Summary
Recently, nm23-H1, an anti-metastasis gene, has been reported to correlate with sensitivity to chemotherapeutic agents including cisplatin in human breast and ovarian carcinoma cells. The aim of this study was to evaluate a role for nm23-H1 in responsiveness to cisplatin-based chemotherapy in patients with oesophageal squamous cell carcinoma (OSCC). The expression of nm23-H1 protein was examined immunohistochemically in 32 eligible patients with OSCC who underwent adjuvant chemotherapy with cisplatin, etoposide, and 5-fluorouracil after tumour resection. Fifteen (46.9%) of 32 patients were positive for nm23-H1 staining and 17 (53.1%) were negative. Both disease-free survival and overall survival rates of nm23-H1-negative patients were significantly shorter than in nm23-H1-positive patients (P < 0.01 for both). There was no significant difference in clinicopathologic characteristics between nm23-H1-positive and nm23-H1-negative groups. Multivariate analysis also showed that nm23-H1 expression was the most significant factor for overall survival of OSCC patients included in this study (P = 0.0007). To further study the role of nm23-H1, a human OSCC cell line (YES-2) was transfected with a plasmid containing a fragment of the nm23-H1 cDNA in an antisense orientation. Reduced expression of nm23-H1 protein in the antisense-transfected (AS) clones was found by Western blot analysis as compared to wild-type YES-2 and YES-2/Neo (clone transfected with the neomycin resistance gene alone). MTT (3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H tetrazolium bromide) assay showed that reduced expression of the nm23-H1 protein in AS clones was consistent with the degree of increased resistance to cisplatin but not etoposide or 5-fluorouracil. These data support the conclusion that reduced expression of nm23-H1 may be associated with resistance to cisplatin, suggesting the value of nm23-H1 expression as a prognostic marker for OSCC patients who are to undergo cisplatin-based chemotherapy.
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References
Andrews, PA & Albright, KD (1992). Mitochondrial defects in cis-diamminedichloroplatinum (II)-resistant human ovarian carcinoma cells. Cancer Res 52: 1895–1901.
Berridge, MV & Tan, AS (1993). Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303: 474–482.
Bosset, JF, Gignoux, M, Triboulet, JP, Tiret, E, Mantion, G, Elias, D, Lozach, P, Ollier, J, Pavy, JJ, Mercier, M & Sahmoud, T (1997). Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 337: 161–167.
Caligo, MA, Cipollini, G, Fiore, L, Calvo, S, Basolo, F, Collecchi, P, Ciardiello, F, Pepe, S, Petrini, M & Bevilacqua, G (1995). NM23 gene expression correlates with cell growth rate and S-phase. Int J Cancer 60: 837–842.
Cox, DR (1972). Regression models and life table. J R Stat Soc 34: 187–220.
de Geovani, C, Landuzzi, L, Frabetti, F, Nicoletti, G, Griffoni, C, Rossi, I, Mazzotti, M, Scotto, L, Nanni, P & Lollini, PL (1996). Antisense epidermal growth factor receptor transfection impairs the proliferative ability of human rhabdomyosarcoma cells. Cancer Res 56: 3898–3901.
Easty, DJ, Maung, K, Lascu, I, Veron, M, Fallowfield, ME, Hart, IR & Bennett, DC (1996). Expression of NM23 in human melanoma progression and metastasis. Br J Cancer 74: 109–114.
Ferguson, AW, Flatow, U, MacDonald, NJ, Larminat, F, Bohr, VA & Steeg, PS (1996). Increased sensitivity to cisplatin by nm23-transfected tumor cell lines. Cancer Res 56: 2931–2935.
Florenes, VA, Aamdal, S, Myklebost, O, Maelandsmo, GM, Bruland, OS & Fodstad, O (1992). Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression. Cancer Res 52: 6088–6091.
Freije, JM, Lawrence, JA, Hollingshead, MG, De la Rosa, A, Narayanan, V, Grever, M, Sausville, EA, Paull, K & Steeg, PS (1997). Identification of compounds with preferential inhibitory activity against low-Nm23-expressing human breast carcinoma and melanoma cell lines. Nat Med 4: 395–401.
Gauthier, T, Denis-Pouxviel, C & Murat, JC (1990). Respiration of mitochondria isolated from differentiated and undifferentiated HT29 colon cancer cells in the presence of various substrates and ADP generating systems. Int J Biochem 22: 411–417.
Higashiyama, M, Doi, O, Yokouchi, H, Kodama, K, Nakamori, S, Tateishi, R & Kimura, N (1992). Immunohistochemical analysis of nm23 gene product/NDP kinase expression in pulmonary adenocarcinoma: Lack of prognostic value. Br J Cancer 66: 533–536.
Hishikawa, Y, Abe, S, Kinugasa, S, Yoshimura, H, Monden, N, Igarashi, M, Tachibana, M & Nagasue, N (1997). Overexpression of metallothionein correlates with chemoresistance to cisplatin and prognosis in esophageal cancer. Oncology 54: 342–347.
Iizuka, N, Oka, M, Noma, T, Nakazawa, A, Hirose, K & Suzuki, T (1995). NM23-H1 and NM23-H2 messenger RNA abundance in human hepatocellular carcinoma. Cancer Res 55: 652–657.
International Union Against Cancer, Sobin, LH & Wittekind, C (1997). TNM Classification of Malignant Tumors, 5th edn, pp. 54–58. Wiley-Liss Inc: New York.
Jiang, WG, Hiscox, S, Bryce, RP, Horrobin, DF & Mansel, RE (1998). The effects of n-6 polyunsaturated fatty acids on the expression of nm-23 in human cancer cells. Br J Cancer 77: 731–738.
Kaplan, BL & Meier, P (1958). Nonparametic estimation from incomplete observations. J Am Stat Assoc 53: 457–481.
Kok, TC, Van der Gaast, A, Dees, J, Eykenboom, WM, Van Overhagen, H, Stoter, G, Tilanus, HW & Splinter, TA (1996). Cisplatin and etoposide in oesophageal cancer: a phase II study. Br J Cancer 74: 980–984.
Lindmark, G (1996). NM-23 H1 immunohistochemistry is not useful as predictor of metastatic potential of colorectal cancer. Br J Cancer 74: 1413–1418.
McLeod, HL, Sludden, J, Murray, GI, Keenan, RA, Davidson, AI, Park, K, Koruth, M & Cassidy, J (1998). Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. Br J Cancer 77: 461–465.
Nguyen, HN, Sevin, BU, Averette, HE, Perras, J, Ramos, R, Donato, D, Ochiai, K & Penalver, M (1993). Cell cycle perturbations of platinum derivatives on two ovarian cancer cell lines. Cancer Invest 11: 264–275.
Nita, ME, Nagawa, H, Tominaga, O, Tsuno, N, Fujii, S, Sasaki, S, Fu, CG, Takenoue, T, Tsuruo, T & Muto, T (1998). 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer 78: 986–992.
Oka, M, Iizuka, N, Yamamoto, K, Gondo, T, Abe, T, Hazama, S, Akitomi, Y, Koshihara, Y, Ohsugi, Y, Ooba, Y, Ishihara, T & Suzuki, T (1996). The influence of interleukin-6 on the growth of human esophageal cancer cell lines. J Interferon Cytokine Res 16: 1001–1006.
Olivero, OA, Semino, C, Kassim, A, Lopez-Larraza, DM & Poirier, MC (1995). Preferential binding of cisplatin to mitochondrial DNA of Chinese hamster ovary cells. Mutation Res 346: 221–230.
Patel, DD, Bhatavdekar, JM, Chikhlikar, PR, Patel, YV, Shah, NG, Ghosh, N, Suthar, TP & Balbar, DB (1997). Clinical significance of p53, nm23, and bcl-2 in T3–4N1M0 oesophageal carcinoma: an immunohistochemical approach. J Surg Oncol 65: 111–116.
Roder, JD, Busch, R, Stein, HJ, Fink, U & Siewert, JR (1994). Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the oesophagus. Br J Surg 81: 410–413.
Rusch, V, Klimstra, D, Venkatraman, E, Oliver, J, Martini, N, Gralla, R, Kris, M & Dmitrovsky, E (1995). Aberrant p53 expression predicts clinical resistance to cisplatin-based chemotherapy in locally advanced non-small cell lung cancer. Cancer Res 55: 5038–5042.
Scambia, G, Ferrandina, G, Marone, M, Benedetti, PP, Giannitelli, C, Piantelli, M, Leone, A & Mancuso, S (1996). Nm23 in ovarian cancer: correlation with clinical outcome and other clinicopathologic and biochemical prognostic parameters. J Clin Oncol 14: 334–342.
Stahl, M, Wilke, H, Fink, U, Stuschke, M, Walz, MK, Siewert, JR, Moll, M, Fett, W, Makoski, HB, Breuer, N, Schmidt, U, Niebel, W, Sack, H, Eigler, FW & Seeber, S (1996). Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer. Interim analysis of a phase II trial. J Clin Oncol 14: 829–837.
Steeg, PS, Bevilacqua, G, Kopper, L, Thorgeirsson, UP, Talmadge, JB, Liotta, LA & Sobel, M (1988). Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80: 200–204.
Timmer-Bosscha, H, Timmer, A, Meijer, C, de Vries, EG, de Jong, B, Oosterhuis, JW & Mulder, NH (1993). cis-diamminedichloroplatinum(ii) resistance in vitro and in vivo in human embryonal carcinoma cells. Cancer Res 53: 5707–5713.
Tokunaga, Y, Urano, T, Furukawa, K, Kondo, H, Kanematsu, T & Shiku, H (1993). Reduced expression of nm23-H1, but not of nm23-H2 is concordant with the frequency of lymph node metastasis of human breast cancer. Int J Cancer 55: 66–71.
Yamamoto, K, Oka, M, Hayashi, H, Tangoku, A, Gondo, T & Suzuki, T (1997). CYFRA 21-1 is a useful marker for esophageal squamous cell carcinoma. Cancer 79: 1647–1655.
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Iizuka, N., Hirose, K., Noma, T. et al. The nm23-H1 gene as a predictor of sensitivity to chemotherapeutic agents in oesophageal squamous cell carcinoma. Br J Cancer 81, 469–475 (1999). https://doi.org/10.1038/sj.bjc.6690717
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DOI: https://doi.org/10.1038/sj.bjc.6690717
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