Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties

Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) w ith a seven-membered beta-hydroxylactone resulting from the insertion of a methylene spacer between the alcohol moiety and the carboxyl function of th e naturally occurring six-membered alpha-hydroxylactone of CPT, This E-ring modification provides a less reactive lactone with enhanced stability and decreased protein binding in human plasma. Biological testing against CPT r evealed that, instead of being detrimental, the modified lactone of hCPT ha s a positive impact on topoisomerase I (Topo I) poisoning properties. In,vi tro tests showed hCPT to fully conserve the ability to stabilize Topo I-DNA cleavage complexes and to stimulate a higher level of DNA cleavage than CP T, A similar trend toward improvement Has also observed,ed in antiprolifera tive assays with human tumor cell Lines (including cells overexpressing P-g lycoprotein). In two distinct in vitro models, using L1210 murine leukemia or human colon carcinoma HT29, hCPT,t as found to be more efficacious than CPT. The slow, but irreversible, hydrolysis of hCPT, instead of the fast eq uilibrium of CPT, may account for its good in vivo activity. Overall, these results provide evidence that a highly reactive lactone is not a requisite for the Topo I-mediated antitumor activity of CPT analogues, and that hCPT is an interesting pharmacological tool with improved solution behavior as well as a promising new template for the preparation of more efficacious To po I poisons.