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Modulation of Both Cisplatin Nephrotoxicity and Drug Resistance in Murine Bladder Tumor by Controlling Metallothionein Synthesis¹

Department of Public Health, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan [M. S., A. N., N. I.], and Department of Pathology, Health Sciences Center [M. S., D. M. K., M. G. C.] and Department of Surgery, University Hospital [S. A. K., J. L. C.], University of Western Ontario, London, Ontario, N6A 5C1, Canada

The role of metallothionein (MT) in cisplatin (cis-DDP) resistance and renal toxicity was investigated in C3H mice inoculated with mouse bladder tumor (MBT-2). C3H mice were inoculated s.c. with 1 x 10⁶ MBT-2 cells/mouse on day 0. Mice were given injections of propargylglycine (PPG) (500 µmol/kg s.c.) once a day for 3 days from day 7 to day 9 and with ZnSO₄ (200 µmol/kg s.c.) once a day for 2 days from day 8 to day 9. cis-DDP (50 µmol/kg i.p.) was administered 10 days after MBT-2 cell inoculation. Since MT contents in the tumor and kidneys were significantly increased by administration of ZnSO₄, both the antitumor activity of cis-DDP and its renal toxicity were reduced. However, coadministration of PPG reduced MT induction in tumor without affecting the level of renal MT. As a result, PPG could clearly overcome the MT-mediated cis-DDP resistance of tumors without compromising the protective effect exerted by renal MT on nephrotoxicity of the drug. It was suggested, therefore, that PPG may be a promising adjunct in cancer chemotherapy to overcome the drug resistance of tumors caused by the elevated level of MT.

¹ Supported by Grant-in-Aid 03258238 for Special Project Research, Cancer-Bioscience, from the Ministry of Education, Science, and Culture, Japan.

² To whom requests for reprints should be addressed.

Received 4/27/92. Accepted 2/11/93.

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