title: Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase I and II activities.
abstract: 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 (KA = 2 x 10(5) 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.
authors.affiliation: Rhône-Poulenc Rorer S.A., Département Biologie, Vitry-sur-Seine Cedex, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Riou
authors.forename: P
authors.initials: P
authors.lastname: Fossé
authors.forename: C H
authors.initials: CH
authors.lastname: Nguyen
authors.forename: A K
authors.initials: AK
authors.lastname: Larsen
authors.forename: M C
authors.initials: MC
authors.lastname: Bissery
authors.forename: L
authors.initials: L
authors.lastname: Grondard
authors.forename: J M
authors.initials: JM
authors.lastname: Saucier
authors.forename: E
authors.initials: E
authors.lastname: Bisagni
authors.forename: F
authors.initials: F
authors.lastname: Lavelle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; C081834:intoplicine