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Preclinical Antitumor Activity of a New Vinca Alkaloid Derivative, S 12363

Institut de Recherches Servier, Division de Cancérologie Expérimentale, 11 rue des Moulineaux, Suresnes, France [A. P., L. K-B., G. L.]; Université Libre de Bruxelles, Laboratoire de Pharmacologie, Boulevard du Triomphe, 1050 Bruxelles, Belgique [G. A.]; CNRS, Laboratoire de Pharmacologie et de Toxicologie Fondamentales, 205 route de Narbonne, 31078 Toulouse, France [S. C.]; CNRS, Institut de Recherches sur le Cancer, 7 rue Guy Moquet, 94802 Villejuif, France [M-F. P.]; Institut de Recherches Internationales Servier, 6 place des Pléades, 92415 Courbevoie Cedex, France [M. B., J-P. B.]

S 12363 is a new Vinca alkaloid derivative obtained by appending an optically active -aminophosphonate at the C₂₃ position of O⁴-deacetyl vinblastine. S 12363 was evaluated for cytotoxic and antitumor activity against a spectrum of murine and human tumors. This compound was, respectively, on average, 72- and 36-fold more cytotoxic than were vincristine and vinblastine, when tested on a panel of 2 murine and 37 human tumor cell lines using the microculture tetrazolium assay. S 12363 exhibited significant antitumor activity against murine transplantable tumors (i.p. and s.c. P388 leukemia, i.p. L1210 leukemia, i.p. and i.v. B16 melanoma, i.p. M5076 sarcoma, and s.c. colon adenocarcinoma 38), while no activity was observed on s.c. Lewis lung carcinoma. S 12363, when administered i.p., showed moderate activity on human NCI-H460 lung and PANC-1 pancreas tumor xenografts in nude mice. However, when it was administered i.v., it exerted a significant activity against human HT-29 colon, NCI-H460 lung, NCI-H125 lung, PANC-1 pancreas, and A-431 vulvar tumor xenografts. S 12363 was also active in vivo against a P388 leukemia subline resistant to vincristine. On the in vivo panel of tumors used in this study, S 12363 was at least as active as reference compounds, while its optimal dosage was 10- to 40-fold lower than that of vinblastine, depending on the models studied. The effects of schedule and route of administration on the antitumor activity of S 12363 were studied in both i.p. inoculated P388 leukemia and B16 melanoma, in which the activity was improved by single and intermittent treatment (Days 1, 8, and 15) and i.p. route. S 12362, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 300-fold less cytotoxic and 1000-fold less potent in vivo than was S 12363. These results suggest that S 12363 could present a therapeutic advantage over its congeners and deserves further pharmacological evaluations.

¹ To whom requests for reprints should be addressed.

Received 11/ 9/90. Accepted 2/19/91.

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