CIS-DIAMMINEDICHLOROPLATINUM(II) RESISTANCE IN-VITRO AND IN-VIVO IN HUMAN EMBRYONAL CARCINOMA-CELLS

In the embryonal carcinoma cell line Tera and its 3.7-fold cis-diammin edichloroplatinum(II) (CDDP)-resistant subline. Tera-CP, parameters we re studied that might have changed in relation to induction of CDDP re sistance. Phenotypes of both lines were embryonal carcinoma. Karyotype s were related with a decreased mean number of chromosomes and fewer c opies of the short arm of chromosome 12 in Tera-CP. Tera-CP showed cro ss-resistance for melphalan and 4-hydroperoxycyclophosphamide and had an 1.4-fold increased glutathione (GSH) level, a 1.5-fold increased gl utathione S-transferase (GST) activity, and a 1.4-fold increased GSTpi expression compared to Tera. Tera-CP was cross-resistant to 5-fluorou racil, but thymidylate synthase activity was not increased. Topoisomer ase 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 lin es were xenografted into nude mice and tumors showed marked differenti ation. 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 i n vivo CDDP resistance with the GSH/GST detoxifying system as an impor tant mechanism. CDDP resistance could be induced without a concomitant increase in differentiation.