Modulation of adriamycin toxicity by tissue-specific induction of metallothionein synthesis in mice

The effect of tissue specific induction of metallothionein (MT) by preadmin istration of metal compounds on the antitumor activity and adverse effects of adriamycin (ADR) was examined using mice bearing colon 38 adenocarcinoma . Significant increase in MT concentration was observed in the heart and bo ne marrow but not in the tumor tissue of the mice given bismuth (Bi) compou nd. Copper (Cu) increased MT in the tumor tissue but did not induce MT eith er in bone marrow or in the heart, whereas zinc (Zn) increased MT level in the heart and bone marrow as well as in the tumor tissue. ADR exerted cardi otoxicity, indicated by increase in lipid peroxidation in the heart, bone m arrow toxicity, indicated by decrease in number of peripheral leukocytes, a nd antitumor activity, assessed by reduction of tumor weight, in tumor-bear ing mice untreated with MT inducing metal compounds. Preadministration of B i significantly reduced the cardiotoxicity and bone marrow toxicity without compromising the antitumor activity of ADR. Cu pretreatment did not affect the extent of cardiotoxicity and bone marrow toxicity but significantly su ppressed the antitumor effect. Pretreatment with Zn markedly reduced not on ly the adverse side effects but also the antitumor activity. The results de scribed above suggest that ADR toxicity can be attenuated in the tissues in which the MT level was elevated and that the: tissue specific induction of MT synthesis may provide a promising regimen for cancer chemotherapy. (C) 2000 Elsevier Science Inc. All rights reserved.