Tumours from a Cell Strain with a High Content of Metallothionein Show Enhanced Resistance against Cis-Dichlorodiammineplatinum

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Abstract
Cultured cells with a high content of the extremely cysteine-rich protein metallothionein (MT) have previously been shown to exhibit resistance when exposed to otherwise lethal doses of cis-dichlorodiammineplatinum (cis-DDP), chlorambucil or prednimustine, and to have a significant proportion of intracellular drug associated with MT after such treatment. To study this protective mechanism in vivo, cells from a MT-rich variant of a murine fibroblast line resistant to cis-DDP and its parent sensitive line with only trace amounts of MT were injected s.c. into nude mice (24 animals in each group), and tumor growth was compared during cis-DDP treatment. Animals in the treatment groups received 3 i.v. doses of either 4 mg/kg or 8 mg/kg of cis-DDP on day 12, 26 and 33 after inoculation of cells, whereas the control groups received saline. The 8 mg/kg dose produced an almost complete growth inhibition of the tumors derived from the parent cells, as well as from the MT-rich variant. Following the injections with 4 mg/kg of cis-DDP, tumor volume was reduced by approximately 80% in tumors from the parent cells, whereas the tumors from MT-rich cells were almost completely resistant. Metallothionein-conferred protection against cis-DDP toxicity evidently is mediated in tumors in vivo.