Tissue-specific induction of metallothionein by bismuth as a promising protocol for chemotherapy with repeated administration of cis-diamminedichloroplatinum (II) against bladder tumor.

The effects of bismuth nitrate pretreatment on the toxicity and antitumor activity of repeatedly administered cis-diamminedichloroplatinum (Cisplatin; CDDP) were examined using nude mice inoculated with human bladder tumor tissues. Lethal and renal toxicities exerted by the repeated administration of CDDP were effectively prevented by pretreatment with bismuth (Bi) without affecting its antitumor activity against transplanted human bladder tumor as in the case of single dose of the drug reported previously. The renal Bi level was gradually increased with the frequency of Bi administration, and metallothionein (MT) induced by Bi in the kidneys maintained its substantially high level during the treatment. It was confirmed that MT was not induced in the tumors even by the 5 cycles of repeated Bi administration. This specific protection shown by the Bi preadministration against the toxicity of repeatedly injected CDDP can be explained by the fact that Bi markedly induces MT in the kidney, a major target organ of CDDP toxicity, but not in the tumor tissues inoculated in the nude mice, probably because Bi is efficiently taken up by the kidney but hardly incorporated into the tumor tissues as reported previously. These data obtained by repeated doses of CDDP as described above strongly suggest a promising protocol for chemotherapy using CDDP with Bi compounds, a tissue specific MT inducer, against advanced bladder tumor in human.