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Homocamptothecin, an E-Ring Modified Camptothecin with Enhanced Lactone Stability, Retains Topoisomerase I-targeted Activity andAntitumor Properties¹

Institut Henri Beaufour, F-91966 Les Ulis, France [L. L-G., D. D., J. C., O. L., D. C. H. B]; Biomeasure Inc., Milford, Massachusetts 01757 [P. G. K.]; Laboratoire d’Histologie, Faculté de Médecine, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium [R. K.]; and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, Institut National de la Santée et de la Recherche Médicale U-524, Institut de la Recherche sur le Cancer de Lille, F-59045 Lille, France [L. D., C. B.]

Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) with a seven-membered ß-hydroxylactone resulting from the insertion of a methylene spacer between the alcohol moiety and the carboxyl function of the naturally occurring six-membered -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 revealed that, instead of being detrimental, the modified lactone of hCPT has a positive impact on topoisomerase I (Topo I) poisoning properties. In vitro 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 CPT. A similar trend toward improvement was also observed in antiproliferative assays with human tumor cell lines (including cells overexpressing P-glycoprotein). In two distinct in vivo models, using L1210 murine leukemia or human colon carcinoma HT29, hCPT was found to be more efficacious than CPT. The slow, but irreversible, hydrolysis of hCPT, instead of the fast equilibrium 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 Topo I poisons.

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