Cancer Chemother Pharmacol (2011) 67:293–304
303
Research Program of the US Army Medical Research and Materiel
Command.
also been shown to be an effective inhibitor of tumor
growth in DU-145 xenograft model, thus supporting a bcl-2
independent mechanism for tubulin inhibitors [31].
The in vivo toxicity study in ICR mice showed no severe
toxicity of 15 at doses up to 250 mg/kg, the maximum dose
tested. Since vinca alkaloids are widely used antimitotic
agents in clinical chemotherapy, we used vinblastine as one
of the positive controls during in vivo efficacy and toxicity
studies. In addition, 15 was compared to docetaxel, a
antimitotic taxane analog, which is the first approved
chemotherapy for the treatment of advanced prostate
cancer. A 25-fold lower dose of 15 (10 mg/kg) was shown
to be as effective in the PC-3 xenograft model as 0.5 mg/kg
vinblastine, a dose only fivefold lower than the sub-chronic
MTD of vinblastine in the q2d regimen. Docetaxel showed
severe body weight loss, as well as tumor growth inhibi-
tion. The body weight loss ([15%) in docetaxel group
(5 mg/kg, i.p., 2 days/week) was observed with 33% T/C
after 2-week treatment. Docetaxel was very efficacious
(21% T/C) but less than 30% of the mice survived by the
end of this study. 15 (10 mg/kg, i.p., q2d) induced tumor
growth inhibition (42% T/C) with no signs of general
toxicity. Ixabepilone (BMS-247550), the most widely
clinically investigated epothilone, produced significant
antitumor activities at doses between 6.6 and 15 mg/kg
(q4d 39, i.v.), but the MTD of ixabepilone was between 10
and 16 mg/kg (q4d 39, i.v.) in several mice xenograft
models [10, 32, 33]. Our data suggest that 15 may also
provide a wider therapeutic window between efficacy and
toxicity than available agents or ixabepilone, perhaps due
to its utilization of the colchicine-binding site in tubulin.
More definitive animal studies to examine the general
safety and neurotoxicity of indole 15 are on-going in our
laboratory.
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Acknowledgments These studies were supported by grant
#PC060380 from the Department of Defense Prostate Cancer
123