Protective function of metallothionein against certain anticancer agents

The possible role of metallothioneins (MT) in the cellular protection against ionizing radiation and alkylating agent cytotoxicity has been investigated by the use of cultured cells with either low or high levels of MT. The cytotoxic activity of the drugs cis-dichlorodiammineplatinum (cis-DDP), chlorambucil and prednimustine was reduced 1,5-3 fold in cells containing high levels of MT, and furthermore about 70% of platinum and 30% chlorambucil was shown to be associated with the protein. Increased resistance was also demonstrated in MT-rich cells during exposure to ionizing radiation. Evidence that MT also may play a role in vivo as a resistance mechanism, was provided in studies of tumors derived from either the MT-rich or MT-poor cells which had been inoculated in nude mice. During treatment of the animals with cis-DDP, the MT-rich tumors exhibited a significant degree of resistance. These results indicate that MT may play an important role in the intrinsic protection of cells against these agents, and raises the question whether it also may be a factor in the acquired resistance of tumors against chemotherapy.