hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents.
Brown, R Hirst, G L Gallagher, W M McIlwrath, A J Margison, Geoffrey P Van der Zee, A G Anthoney, D A
Brown, R
Hirst, G L
Gallagher, W M
McIlwrath, A J
Margison, Geoffrey P
Van der Zee, A G
Anthoney, D A
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Abstract
Loss of expression of the hMLH1 and hPMS2 subunits of the MutL alpha-mismatch repair complex is a frequent event (9/10) in independent cisplatin resistant derivatives of a human ovarian carcinoma cell line. However, only hMLH1 mRNA is decreased in these MutL alpha-deficient lines. No alterations in the levels of the hMSH2 and hMSH6 (GTBP) subunits of the MutS alpha-complex are observed. An increase in the proportion of ovarian tumours negative for the hMLH1 subunit is observed in samples taken at second look laparotomy after chemotherapy (36%: 4/11), compared to untreated tumours (10%: 4/39). No significant difference is observed for hMSH2, hMSH6 or hPMS2. Furthermore, cisplatin and doxorubicin-resistant ovarian lines deficient in hMLH1 expression are cross-resistant to 6-thioguanine and the methylating agent N-methyl-N-nitrosourea (MNU). Depletion of O6-alkylguanine-DNA-alkyltransferase (ATase) activity confers only limited increased sensitivity to MNU. Thus the mismatch repair deficient lines retain DNA damage tolerance even after ATase depletion. The hMLH1 deficient lines also lose ability to engage G1 and G2 cell cycle arrest after cisplatin damage. Together these data suggest that loss of hMLH1 expression may be a high frequency event following exposure of ovarian tumour cells to cisplatin and may be critically involved in the development of drug resistance. Thus, the hMLH1 status of these cells appears to be highly correlated with the ability to engage cell death and cell cycle arrest after DNA damage induced by cisplatin.
Description
Date
1997-07-03
Publisher
Collections
Keywords
Cancer Drug Resistance
Cancer Proteins
Ovarian Cancer
Cultured Tumour Cells
Cancer Proteins
Ovarian Cancer
Cultured Tumour Cells
Type
Article
Citation
hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. 1997, 15 (1):45-52 Oncogene