Relatioship between HER-2/neu gene status and chemosensitivity of human endometrial cancer cell lines
Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama, Japan
AIM; This study was performed to evaluate the growth inhibitory effects of various anticancer drugs on human endometrial cancer cell lines (Ishikawa, HEC-1A, HEC-50B, HEC-59, and HEC-108)and relevance of HER-2/neu status to chemosensitivity. METHODS;The IC50 of the cell lines to various anticancer drugs containing cisplatin (CDDP), paclitaxel (Tx) and etoposide (VP-16) was determined by using crystal violet staining method. Combined effects of Tx with other anticancer drugs were analyzed by median-effect analysis. Immunohistochemistry was performed according to the protocol for the HercepTest for the evaluation of HER-2/neu status. RESULTS;When in vitro sensitivity was defined as an IC50 lower than 10% of the peak plasma concentration, all endometrial cancer cells were sensitive to paclitaxel(Tx). When the combined effects of Tx with another drug were determined by median-effect analysis, Tx followed by cisplatin resulted in synergistic effects on all cell lines. Tx followed by SN-38 (the active metabolite of irinitecan) and etoposide followed by Tx also had synergistic effects on four cell lines. Tx followed by pirarubicin (THP) and THP followed by Tx showed synergistic effects on three cell lines. HER-2/neu overexpression, determined by immunohistochemistry (HercepTest; Dako, CA, USA), was seen only in SPAC-1-L cells, which were the most resistant cells to Tx and doxorubicin (ADR)among the six cell lines. Induction of HER-2/neu overexoression by dexamethasone was seen in Ishikawa and HEC-1A cells. Furthermore, induction of HER-2/neu overexpression by Tx was seen in HEC-59 cells. Chemosensitivity of these HER-2/neu-overexpressing cells to Tx and ADR varied with the change of HER-2/neu gene status. However, there was no common relationship between HER-2/neu gene status and chemosensitivity in all cells. The IC50 values of herceptin (Trastumab Roche; Basel, Switzerland; humanized anti HER-2/neu monoclonal antibody) in these cells were not obtained at the micromolar level.CONCLUSION;HER-2/neu overexpression was observed in SPAC-1-L cells, while its induction was also observed in some other cell lines used in the present study, suggesting intervention strategies to Tx-resistance. To confirm the conclusion, further studies to quantify HER-2/neu gene amplification are needed.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 893 (Molecular pathology).