Abstract
To clarify the mechanism of acquired CDDP resistance in ovarian cancer, we compared the microsatellite instability (MSI) by the amplification of 10 microsatellite loci and immunohistochemical detection of hMSH2 and hMLH1 expression between the primary resected tumours and the secondary resected residual tumours after 5 or 6 courses of CDDP-based chemotherapy in the 24 cases of ovarian cancer. Of the 24 primary resected tumours, 9 (37.5%) showed MSI (7 cases of MSI-L, 2 cases of MSI-H), while 15 (72.5%) were microsatellite stable tumours (MSS). The primary tumours also had MSI in the residual tumours after CDDP-based chemotherapy. However, all of the cases with MSS in the primary resected tumours exhibited MSI (2 cases were MSI-L, and 13 cases were MSI-H) in the residual tumours after CDDP-based chemotherapy (P< 0.001). Furthermore, 11 (73.3%) of these cases which changed from MSS to MSI also had a change in the expression of hMLH1 from positive to undetectable (P< 0.001). Our data suggest that tumour MSI changes during CDDP-based chemotherapy, and that the loss of hMLH1 expression is one of the factors that has the greatest effect on this transformation. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
Keywords: microsatellite instability, CDDP-based chemotherapy, acquired resistance, ovarian cancer
Full Text
The Full Text of this article is available as a PDF (60.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aebi S., Kurdi-Haidar B., Gordon R., Cenni B., Zheng H., Fink D., Christen R. D., Boland C. R., Koi M., Fishel R. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res. 1996 Jul 1;56(13):3087–3090. [PubMed] [Google Scholar]
- Aebi S., Kurdi-Haidar B., Gordon R., Cenni B., Zheng H., Fink D., Christen R. D., Boland C. R., Koi M., Fishel R. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res. 1996 Jul 1;56(13):3087–3090. [PubMed] [Google Scholar]
- Allen H. J., DiCioccio R. A., Hohmann P., Piver M. S., Tworek H. Microsatellite instability in ovarian and other pelvic carcinomas. Cancer Genet Cytogenet. 2000 Mar;117(2):163–166. doi: 10.1016/s0165-4608(99)00167-3. [DOI] [PubMed] [Google Scholar]
- Anthoney D. A., McIlwrath A. J., Gallagher W. M., Edlin A. R., Brown R. Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells. Cancer Res. 1996 Mar 15;56(6):1374–1381. [PubMed] [Google Scholar]
- Arzimanoglou I. I., Lallas T., Osborne M., Barber H., Gilbert F. Microsatellite instability differences between familial and sporadic ovarian cancers. Carcinogenesis. 1996 Sep;17(9):1799–1804. doi: 10.1093/carcin/17.9.1799. [DOI] [PubMed] [Google Scholar]
- Boland C. R., Thibodeau S. N., Hamilton S. R., Sidransky D., Eshleman J. R., Burt R. W., Meltzer S. J., Rodriguez-Bigas M. A., Fodde R., Ranzani G. N. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998 Nov 15;58(22):5248–5257. [PubMed] [Google Scholar]
- Bunz F., Hwang P. M., Torrance C., Waldman T., Zhang Y., Dillehay L., Williams J., Lengauer C., Kinzler K. W., Vogelstein B. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest. 1999 Aug;104(3):263–269. doi: 10.1172/JCI6863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Codegoni A. M., Bertoni F., Colella G., Caspani G., Grassi L., D'Incalci M., Broggini M. Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. Oncol Res. 1999;11(7):297–301. [PubMed] [Google Scholar]
- D'Incalci M., Bonfanti M., Pifferi A., Mascellani E., Tagliabue G., Berger D., Fiebig H. H. The antitumour activity of alkylating agents is not correlated with the levels of glutathione, glutathione transferase and O6-alkylguanine-DNA-alkyltransferase of human tumour xenografts. EORTC SPG and PAMM Groups. Eur J Cancer. 1998 Oct;34(11):1749–1755. doi: 10.1016/s0959-8049(98)00191-9. [DOI] [PubMed] [Google Scholar]
- Fink D., Nebel S., Norris P. S., Aebi S., Kim H. K., Haas M., Howell S. B. The effect of different chemotherapeutic agents on the enrichment of DNA mismatch repair-deficient tumour cells. Br J Cancer. 1998 Mar;77(5):703–708. doi: 10.1038/bjc.1998.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haas C. J., Diebold J., Hirschmann A., Rohrbach H., Schmid S., Löhrs U. Microsatellite analysis in serous tumors of the ovary. Int J Gynecol Pathol. 1999 Apr;18(2):158–162. doi: 10.1097/00004347-199904000-00010. [DOI] [PubMed] [Google Scholar]
- Hickey K. P., Boyle K. P., Jepps H. M., Andrew A. C., Buxton E. J., Burns P. A. Molecular detection of tumour DNA in serum and peritoneal fluid from ovarian cancer patients. Br J Cancer. 1999 Aug;80(11):1803–1808. doi: 10.1038/sj.bjc.6690601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karran P., Hampson R. Genomic instability and tolerance to alkylating agents. Cancer Surv. 1996;28:69–85. [PubMed] [Google Scholar]
- Kusaba H., Nakayama M., Harada T., Nomoto M., Kohno K., Kuwano M., Wada M. Association of 5' CpG demethylation and altered chromatin structure in the promoter region with transcriptional activation of the multidrug resistance 1 gene in human cancer cells. Eur J Biochem. 1999 Jun;262(3):924–932. doi: 10.1046/j.1432-1327.1999.00469.x. [DOI] [PubMed] [Google Scholar]
- Leith C. P., Kopecky K. J., Chen I. M., Eijdems L., Slovak M. L., McConnell T. S., Head D. R., Weick J., Grever M. R., Appelbaum F. R. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood. 1999 Aug 1;94(3):1086–1099. [PubMed] [Google Scholar]
- Mackay H. J., Cameron D., Rahilly M., Mackean M. J., Paul J., Kaye S. B., Brown R. Reduced MLH1 expression in breast tumors after primary chemotherapy predicts disease-free survival. J Clin Oncol. 2000 Jan;18(1):87–93. doi: 10.1200/JCO.2000.18.1.87. [DOI] [PubMed] [Google Scholar]
- McGuire W. P., Hoskins W. J., Brady M. F., Kucera P. R., Partridge E. E., Look K. Y., Clarke-Pearson D. L., Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996 Jan 4;334(1):1–6. doi: 10.1056/NEJM199601043340101. [DOI] [PubMed] [Google Scholar]
- Muggia F. M., Braly P. S., Brady M. F., Sutton G., Niemann T. H., Lentz S. L., Alvarez R. D., Kucera P. R., Small J. M. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000 Jan;18(1):106–115. doi: 10.1200/JCO.2000.18.1.106. [DOI] [PubMed] [Google Scholar]
- Nishimura T., Newkirk K., Sessions R. B., Andrews P. A., Trock B. J., Rasmussen A. A., Montgomery E. A., Bischoff E. K., Cullen K. J. Immunohistochemical staining for glutathione S-transferase predicts response to platinum-based chemotherapy in head and neck cancer. Clin Cancer Res. 1996 Nov;2(11):1859–1865. [PubMed] [Google Scholar]
- Omura G. A., Bundy B. N., Berek J. S., Curry S., Delgado G., Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 1989 Apr;7(4):457–465. doi: 10.1200/JCO.1989.7.4.457. [DOI] [PubMed] [Google Scholar]
- Ozols R. F. Update of the NCCN ovarian cancer practice guidelines. Oncology (Williston Park) 1997 Nov;11(11A):95–105. [PubMed] [Google Scholar]
- Pieretti M., Cavalieri C., Conway P. S., Gallion H. H., Powell D. E., Turker M. S. Genetic alterations distinguish different types of ovarian tumors. Int J Cancer. 1995 Dec 20;64(6):434–440. doi: 10.1002/ijc.2910640614. [DOI] [PubMed] [Google Scholar]
- Plumb J. A., Strathdee G., Sludden J., Kaye S. B., Brown R. Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000 Nov 1;60(21):6039–6044. [PubMed] [Google Scholar]
- Samimi G., Fink D., Varki N. M., Husain A., Hoskins W. J., Alberts D. S., Howell S. B. Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy. Clin Cancer Res. 2000 Apr;6(4):1415–1421. [PubMed] [Google Scholar]
- Strathdee G., MacKean M. J., Illand M., Brown R. A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene. 1999 Apr 8;18(14):2335–2341. doi: 10.1038/sj.onc.1202540. [DOI] [PubMed] [Google Scholar]
- Zheng M., Wang H., Zhang H., Ou Q., Shen B., Li N., Yu B. The influence of the p53 gene on the in vitro chemosensitivity of colorectal cancer cells. J Cancer Res Clin Oncol. 1999;125(6):357–360. doi: 10.1007/s004320050286. [DOI] [PubMed] [Google Scholar]
- de las Alas M. M., Aebi S., Fink D., Howell S. B., Los G. Loss of DNA mismatch repair: effects on the rate of mutation to drug resistance. J Natl Cancer Inst. 1997 Oct 15;89(20):1537–1541. doi: 10.1093/jnci/89.20.1537. [DOI] [PubMed] [Google Scholar]