Assessment of toxicity of bis-platinum complexes in hypoxic and aerobic cells

There is considerable interest in the bis-platinum series of complexes as potential chemotherapeutic agents, due to their activity in cisplatin-resistant lines and in various tumor types. Our interest in their hypoxic selectivity stems from the fact that cisplatin exhibits greater cytotoxicity in hypoxic than aerobic cells. Unlike nitroaromatics, quinones, tirapazamine and many other hypoxia selective agents, a 'bioreductive' moiety cannot explain these observations. We hypothesized that DNA-protein cross-links (D-P) might play a role in the mechanism. Bis-platinum complexes have variable cross-linking potentials, and their toxicities were assessed in air or hypoxia in CHO cells. Of the three classes examined, only those from the 2,2/cis,cis series show greater hypoxic selectivity than cisplatin. These have greater potential for cross-links than cisplatin, being potentially bifunctional at each platinum, with the two leaving groups (X) in the cis position, and with variable distance (n) between the platinum centers: cis-[(PtX2(NH3))2H2N(CH2)nNH2]. Cellular platinum accumulation and DNA binding were also measured, and like cisplatin, results are consistent with a more toxic lesion formed in hypoxia. Lower hypoxic selectivity in the UV20 cell line may reflect an inability to excise the relevant lesion. These results support the D-P hypothesis. Further support comes from a 1,1/trans,trans complex which does not form D-P and which exhibited the reverse behavior to 2,2/cis,cis or cisplatin, i.e. higher toxicity in aerobic than in hypoxic cells. This study examines the possibility of an additional mechanism of selection for hypoxic toxicity involving DNA-protein cross-links.