Tumours from a cell strain with a high content of metallothionein show enhanced resistance against cis-dichlorodiammineplatinum.
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. In order 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 subcutaneously into nude mice (24 animals in each group), and tumour growth was compared during cis-DDP treatment. Animals in the treatment groups received 3 intravenous 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 tumours derived from the parent cells, as well as from the MT-rich variant. However, following the injections with 4 mg/kg of cis-DDP, tumour volume was reduced by approximately 80% in tumours from the parent cells, whereas the tumours from MT-rich cells were almost completely resistant. This study provides for the first time evidence that metallothionein-conferred protection against cis-DDP toxicity also is mediated in tumours in vivo.
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
D002104:Cadmium; D008668:Metallothionein; D002945:Cisplatin