Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition.
OBJECTIVE
To test for in vitro radiopotentiation by the orally-administered platinum (IV) complex, JM216; to compare these results to cisplatin and carboplatin; and to investigate whether the mechanism of radiopotentiation involves repair inhibition of radiation-induced DNA damage.


METHODS
H460 human lung carcinoma cells were incubated with the drugs for 1 h at 37 degrees C, irradiated at room temperature, and returned to 37 degrees C for 20 min. Cells were then rinsed and colony forming ability was assessed. Wild-type V79 Chinese hamster cells and radiosensitive, DNA repair-deficient mutant cells (XR-V15B) were also studied along with H460 cells. Ku86 cDNA, which encodes part of a protein involved in DNA repair, was transfected into XR-V15B cells as previously described. The effect of JM216 on sublethal damage repair (SLDR) was also assessed using split-dose recovery.


RESULTS
Using equally cytotoxic doses of JM216, cisplatin, and carboplatin, the radiation dose enhancement ratios (DER) were 1.39, 1.31, and 1.20, respectively; the DER with 20 microM JM216 was 1.57. JM216 (20 microM) did not significantly change the final slope of radiation survival curves, but greatly reduced the survival curve shoulder. V79 cells also showed radioenhancement using 20 microM JM216, but no enhancement occurred using XR-V15B cells. Transfection of Ku86 cDNA into XR-V15B cells restored radiopotentiation by JM216 to wild-type V79 levels. In addition, 20 microM JM216 completely inhibited sublethal damage repair in H460 cells.


CONCLUSIONS
Our results show that JM216 can potentiate the effects of radiation in human lung cancer cells, and that the mechanism of this effect is probably inhibition of DNA repair by JM216.
Amorino
G P
GP
Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Freeman
M L
ML
Carbone
D P
DP
Lebwohl
D E
DE
Choy
H
H
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011853:Radiobiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; C081294:satraplatin; D016190:Carboplatin; D002945:Cisplatin