DIFFERENTIAL TOXICITY OF CAMPTOTHECIN, TOPOTECAN AND 9-AMINOCAMPTOTHECIN TO HUMAN, CANINE, AND MURINE MYELOID PROGENITORS (CFU-GM) IN-VITRO

Purpose: 20(S)-Camptothecin (CAM), topotecan (TPT, active ingredient i n Hycamtin) and 9-amino-20(S)camptothecin (9AC) are topoisomerase I in hibitors that cause similar dose-limiting toxicities to rapidly renewi ng tissues, such as hematopoietic tissues, in humans, mice, and dogs. However, dose-limiting toxicity occurs at tenfold lower doses in human s than in mice. The purpose of the current study was to determine whet her hematopoietic progenitors of the myeloid lineage from humans, mice , and dogs exhibit the differential sensitivity to these compounds tha t is evident in vivo. Methods: Drug-induced inhibition of in vitro col ony formation by a myeloid progenitor in human, murine, and canine mar row colony-forming unit-granulocyte/macrophage (CFU-GM) provided the b asis for interspecies comparisons at concentrations which inhibited co lony formation by 50% (IC50) and 90% (IC90). Results: Murine IC90 valu es were 2.6-, 2.3-, 10-, 21-, 5.9-, and 11-fold higher than human valu es for CAM lactone (NSC-94600) and sodium salt (NSC-100880), TPT (NSC- 609699), and racemic (NSC-629971), semisynthetic and synthetic prepara tions (NSC-603071) of 9AC, respectively. In contrast, canine IC90 valu es were the same as, or lower than, the human IC90 values for all six compounds. Conclusions: The greater susceptibility of humans and dogs to the myelotoxicity of camptothecins, compared to mice, was evident i n vitro at the cellular level. Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of TPT and 9AC in mice with human tumor xenografts are not achievable in pati ents. Realizing the curative potential of these compounds in humans wi ll require the development of therapies to increase drug tolerance of human CFU-GM at least to a level equal to that of murine CFU-GM. Becau se these interspecies differences are complicated by species-specific effects of plasma proteins on drug stability, not all in vitro assay c onditions will yield results which can contribute to the development o f such therapies.