ORAL PLATINUM ANALOG JM216, A RADIOSENSITIZER IN OXIC MURINE CELLS

This study was designed to compare radiosensitization by the oral plat inum compound JM216 with cisplatin. RIF1 mouse tumour cells were treat ed al various doses and at various exposure times with JM216 and irrad iated 15 min before the end of drug exposure. The fraction of cells su rviving treatment was assessed by colony formation. Results were compa red with those for equivalent treatments with cisplatin. JM216 alone s howed exponential killing of RIF1 cells, being approximately three tim es less efficient than cisplatin on a molar basis. For radiosensitizat ion studies, drug doses used gave approximately 50 or 90% cell killing alone. No radiosensitization was seen after 2-h drug exposures, but s ignificant radiosensitization occurred after 1- and 0.5-h exposures (s horter times required proportionally higher drug doses, giving equival ent drug kill). The enhancement ratio and time dependence were similar for the two platinum compounds, reaching 1.5 at the highest concentra tions tested. Drug-DNA adduct formation was assessed using immunocytoc hemistry with the NKI-A59 antiserum raised to cisplatin-DNA adducts. T he antiserum was shown to recognize JM216-DNA adducts in a dose-depend ent manner and maximum nuclear staining was found to be correlated wit h cell kill for both drugs. However, neither the level of staining at the time of irradiation nor at the time of maximum adducts correlated with radiosensitization, indicating that the number of DNA adducts did not determine radiosensitization. Intracellular glutathione levels we re shown to be decreased by the drug, but only by approximately 50%, i mplying that this was not the cause of the increased radiosensitivity. In summary, JM216 was shown capable of radiosensitizing a platinum-se nsitive tumour line to an extent similar to cisplatin. Radiosensitizat ion was exposure-time and drug-concentration dependent, but was not de pendent on DNA adduct levels nor glutathione depletion. In contrast, c ell kill after drug alone was well correlated with adduct levels. Thes e data suggest that JM216 could replace cisplatin in combined radiothe rapy-chemotherapy studies, and also indicate that the NKI-A59 antibody could be used to monitor exposure levels in vivo.