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Intoplicine (RP 60475) and Its Derivatives, a New Class of Antitumor Agents Inhibiting Both Topoisomerase I and II Activities

Rhône-Poulenc Rorer S.A., Unité de Cancérologie, Département Biologie, Centre de Recherche de Vitry-Alfortville, 94403 Vitry-sur-Seine Cedex, France [J.-F. R., M-C. B., L. G., F. L.]; Laboratoire de Biochimie-Enzymologie, CNRS URA 147, INSERM U140, Institut Gustave Roussy, 94805 Villejuif Cedex, France [P. F., A. K. L., J-M. S.]; and CNRS URA 1387, Synthèse Organique, Institut Curie, section de Biologie, 91405 Orsay Cedex, France [C. H. N., E. B.]

Intoplicine (RP 60475, NSC 645008) is an antitumor derivative in the 7H-benzo[e]pyrido[4,3-b]indole series which is now being tested in clinical trials. Intoplicine strongly binds DNA (K_A = 2 x 10⁵ M^–1) and thereby increases the length of linear DNA. These properties are consistent with DNA unwinding by intoplicine. Intoplicine was found to be a dual topoisomerase I and II inhibitor, with DNA sites of enzyme inhibition being different for these two enzymes. In this study, 22 analogues of intoplicine were evaluated for their effects on topoisomerase I- and II-mediated DNA cleavage reactions by using enzymes purified from calf thymus. Site-specific DNA cleavage mediated by topoisomerase I was observed with 7H-benzo[e]pyrido[4,3-b]indole derivatives but not with 11H-benzo[g]pyrido[4,3-b]indole derivatives. Site-specific DNA cleavage mediated by topoisomerase II occurred with derivatives having hydroxyl groups at the 3-position on the 7H-benzo[e]pyrido[4,3-b]indole ring or at the 4-position on the 11H-benzo[g]pyrido[4,3-b]indole ring. Study of the relationships between the in vivo antitumor activity on P388 leukemia and the topoisomerase I- and/or II-mediated DNA cleavage activity revealed that the most highly active antitumor compounds possessed both topoisomerase I- and II-inhibitory properties. Compounds selectively inhibiting either topoisomerase I or II were less active. These results suggest that dual topoisomerase I and II inhibition is critical for the antitumor activity of this new series of antitumor compounds.

¹ To whom requests for reprints should be addressed, at Rhône-Poulenc Rorer S.A., CRVA 14, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cedex, France.

Received 3/17/93. Accepted 10/ 8/93.

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