Abstract
Matrix metalloproteinases (MMPs) play an important role in various physiological and pathological conditions such as tissue remodeling, and cancer cell invasion and metastasis. The aim of this study was to determine the effect of the antitumor compounds cis-dichlorodiammine platinum (ii) (cisplatin) and 1, 3 bis (2-chloroethyl)-1-nitrosourea (BCNU) on 72-kDa type IV collagenase activity (MMP-2) in human gliomas. Human glioblastoma cell lines were treated with cisplatin (25μM), and BCNU (50μM), and the levels of MMP-2 were estimated in serum-free conditioned medium and in cell extracts at different time intervals. Gelatin zymography revealed increased levels of MMP-2 in serum-free conditioned medium and in cell extracts of untreated glioblastoma cell cultures during a 72-h period. In contrast, MMP-2 levels were significantly decreased in cisplatin-treated cells both in conditioned medium and cell extracts. However, no significant changes of MMP-2 levels were noted in BCNU-treated cells. Quantitative analysis of MMP-2 enzyme activity by densitometry and amount of MMP-2 protein by ELISA showed significantly decreased levels of MMP-2 in cisplatin-treated cells compared to BCNU and untreated glioblastoma cells. The results indicate that decreased levels of MMP-2 might represent an additional mechanism by which cisplatin provides its antineoplastic effects.
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Liotta LA, Tryggvason K, Garbisa S, et al. 1980, Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature, 284, 67–8.
Nakajima M, Welch D, Belloni PN, et al. 1987, Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials. Cancer Res, 47, 4869–76.
Stetler-Stevenson WG, 1990, Type IV collagenase in tumor invasion and metastasis. Cancer Metastasis Rev, 9, 289–3.
Rao JS, Steck PA, Mohanam S, et al. 1993, Elevated levels of Mr 92,000 type IV collagenase in human brain tumors. Cancer Res, 53(suppl), 2208–11.
Rao JS, Steck PA, Tofilon P, et al. 1993, Role of plasminogen activator and 92-kDa type IV collagenase in glioblastoma invasion using an in vitro Matrigel model. J Neuro-Oncol, 18, 129–38.
Rao JS, Yamamoto Y, Mohanam S, et al. 1996, Expression and localization of 92-kDa type IV collagenase/ gelatinase B (MMP-9) in human gliomas. Clin Exp Metastasis, 14, 12–18.
Sawaya R, Yamamoto M, Gokaslan ZL, et al. 1996, Expression and localization of 72-kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis, 14, 35–42.
Sexauer CL, Khan A, Burger PC, et al. 1985, Cisplatin in recurrent pediatric brain tumors. A POG phase II study. A pediatric oncology group study. Cancer, 56, 1497–501.
Bertolone SJ, Baum ES, Krivit W, et al. 1989, A phase II study of cisplatin therapy in recurrent childhood brain tumors. A report from the Childrens Cancer Study Group. J Neuro-Oncol, 7, 5–11.
Shapiro RJ, Ebrahim SAD, Mohamad AN, et al. 1993, BCNU-sensitivity in parental cell and clones from freshly resected near-diploid human gliomas: an astrocytoma, an anaplastic astrocytoma and two glioblastoma multiforme. J Neuro-Oncol, 15, 209–23.
Cece R, Barajoin I and Tredici G, 1995, Cisplatin induces apoptosis in SH-SY5Y human neuroblastoma cell line. Anticancer Res, 15, 777–82.
Barry MA, Behnke CA and Eastman A, 1990, Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol, 40, 2353–62.
Eastman A, 1990, Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells, 2, 275–80.
Sorenson CM, Barry MA and Eastman A, 1990, Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin. J Natl Cancer Inst, 82, 749–55.
Kondo S, Yin D, Morimura T, et al. 1995, Combination therapy with cisplatin and nifedipine induces apoptosis in cisplatin-sensitive and cisplatin-resistant human glioblastoma cells. Br J Cancer, 71, 281–9.
Ali-Osman F, Stein DE and Renwick A, 1990, Glutathione content and glutathione-S-transferase expression in 1,3-bis (2-chloroethyl)-1-nitrosourea resistant human malignant astrocytoma cell lines. Cancer Res, 50, 6976–80.
Nakajima M, Latan D, Baig M, et al. 1989, Inhibition by retinoic acid of type IV collagenolysis and invasion through reconstituted basement membrane by metastatic rat mammary adenocarcinoma cells. Cancer Res, 49, 1698–706.
Bradford MM, 1976, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem, 72, 248–54.
Laemmli UK, 1970, Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680–5.
Ewig RAG and Kohn KW, 1977, DNA damage and repair in mouse leukemia L1210 cells treated with nitrogen mustard, 1,3-bis (2-chloroethyl)-1-nitro sourea, and other nitrosoureas. Cancer Res, 37, 2114–22.
Tew KD, Sudhakar S, Schein PS, et al. 1978, Binding of chlorozotocin and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea to chromatin and nucleosomal fractions of HeLa cells. Cancer Res, 38, 3371–8.
Aas AT, Salford LG, Lonn S, et al. 1994, Reduced formation of high molecular weight DNA in murine gliomas treated with nitrosourea and chlorpromazine. Anticancer Res, 14, 1133–6.
Ali-Osman F, Rairkar A and Younp P, 1995, Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand cross links in human glioma cells. Biochem Biophys Res Commun, 14, 231–41.
Morikawa T, Shibuya M, Sakai S, et al. 1995, Effect of anticancer drugs on invasive capacity of human small-cell lung cancer cells in vitro. Nippon Ika Diagaku Zasshi, 62, 320–8.
Matrisian LM, 1990, Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet, 6, 121–5.
Matrisian LM, 1992, The matrix degrading metalloproteinases. BioEssays, 14, 455–63.
Liotta LA and Stetler-Stevenson WG, 1991, Tumor invasion and metastasis: an imbalance of positive and negative regulators. Cancer Res, 51, 50543–95.
Liotta LA, Steeg PS and Stetler-Stevenson WG, 1991, Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell, 64, 327–36.
Colton CA, Kewri JE, Chen WT, et al. 1993, Protease production by cultured microglia: substrate gel analysis and immobilized matrix degradation. J Neurosci Res, 35, 297–304.
Reich R, Thompson EW, Iwamoto Y, et al. 1988, Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res, 48, 3307–12.
Wang M and Stearns ME, 1988, Blocking of collagenase secretion by estamustine during in vitro tumor cell invasion. Cancer Res, 48, 6262–71. 1
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Chintala, S.K., Ali-Osman, F., Mohanam, S. et al. Effect of cisplatin and BCNU on MMP-2 levels in human glioblastoma cell lines in vitro. Clin Exp Metastasis 15, 361–367 (1997). https://doi.org/10.1023/A:1018442003163
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DOI: https://doi.org/10.1023/A:1018442003163