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cis-Diamminedichloroplatinum(II) Resistance in Vitro and in Vivo in Human Embryonal Carcinoma Cells¹

Division of Medical Oncology, Department of Internal Medicine [H. T-B., C. M., E. G. E. d. V., N. H. M.], and Departments of Pathology [A. T.] and Medical Genetics [B. d. J.], University Hospital, Gronogen, and Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

² To whom requests for reprints should be addressed, at Division of Medical Oncology, Department of Internal Medicine, University Hospital, Oostersingel 59, 9713 EZ Groningen, the Netherlands.

In the embryonal carcinoma cell line Tera and its 3.7-fold cis-diamminedichloroplatinum(ll) (CDDP)-resistant subline, Tera-CP, parameters were studied that might have changed in relation to induction of CDDP resistance. Phenotypes of both lines were embryonal carcinoma. Karyotypes were related with a decreased mean number of chromosomes and fewer copies of the short arm of chromosome 12 in Tera-CP. Tera-CP showed cross-resistance for melphalan and 4-hydroperoxycyclophosphamide and had an 1.4-fold increased glutathione (GSH) level, a 1.5-fold increased glutathione 5-transferase (GST) activity, and a 1.4-fold increased GST expression compared to Tera. Tera-CP was cross-resistant to 5-fluorouracil, but thymidylate synthase activity was not increased. Topoisomerase I and II activities and c-myc RNA and protein expression were the same in both lines. Platinum accumulation was equal in both lines, and platinum-DNA binding was lower in Tera-CP than in Tera. Both cell lines were xenografted into nude mice and tumors showed marked differentiation. Tera-CP tumors were 2.8-fold resistant to CDDP compared to Tera tumors. In new cell lines derived from xenografts of Tera and Tera-CP CDDP sensitivity, GST activity and GSH level corresponded with their sensitivity and resistant origin. Tera-CP is a model of in vitro and in vivo CDDP resistance with the GSH/GST detoxifying system as an important mechanism. CDDP resistance could be induced without a concomitant increase in differentiation.

¹ Supported by Grants GUKC 88-11 and 90-18 from the Dutch Cancer Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/21/93. Accepted 9/23/93.

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