Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2, TGF?-RII, KRAS2, TP53 and/or CDNK2A

Abstract

To address the cellular basis for the response to ovarian cancer treatment, we characterized the chemosensitivity and radiosensitivity of four human epithelial ovarian cancer cell lines that harbor different genetic alterations. The TOV-21G, TOV-81D, OV-90, and TOV-112D cell lines were derived from ovarian tumors (TOV) or ascites (OV) from chemotherapy- and radiotherapy-naive patients and were characterized by their mutation spectrum of BRCA2, TGFbeta-RII, KRAS2, TP53, and CDKN2A. Cells were monitored for survival following exposure at various concentrations to different cytotoxic agents including cisplatin, camptothecin or paclitaxel or to different doses of gamma-irradiation. At the lowest doses, the TGFbeta-RII-mutated and KRAS2-mutated cell line, TOV-21G, and the BRCA2-mutated cell line, TOV-81D, demonstrated a significantly higher sensitivity to cisplatin and gamma-irradiation than the TP53-mutated cell lines, TOV-112D and OV-90. At higher doses, differences between the TP53-mutated lines were observed with TOV-112D being less sensitive to cisplatin than OV-90 that also harbors a CDNK2A mutation. All cell lines were similarly sensitive to high doses of gamma-irradiation. In contrast, sensitivity to camptothecin or paclitaxel was not significantly different between all cell lines, irrespective of the mutation status of BRCA1, BRCA2, TGFbeta-RII, KRAS2, TP53, and CDKN2A. The observed responses to treatment are consistent with the current knowledge concerning BRCA2, TGFbeta-RII, KRAS2, TP53, and/or CDKN2A aberrant function.

Allelic Transcripts Dosage Effect in Morphologically Normal Ovarian Cells from Heterozygous Carriers of a BRCA1/2 French Canadian Founder Mutation

“…A specific phenotype has been reported in the BRCA2 heterozygous chicken B cell line DT40, characterized by reduced cell proliferation rates, increased cell death, greater sensitivity to DNA-damaging agents, and decreased RAD51 foci formation after irradiation. This phenotype is strikingly similar to the one described in the BRCA2 human ovarian tumor cell line TOV-81D, which retains both the normal and mutant copy of BRCA2 (13,14). Thus, it appears that, even in the context of cancer, the presence of a BRCA2 heterozygous mutation might be associated with distinct phenotypic changes.…”

“…An extensive description of the clinical data, BRCA1/2 mutation status, culture characteristics, and analyses associated with each sample is provided in Tables 1 and 2. The unique cell line used in this study, TOV-81D, has previously been established and described by our laboratory (13,14). All extractions were conducted within fewer than 6 months from resuscitation of frozen stocks established at the time of their original description.…”

A Mouse Model for the Molecular Characterization of Brca1-Associated Ovarian Carcinoma

“…S3). Similarly, it has been shown that the K-ras status in human ovarian cancer cell lines does not affect chemosensitivity to paclitaxel and cisplatin (17,18).…”

“…To test whether Brca1 status influences the sensitivity of OSE cells to drugs with different mechanisms of action, we compared the sensitivity of Brca1 wild-type and Brca1-deficient OSE cells to paclitaxel and cisplatin. OSE cell lines that are wild-type (C1, C2, C3, T1, T2, and T3) or deficient for Brca1 (BR2, BR5, BR6, TBR2, TBR5, and TBR6) were tested for their rate of survival in increasing concentrations of paclitaxel and cisplatin at doses that are effective in human ovarian cancer cell lines that harbor defined genetic alterations in genes such as Brca2, p53, K-ras, TGFb-RII, and CDNK2A (17). We showed that transformed Brca1 wild-type and Brca1-deficient mouse OSE cell lines have a similar sensitivity to the microtubule poison paclitaxel (Fig.…”

Acute Chemotherapy–Related Toxicity Is Not Increased in BRCA1 and BRCA2 Mutation Carriers Treated for Breast Cancer in the United Kingdom

“…Studies using brca1-homozygous null murine ES cells have shown increased cell death induced by the alkylating agent, mitomycin C, platinum, and the topoisomerase inhibitors including doxorubicin (which is also an anthracycline) and mitoxantrone compared with wild-type cells (2 -4), but there were no differences for cells treated with antimetabolites. A study of a BRCA2 heterozygous mutant ovarian cancer cell line has shown heightened sensitivity to cisplatin compared with paclitaxel, but this study did not have a wild-type cell line control (5).…”