Differential sensitivity to platinum-based chemotherapy in primary uterine serous papillary carcinoma cell lines with high vs low HER-2/neu expression in vitro

Abstract

Objective-To identify effective chemotherapy regimens against uterine-serous-papillarycarcinoma (USPC).Study Design-Six UPSC, half of which overexpress HER-2/neu at 3+ level, were evaluated for growth-rate and in-vitro-sensitivity to fourteen single-agent chemotherapies and five combinations by ChemoFx (Precision Therapeutics, Pittsburgh, PA).Results-Cell lines overexpressing HER-2/neu showed higher proliferation when compared to low HER-2/neu-expressing cell lines and a lower half-maximum inhibitory concentration (IC 50 ) when exposed to the majority of single-agent chemotherapies. High HER-2/neu-expressors were more sensitive to platinum compounds, manifesting a 5.22-fold decrease in carboplatin-IC 50 (P=0.005) and a 5.37-fold decrease in cisplatin-IC 50 (P=0.02). When all cell lines were analyzed as a group, chemotherapy agents tested demonstrated lower IC 50 s when used in combination than as individual agents.Conclusions-USPC overexpressing HER-2/neu display greater in-vitro-sensitivity to platinum-compounds when compared to low HER-2/neu-expressors. Higher proliferative capability rather than increased drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in USPC.

Uterine serous papillary carcinomas overexpress human trophoblast‐cell‐surface marker (trop‐2) and are highly sensitive to immunotherapy with hRS7, a humanized anti‐trop‐2 monoclonal antibody

“…Therefore, USPC cell lines may potentially respond to anti-Trop-2 therapy, regardless of their different sensitivity/resistance to various chemotherapy or immunotherapy ( i.e. anti-HER2/neu-targeted) agents (24, 28). In agreement with our qRT-PCR and protein expression results, all high Trop-2 expressing primary USPC cell lines were highly sensitive to ADCC in the presence of hRS7.…”

Development of targeted therapy in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer

“…Thus, to identify effective chemotherapy regimens against USC, six primary tumor cell lines, half of which overexpress HER2/neu at 3+ level, have recently been evaluated for their in vitro sensitivity to 14 single-agent chemotherapies and five combinations by ChemoFx ® (Precision Therapeutics Inc., PA, USA) [64]. Cell lines overexpressing HER2/neu showed higher proliferation when compared with low HER2/neu-expressing cell lines and a lower IC 50 when exposed to the majority of single-agent chemotherapies.…”

“…Surprisingly, high HER2/neu expressors were found to be more sensitive to platinum compounds, manifesting a 5.22-fold decrease in carboplatin IC 50 (p = 0.005) and a 5.37-fold decrease in cisplatin IC 50 (p = 0.02). These data suggest that the apparent lack of response to chemotherapy among patients with HER2/neu-positive tumors seen in clinical trials may be due to rapid tumor regrowth of surviving tumor cells following initial response to chemotherapy, rather than intrinsic chemotherapeutic drug resistance at the time of chemotherapy treatment [64]. …”

Mammaglobin B (SCGB2A1) is a novel tumour antigen highly differentially expressed in all major histological types of ovarian cancer: implications for ovarian cancer immunotherapy

“…Tumour specimens used in cytotoxicity studies were obtained from a 67-year-old patient harbouring a stage IV high-grade serous carcinoma of the ovary before chemotherapy (i.e., primary chemo-naive cell line established from an ovarian tumour biopsy collected at the time of the primary tumour debulking) and at the time of disease progression after multiple regimens of chemotherapy (i.e., metastatic chemotherapy-resistant cell line established from pleural effusion), under approval of the Institutional Review Board. The in vivo chemotherapy resistance of the metastatic/recurrent tumour was confirmed in vitro by measuring chemotherapy resistance as percentage cell inhibition (PCI) by ChemoFx (Precision Therapeutics, Pittsburgh, PA, USA) (Cross et al , 2010). Both tumour lines were cultured in RPMI-1640 supplemented with HEPES buffer, ℒ-glutamine, penicillin and 10% heat-inactivated FBS.…”