Antitumor activity and pharmacokinetics following oral administration of natural product DNA topoisomerase I inhibitors 10-hydroxycamptothecin and camptothecin in SCID mice bearing human breast cancer xenografts

Academic Article

Abstract

  • The DNA topoisomerase I inhibitors, 10-hydroxy-camptothecin (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 in vitro inhibitory effect on tumor growth was observed with breast cancer cell line MDA-MB-468. The HI vivo antitumor effects were then determined using severe combined immunodeficient (SCID) mice bearing MDAMB-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 pharmacokinctics of HCPT and CPT were determined in tumor-bearing SCID mice following i.v. or oral administration of 3H-HCPT or 3H-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.
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    Author List

  • Zhang R; Cai Q; Russell Lindsey J; Li Y; Chambless B; Naguib FNM
  • Start Page

  • 1147
  • End Page

  • 1156
  • Volume

  • 10
  • Issue

  • 6