ANTITUMOR-ACTIVITY AND PHARMACOKINETICS FOLLOWING ORAL-ADMINISTRATIONOF NATURAL PRODUCT DNA TOPOISOMERASE-I INHIBITORS 10-HYDROXYCAMPTOTHECIN AND CAMPTOTHECIN IN SCID MICE BEARING HUMAN BREAST-CANCER XENOGRAFTS

The DNA topoisomerase I inhibitors, 10-hydroxycamptothecin (HCPT) and camptothecin (CPT), are indole alkaloids isolated from the Chinese tre e, Camptotheca acuminata. They have been shown to have a wide spectrum of anticancer activity both in vitro and in vivo. However, their use has been limited due to their water-insolubility. The purpose of the p resent study was 2-fold, to determine the in vitro and in vivo activit y of HCPT and CPT against human breast cancer and to determine the pha rmacokinetics of the two drugs to better understand how they can best be used therapeutically. The bl vitro inhibitory effect on tumor growt h was observed with breast cancer cell line MDA-MB-468. The in vivo an titumor effects were then determined using severe combined immunodefic ient (SCID) mice bearing MDA-MB-468 xenografts. The tumor-bearing mice were orally administered HCPT (1, 3, 6, 9 mg/kg/day, 5 days per week) or CPT (1, 3, 6 mg/kg/day, 5 days per week) for 3 weeks. Growth of th e MDA-MB-468 cells was inhibited by HCPT and CPT in vitro and in vivo in a dose-dependent manner. Complete regression of the tumor xenograft s, determined by tumor measurement and microscopic examination, occurr ed in the groups of animals treated with doses of HCPT or CPT of 3 mg/ kg/day or more. In general, HCPT was more effective and less toxic tha n CPT. To determine the potential mechanisms for the pharmacologic dif ferences, the comparative pharmacokinetics of HCPT and CPT were determ ined in tumor-bearing SCID mice following i.v. or oral administration of H-3-HCPT or H-3-CPT. Parent drugs and their metabolites in plasma, urine, feces, and various tissues were quantified by a recently develo ped reversed-phase HPLC method. Significant absorption of both HCPT an d CPT was observed after oral administration, with CPT having a higher bioavailability. HCPT and CPT were distributed widely into various ti ssues including the tumor, enterohepatic system, kidneys, and bone mar row. These studies indicate that HCPT and CPT are of potential use in treatment of breast cancer, providing the basis for the design of futu re human trials with these anticancer drugs.