Modulation of the antiproliferative activity of anticancer drugs in hematopoietic tumor cell lines by the poly(ADP-ribose) polymerase inhibitor 6(5H)-phenanthridinone.
Poly (ADP-ribose) polymerase (PARP) is involved in the cellular responses to genotoxic damage and its inhibition has been proposed as potentiating anticancer drug activity. Here, we evaluated the ability of the PARP inhibitor, 6(5H)-phenanthridinone, to modulate the antiproliferative activity of bleomycin, carmustin and doxorubicin in a murine (RDM4) and a human (U937) lymphoma cell lines. 6(5H)-phenanthridinone was shown to suppress PARP activity with the same potency in both cell lines. At 25 microM, this compound potentiated the activity of carmustin in RDM4 but not in U937 cells. In contrast, 6(5H)-phenanthridinone failed to affect the doxorubicin toxicity in murine lymphoma cells, whereas it prevented the cytotoxicity of this drug in the human cell line. Altogether, these findings indicated that 6(5H)-phenanthridinone modulates the cytotoxicity of anticancer agents differently according to the cell type and the drug. Therefore, this PARP inhibitor could be considered as the prototype of a new class of adjuncts in cancer chemotherapy.
Holl
V
V
Laboratoire de Cancérologie Expérimentale et de Radiobiologie (LCER), Université Louis Pasteur, Faculté de Médecine, Strasbourg, France.
Coelho
D
D
Weltin
D
D
Hyun
J W
JW
Dufour
P
P
Bischoff
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001761:Bleomycin / Q000378:metabolism / Q000494:pharmacology*; D002330:Carmustine / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004336:Drug Antagonism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008223:Lymphoma; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D001761:Bleomycin; D004317:Doxorubicin; C040601:phenanthridone; D011065:Poly(ADP-ribose) Polymerases; D002330:Carmustine