hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents.
Authors
Brown, RHirst, G L
Gallagher, W M
McIlwrath, A J
Margison, Geoffrey P
Van der Zee, A G
Anthoney, D A
Affiliation
Department Medical Oncology, CRC Beatson Laboratories, Glasgow University, UK.Issue Date
1997-07-03
Metadata
Show full item recordAbstract
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.Citation
hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. 1997, 15 (1):45-52 OncogeneJournal
OncogeneDOI
10.1038/sj.onc.1201167PubMed ID
9233776Type
ArticleLanguage
enISSN
0950-9232ae974a485f413a2113503eed53cd6c53
10.1038/sj.onc.1201167
Scopus Count
Collections
Related articles
- Human colon cancer cells surviving high doses of cisplatin or oxaliplatin in vitro are not defective in DNA mismatch repair proteins.
- Authors: Sergent C, Franco N, Chapusot C, Lizard-Nacol S, Isambert N, Correia M, Chauffert B
- Issue date: 2002 Jun
- Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells.
- Authors: Aebi S, Fink D, Gordon R, Kim HK, Zheng H, Fink JL, Howell SB
- Issue date: 1997 Oct
- Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin.
- Authors: Moreland NJ, Illand M, Kim YT, Paul J, Brown R
- Issue date: 1999 May 1
- Transient mismatch repair gene transfection for functional analysis of genetic hMLH1 and hMSH2 variants.
- Authors: Brieger A, Trojan J, Raedle J, Plotz G, Zeuzem S
- Issue date: 2002 Nov
- Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy.
- Authors: Samimi G, Fink D, Varki NM, Husain A, Hoskins WJ, Alberts DS, Howell SB
- Issue date: 2000 Apr