Abstract
Metallothioneins are a family of intracellular metalloproteins that have been thought to be involved in anticancer drug resistance. However, the role of metallothioneins in pancreatic cancer has not been investigated in detail The immunohistochemical localization of metallothionein was examined in normal human adult pancreas tissue and in 75 pancreatic duct cell carcinomas, using monoclonal anti-metallothionein antibody. Furthermore, in vitro studies on the sensitivity of pancreatic cancer to cisplatin were performed in 10 cases of pancreatic carcinoma. Metallothionein staining was wekly positive in the acinar and islet cells and intralobular ducts but was negative in the large pancreatic ducts. In pancreatic carcinomas, metallothionein staining was diffusely positive in 6 (8%), focally positive in 25 (33%) and negative in 44 (59%) of the 75 pancreatic carcinomas. The expression of metallothioneins in pancreatic tumors was related to metastasis, poor prognosis and poor histological grading (poorer glandular differentiation and nuclear anaplasia). The in vitro study of tumor sensitivity to cisplatin showed no significant correlation between metallothionein expression and resistance to cisplatin. Metallothionein-positive pancreatic carcinoma will be potentially highly malignant or acquire an enhanced ability to produce metallothioneins as the malignant potential increases. The expression of metallothionein could be a prognostic indicator in pancreatic carcinomas.
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References
Bahnson RR, Banner BF, Ernstoff MS, Lazo JS, Cherian MG, Banerjee D, Chin JL (1991) Immunohistochemical localization of metallothionein in transitional cell carcinoma of the bladder. J Urol 146:1528–1520
Bakka A, Enresen L, Johnsen ABS, Edminson PD, Rugstad HE (1981) Resistance againstcis-dichlorodiammineplatinum in cultured cells with a high content of metallothionein. Toxicol Appl Pharmacol 61:215–226
Banerjee D, Onosaka S, Cherian MG (1982) Immunohistochemical localization of metallothionein in cell nucleus and cytoplasm of rat liver and kidney. Toxicology 24:95–105
Bremner I, Williams RB, Young BW (1977) Distribution of copper and zinc in the liver of the developing fetus. Br J Nutr 38:87–92
Chin JL, Banerjee D, Kadhim SA, Kontozoglou TE, Chauvin PJ, Cherian MG (1993) Metallothionein in testicular germ cell tumors and drug resistance. Clin Correl Cancer 72:3029–3035
Collier JD, Bennett MK, Hall A, Cattan AR, Lendrum R, Bassendine MF (1994) Expression of glutathione S-transferases in normal and malignant pancreas: an immunohistochemical study. Gut 35:266–269
Dougherty JB, Kelsen D, Kemeny M, Magill G, Botet J, Niedzwiecki D (1989) Advanced pancreatic cancer: a phase, I–II trial of cisplatin, high-dose cytarabine, and caffeine. J Natl Cancer Inst 81:1735–1737
Gibson JB (1978) Histological typing of tumours of the l tract and pancreas. International histological classification of tumours. World Health Organization, Geneva
Haerslev T, Jakobsen K, Nedergaard L, Zedeler K (1994) Immunohistochemical detection of metallothionein in primary breast carcinomas and their axillary lymph node metastases. Pathol Res Pract 190:675–681
Hamilton, C, Winker MA, Louie KG, Batist G, Behrens BC, Tsuruo T, Grotzinger KR, McKoy WM, Young RC, Ozols RF (1985) Augmentation of Adriamycin, melphalan, and cisplatin, cytotoxicity in drug-resistant and-sensitive human ovarian carcinoma cell lines by buthionine, sulfoximine mediated glutathione depletion. Biochem Pharmacol 34:2583–2586
Kagi JHR, Schäffer A (1988) Biochemistry of metallothionein. Biochemistry 27:8509–8515
Kasahara K, Fujiwara Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K, Matsuda T, Saijo N (1991) Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Res 51:3237–3242
Karin M (1985) Metallothioneins: proteins in search of function. Cell 41:9–10
Kelley S, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS (1988) Overexpression of metallothionein confers resistance to anticancer drugs. Science 241:1813–1815
Kloppel G, Lingenthal G, Vonbulow M, Kern HF (1985) Histological and fine structural features of pancreatic ductal adenocarcinomas in relation to growth and prognosis: studies in xenografted tumours and clinico-histopathological correlation in a series of 75 cases. Histopathology 9:841–856
Kraker A, Schmidt J, Krezoski S, Petering H (1985) Binding ofcis-dichlorodiammine platinum (II) to metallothionein in Ehrlich cells. Biochem. Biophys Res Commun 130:786–792
Masuda H, Ozols RF, Lai MG, Fojo A, Rothenberg M, Hamilton TC (1988) Increased DNA repair as a mechanism of acquired resistance tocis-diamminedichloroplatinum (II) in human ovarian cancer cell lines. Cancer Res 48:5713–5716
Meitner PA (1991) The fluoresecent cytoprint assay: a new approach to in vitro chemosensitivity testing. Oncology 5:75–81
Moertel CG, Rubin J, O'Connell MJ, Schutt AJ, Wieand HS (1986) A phase II study of combined 5-fluorouracil, doxorubicin and cisplatin in the treatment of upper gastrointestinal adenocarcinoma. J Clin Oncol 4:1053–1057
Morton K, Jones BJ, Sohn MH, Datz FL, Lynch RE (1993) Enrichment for metallothionein does not confer resistance to cisplatin in transfected NIH/3T3 cells. J Pharmacol Ther 267:697–702
Nartey N, Cherian MG, Banerjee D (1987) Immunohistochemical localization of metallothionein in human thyroid tumors. AM J Pathol 129:177–182
Öfner D, Maier H, Riedmann B, Bammer T, Rumer, A, Winde G, Böcker W, Jasani B, Schmid KW (1994) Immunohistochemical metallothionein expression in colorectal adenocarcinoma: correlation with tumour stage and patient survival. Virchows Arch [A] 425:491–497
Ohshio G, Yoshioka H, Manabe T, Sakahara H, Yamabe H, Imamura M, Inoue M, Tanaka N, Nakada H, Yamashina I (1994) Expression of sialosyl-Tn antigen (monoclonal antibody MLS102 reactive), in normal tissues and malignant tumors of the digestive tract. J Cancer Res Clin Oncol 29:325–330
Richon VM, Schulte N, Eastman A (1987) Multiple mechanisms of resistance tocis-diamminedichloroplatinum (II) in murine leukemia L1210 cells. Cancer Res 47:2056–2961
Ryden L, Deutsch HF (1978) Preparation and, properties of the major copper-binding component in human fetal liver. J Biol Chem 253:519–524
Sato M, Bremner I (1993) Oxygen free radicals and metallothionein. Free Radical Biol Med 14:325–337
Schilder RJ, Hall L, Monks A, Hancel LM, Fornace AJ Jr, Ozols RF, Fojo AT, Hamilton TC (1990) Metallothionein gene expression and resistance to cisplatin in human ovarian cancer. Int J Cancer 45:416–422
Wils JA, Kok T, Wagener DJTh, Selleslags, J., Duez N (1993) Activity of cisplatin in adenocarcinoma of the pancreas. Eur J Cancer 29A:203–204
Zelazowski AJ, Garvey JS, Hoeschele JD (1984) In vivo and in vitro binding of platinum to metallothionein. Arch Biochem Biophys 229:246–252
Zelger B, Hittmair A, Schir M, Öfner C, Öfner D, Fritsch PO, Böcker W, Jasani B, Schmid KW (1993) Immunohistochemically demonstrated metallothionein expression in malignant melanoma. Histopathology 23:257–264
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Ohshio, G., Imamura, T., Okada, N. et al. Immunohistochemical study of metallothionein in pancreatic carcinomas. J Cancer Res Clin Oncol 122, 351–355 (1996). https://doi.org/10.1007/BF01220802
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DOI: https://doi.org/10.1007/BF01220802