Metallothionein expression prevents apoptosis. II: Evaluation of the role of metallothionein expression on the chemotherapy-induced apoptosis during the treatment of acute leukemia

Metallothioneins (MT) are low molecular weight cysteine-rich proteins, pres ent in a wide variety of eukaryotes. Although their physiological function is not entirely understood, recently if was found that in vitro human MTs ( hMTs) expression prevents apoptosis. In the present study, the apoptosis pr eventing effect of hMTs is evaluated in vivo, in order to correlate the apo ptotic effect of chemotherapy during the treatment of acute leukemia with t he expression of hMTs. The expression of hMTs was studied immunocytochemica lly in bone marrow smears and peripheral blood cytocentrifugations of 47 ch ildren with acute leukemia at diagnosis and during treatment. Apoptosis was quantitatively studied in peripheral blood samples during the induction th erapy. Eighteen cases were found to be positive for hMTs expression at diag nosis and the mean apoptosis curve of these cases showed maximal effect on the second day of treatment, the apoptotic action of chemotherapy being com pleted on the tenth day. The mean apoptosis curve of the hMTs negative case s (29 cases) showed maximal effect on the first day of treatment and the ap optotic action of chemotherapy was completed on the sixth day. When conside ring the day on which the maximal apoptotic effect appeared and the day on which the apoptotic action of treatment was completed, the results indicate d retardation of the chemotherapy- induced apoptosis dependent on hMTs expr ession as a result of resistance to treatment. Furthermore, the study of hM Ts expression during treatment, showed that although the apoptotic action o f chemotherapy eliminates blast cells, a cell population positive for hMTs survived and increased during treatment, since they were able to escape apo ptotic cell death. These findings, indicated that in vivo, hMTs constitute a cellular protective mechanism preventing chemotherapy-induced apoptosis t hus regulating the response of patients to treatment.