The
DNA topoisomerase I inhibitors,
10-hydroxycamptothecin (
HCPT) and
camptothecin (
CPT), are
indole alkaloids isolated from the Chinese tree, 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 present study was 2-fold, to determine the in vitro and in vivo activity of
HCPT and
CPT against human
breast cancer and to determine the pharmacokinetics of the two drugs to better understand how they can best be used therapeutically. The bl vitro inhibitory effect on
tumor growth was observed with
breast cancer cell line MDA-MB-468. The in vivo antitumor effects were then determined using severe combined immunodeficient (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 the 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 xenografts, determined by
tumor measurement and microscopic examination, occurred 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 than
CPT. To determine the potential mechanisms for the pharmacologic differences, the comparative pharmacokinetics of
HCPT and
CPT were determined 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 developed reversed-phase HPLC method. Significant absorption of both
HCPT and
CPT was observed after
oral administration, with
CPT having a higher bioavailability.
HCPT and
CPT were distributed widely into various tissues including the
tumor, enterohepatic system, kidneys, and bone marrow. These studies indicate that
HCPT and
CPT are of potential use in treatment of
breast cancer, providing the basis for the design of future human trials with these anticancer drugs.