Epothilones, 16-membered
macrolides isolated from a myxobacterium in soil, exert their antitumor effect, like
Taxol, by induction of microtubule polymerization and microtubule stabilization. They are effective against
tumor cells that are resistant to
Taxol or
vinblastine. We recently designed, via molecular editing and total synthesis, a new class of
epothilones represented by
26-trifluoro-(E)-9,10-dehydro-12,13-desoxy-epothilone B (
Fludelone), which has emerged as a lead candidate for clinical development. Treatment of nude mice bearing MX-1
human mammary carcinoma xenografts (as large as 3.4%
body weight) with
Fludelone (6-hour i.v. infusion, 25 mg/kg, q3d x 5, q3d x 4) led to complete disappearance and de facto "cure" (i.e., remission without a relapse for over 15% of the average life span of 2 years). The toxicities induced by bolus i.v. injection could be avoided through prolonged i.v. infusion, which allowed for a 10-fold increase in maximal tolerated dose. Complete remission of MX-1 xenografts was achieved with only one third of this maximal tolerated dose. Parallel studies with
Taxol and
Fludelone [20 mg/kg, 6-hour i.v. infusion (q2d x 4) x3] against HCT-116 human colon
carcinoma xenografts revealed that both drugs achieved
tumor remission; however, all
Taxol-treated mice relapsed in approximately 1.3 months, whereas the
Fludelone-treated mice were cured without any relapse for over 7 months. Furthermore,
tumor remission was achieved by
Fludelone against SK-OV-3 (ovary), PC-3 (prostate), and the
Taxol-resistant CCRF-CEM/
Taxol (
leukemia) xenograft
tumors. Most remarkably, p.o. administration of
Fludelone (30 mg/kg, q2d x 7, q2d x 9, q2d x 5) against MX-1 xenografts achieved a nonrelapsing cure for as long as 8.4 months. The above results indicate that
Fludelone is a highly promising compound for
cancer chemotherapeutics.