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-diamminedichloroplatinum(II) (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 S-transferase (GST) activity, and a 1.4-fold increased GST pi 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.
Timmer-Bosscha
H
H
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Timmer
A
A
Meijer
C
C
de Vries
E G
EG
de Jong
B
B
Oosterhuis
J W
JW
Mulder
N H
NH
D000818:Animals; D018236:Carcinoma, Embryonal; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D054278:Embryonal Carcinoma Stem Cells; D005978:Glutathione / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*
D004247:DNA; D005978:Glutathione; D002945:Cisplatin