The novel indolocarbazole
edotecarin (J-107088, formerly ED-749) differs from other
topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human
cancer cell lines.
Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various
cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of
edotecarin when used either alone or in combination with other agents (i.e.,
5-fluorouracil,
irinotecan,
cisplatin,
oxaliplatin, and
SU11248) in the HCT-116 human
colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of
tumors in
drug-treated versus vehicle control-treated groups. In all studies,
edotecarin was active both as a single agent and in combination with other agents. Combination
therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose
edotecarin/
oxaliplatin group. The results suggest that
edotecarin may serve as effective
chemotherapy of
colon cancer when used as a single agent, in combination with standard regimens and other
topoisomerase inhibitors or with novel agents, such as the multitargeted
tyrosine kinase inhibitor SU11248.