Gastrointestinal cancers pose major public health problems worldwide, in part because little progress has been made in the treatment of colorectal cancers. The present study explored the potential use of natural product topoisomerase I inhibitors, 10-hydroxycamptothecin (HCPT) and camptothecin (CPT), in the treatment of human colon cancers. HCPT and CPT are indole alkaloids originally isolated from th. Chinese tree, Camptotheca acuminata. They have been shown to have a wide spectrum of anticancer activity both in vitro and in vivo. The use of these camptothecins, however, has been hampered by their water-insolubility. In the present study, following screening of their in vitro antitumor activity, we determined their in vivo antitumor effects using C.B-17-scid/scid mice bearing LS174T or DLD-1 xenografts. Tumor-bearing mice were treated with oral doses of HCPT (1, 3, or 6 mg/kg/day) or CPT (1 or 3 mg/kg/day), 5 days per week for 2 weeks (LS 174T) or 3 weeks (DLD-1). Growth of the xenografts was significantly inhibited by HCPT and CPT in a dose-dependent manner, with marked reductions in tumor mass occurring in those groups given HCPT at 6 mg/kg/day or CPT at 3 mg/kg/day. Pathologic examination confirmed the dose-dependent atrophy of the adenocarcinomas. In summary, this study demonstrates the potential use of water-insoluble camptothecins when given by the oral route for treatment of human colon cancer, and provides the basis for the design of future human trials with these anticancer drugs.

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