Characterization of the biological and biochemical activities of F 11782 and the bisdioxopiperazines, ICRF-187 and ICRF-193, two types of topoisomerase II catalytic inhibitors with distinctive mechanisms of action.
F 11782 is a newly identified catalytic inhibitor of topoisomerases I and II, without any detectable interaction with DNA. This study aimed to establish whether its catalytic inhibition of topoisomerase II was mediated by mechanisms similar to those identified for the bisdioxopiperazines. In vitro combinations of F 11782 with etoposide resulted in greater than additive cytotoxicity in L1210 cells, contrasting with marked antagonism for combinations of etoposide with either ICRF-187 or ICRF-193. All three compounds caused a G2/M blockade of P388 cells after an 18-h incubation, but by 40 h polyploidization was evident only with the bisdioxopiperazines. Gel retardation data revealed that only F 11782, and not the bisdioxopiperazines, was capable of completely inhibiting the DNA-binding activity of topoisomerase II, confirming its novel mechanism of action. Furthermore, unlike ICRF-187 and ICRF-193, the cytotoxicity of F 11782 appeared mediated, at least partially, by DNA damage induction in cultured GCT27 human teratoma cells, as judged by a fluorescence-enhancement assay and monitoring p53 activation. Finally, the major in vivo antitumor activity of F 11782 against the murine P388 leukemia (i.v. implanted) and the B16 melanoma (s.c. grafted) contrasted with the bisdioxopiperazines' general lack of activity. Overall, F 11782 and the bisdioxopiperazines appear to function as quite distinctive catalytic topoisomerase II inhibitors.
van Hille
B
B
Division de Cancérologie, Centre de Recherche Pierre Fabre, Castres, France.
Etiévant
C
C
Barret
J M
JM
Kruczynski
A
A
Hill
B T
BT
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D054659:Diketopiperazines; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011714:Pyrans / Q000008:administration & dosage / Q000494:pharmacology*; D011929:Razoxane / Q000008:administration & dosage / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D010879:Piperazines; D011714:Pyrans; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D011929:Razoxane; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; C405744:tafluposide