Development of resistance to cisplatin is associated with decreased expression of the gp185c-erbB-2 protein and alterations in growth properties and responses to therapy in an ovarian tumor cell line.
Overexpression of the c-erbB-2 protein (gp185c-erbB-2) is correlated with a tumorigenic phenotype and may contribute to disease progression. We have reported previously on an anti-gp185c-erbB-2 antibody, TAb 250, that inhibits in vitro and in vivo growth of breast and ovarian cell lines that overexpress the protein and enhances the inhibitory activity of cisplatin (CDDP). To assess whether CDDP resistance is related to gp185c-erbB-2 expression levels, alterations in tumor cell growth characteristics, or efficacy of antibody plus drug combination treatments, an SKOV-3 ovarian tumor cell line was made resistant to escalating doses of CDDP. Parental cells were 12-fold more sensitive to CDDP with 7 times more gp185c-erbB-2 sites than the most resistant variant (SKOV-3/C12). Additionally, the resistant cells demonstrated a longer lag phase for in vivo growth than the parental cells. While TAb 250 enhanced the in vivo inhibitory effect of CDDP against parental SKOV-3 cells, the antibody did not significantly alter the CDDP responsiveness of the resistant population. Growth inhibition by TAb 250 alone of both the parental and the SKOV-3-resistant variants was similar; however, TAb 250 was able to prolong the lag-phase of tumor growth of the resistant variant by up to 25 days. These results indicate that the development of CDDP resistance is associated with lowered levels of gp185c-erbB-2 expression, slower tumor cell growth, and enhanced efficacy of antibody treatment of the resistant cells.
Langton-Webster
B C
BC
Department of Oncology, Berlex Biosciences, Richmond, California 94804.
Xuan
J A
JA
Brink
J R
JR
Salomon
D S
DS
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001943:Breast Neoplasms; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000627:therapeutic use* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000276:immunology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000906:Antibodies; D002945:Cisplatin; D018719:Erb-b2 Receptor Tyrosine Kinases