.v,) gave similar therapeutic effects. In nude mice bearing a huma n mammary carcinoma xenograft (MX-1), marked tumor regression and dare s were obtained with dEpoB.