Effect of 6(5H)-phenanthridinone, a poly (ADP-ribose)polymerase inhibitor, and ionizing radiation on the growth of cultured lymphoma cells.
The ability of 6(5H)-phenanthridinone (Phen), a new potent poly(ADP-ribose)polymerase (PARP) inhibitor, to potentiate the effect of ionizing radiation on tumour cells was evaluated. RDM4 murine lymphoma cells were irradiated using a 60Co panoramic source and then examined for their growth, cell cycle distribution and apoptosis. Phen (100 microM) was found to inhibit more than 90% of the PARP activity in control and irradiated cells. Cell proliferation was assessed using Alamar Blue, a new fluorometric assay. Phen was found to sharply increase the radiation-induced inhibition of cell proliferation. Indeed, at 2.5 Gy the relative cell number of Phen-treated cells was 60% below control levels. At the same radiation dose, the G2M arrest was also significantly reinforced by the addition of Phen. Furthermore, this PARP inhibitor was shown to significantly increase the amount of DNA fragmentation as revealed by the DNA migration pattern in agarose gel electrophoresis. Comparable results were obtained with 3-aminobenzamide, another PARP inhibitor, but at concentrations 200-fold higher. Taken together, these results indicate the potential interest of Phen as a valuable pharmacological probe for investigating the role of PARP in cellular responses to radiation. They also suggest a possible use of Phen as an adjuvant in radiotherapy.
Weltin
D
D
Laboratoire de Cancérologie Expérimentale et de Radiobiologie, Institut d'Hématologie et d'Immunologie, Faculté de Médecine, Strasbourg, France.
Holl
V
V
Hyun
J W
JW
Dufour
P
P
Marchal
J
J
Bischoff
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008223:Lymphoma / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008806:Mice, Inbred AKR; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C040601:phenanthridone