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Metallothionein Induction and Deinduction in Human Prostatic Carcinoma Cells: Relationship with Resistance and Sensitivity to Adriamycin¹

Division of Urology, Department of Surgery [M. M. W., S. M. M. R., G. T. J.], and Department of Biochemistry, Biophysics, and Genetics [M. M. W.], University of Colorado Health Sciences Center, Denver, Colorado 80262

Human prostate carcinoma cell line DU-145 was used to examine the relationship between the intracellular levels of cysteine-rich metallothionein (MT) and the sensitivity or resistance of cells to Adriamycin (ADR). The basis for the poor response of human prostate carcinomas to ADR was studied. Cadmium-resistant (Cd^r) cells, capable of growth in 10^-5 M cadmium, were derived from DU-145 cadmium-sensitive (Cd^s) cells, by exposure to increasing concentrations of cadmium. The relative rates of MT synthesis were measured by L-[³⁵S]cysteine incorporation and MT separation by high-performance liquid chromatography. Cd^r cells, continuously exposed to cadmium, show a steady-state rate of MT synthesis (designated as control = 100%) which is 3.5 times the basal rate in Cd^s cells (29%). Dose-response curves, using clonal and cell count assays, show that the dose levels required to produce inhibition of growth to 50% and 90% of control, respectively, of ADR for Cd^r cells (19.00 and 132.0 ng/ml) are 1.5 to 1.7 times those for Cd^s cells (12.5 and 77.5 ng/ml). In the absence of cadmium, deinduction of MT occurs with MT synthesis declining, after 70 and 118 h, to 29% and 19% of control. Correspondingly, in such deinduced cells (Cd^r minus cadmium), the 50% inhibitory doses of ADR in clonal and growth assays are 3.5 and 4.8 ng/ml, respectively. Thus, deinduced cells are 3 and 4 times more sensitive to ADR than Cd^s and Cd^r cells. This increased sensitivity is explained by the rapid and marked inhibition of MT synthesis upon exposure to ADR, even in the presence of cadmium, so that after 6 and 10 h in the presence of 10 ng/ml of ADR, the rates drop to 62% and 19% of control. On the basis of these results, we propose that: (a) the increased levels of MT increase the resistance of Cd^r cells to ADR and that this may be partly responsible for the poor response of prostate carcinomas to ADR; (b) MT deinduction results in increased sensitivity to ADR; and (c) ADR inhibits MT synthesis. Thus, it is suggested that a treatment regimen consisting of ADR exposure followed by a second exposure, during increased ADR sensitivity, may be effective for growth inhibition of slow-growing prostatic carcinomas.

¹ Supported in part by USPHS Grants CA-33169 and CA-34308 from the National Cancer Institute, Department of Health and Human Services, and by a grant from the Center for Alternatives to Animal Testing, The Johns Hopkins School of Hygiene and Public Health.

² To whom requests for reprints should be addressed, at Division of Urology, University of Colorado Health Sciences Center, Box C-319, 4200 East 9th Avenue, Denver, CO 80262.

Received 9/21/87. Revised 4/19/88. Accepted 5/ 4/88.

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