Abstract
Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917±444 mg (range, 300–1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8–10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-α,-μ, and-π) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), β-glucuronidase (βG), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-α, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P<0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-μ, GST-π, GSH, and βG). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P<0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.
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References
Akerboom TP, Sies H (1981) Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol 77: 373
Beaune PH, Flinois JP, Kiffel L, Kremers P, Leroux JP (1985) Purification of a new cytochrome P-450 from human liver microsomes. Biochim Biophys Acta 860: 364
Beaune PH, Kremers P, Letawe-Goujon, F, Gielen JE (1985) Monoclonal antibodies against human liver cytochrome P-450. Biochem Pharmacol 34: 3547
Beaune PH, Cresteil T, Flinois JP, Leroux JP (1988) Hydrophobic chromatography: a one step method for purification of human liver microsomal epoxide hydrolase. J Chromatogr Biomed Appl 426: 169
Bissery M-A, Guénard D, Guéritte-Voegelein F, Lavelle F (1991) Experimental antitumor activity of taxotere (RP 56976, NSC 6285.3), a taxol analogue. Cancer Res 51: 4845
Clarke L, Waxman DJ (1989) Oxidative metabolism of cyclophosphamide: identification of the hepatic monooxygenase catalysts of drug activation. Cancer Res 49: 2344
Corbett TH, Griswold DP, Roberts BJ, Peckham J, Schabel FM (1975) A mouse colon tumor model for experimental therapy. Cancer Chemother Rep 5: 169
Corbett TH, Griswold DP, Roberts BJ, Peckham JC, Schabel FM (1977) Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer 40: 2660
El Mouelhi M, Didolkar MS, Elias EG, Guengerich FP, Kauffman FC (1987) Hepatic drug-metabolizing enzymes in primary and secondary tumors of human liver. Cancer Res 47: 460
Evans CG, Bodell WJ, Tokuda K, Doane-Setzer P, Smith M (1987) Glutathione related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard. Cancer Res 47: 2525
Griswold DP, Corbett TH (1978) Use of experimental models in the study of approaches to treatment of colorectal cancer. In: Lipkin M, Good RA (eds) Gastrointestinal tract cancer. Plenum, New York, p 399
Guengerich FP (1988) Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res 48: 2946
Guengerich FP, Dannan GA, Wright ST, Martin MV, Kaminsky LS (1982) Purification and characterization of liver microsomal cytochromes P-450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isoenzymes isolated from rats treated with phenobarbital or β-naphtoflavone. Biochemistry 21: 6019
Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249: 7130
Jakoby WB, Habig WH (1980) Glutathione transferases. In: Jakoby WB (ed) Enzymatic basis of detoxication. Academic Press, New York, p 6
Kremers P, Beaune PH, Cresteil T, de Graeve J, Columelli S, Leroux J-P, Gielen JE (1981) Cytochrome P-450 monooxygenase activity in human and rat liver microsomes. Eur J Biochem 118: 599
Laemmli UK (1970) Cleavage of structural proteins during assembly of the head of bacteriophage T4. Nature 227: 680
Mannervik B (1985) The isoenzymes of glutathione-S-transferase. Adv Enzymol 57: 357
Marchand DH (1988) The role of glutathione and glutathione-S-transferases in the metabolism of busulfan. Diss Abstr Int B 128: 3525
Massaad L, de Waziers I, Ribrag V, Janot F, Beaune PH, Morizet J, Gouyette A, Chabot GG (1992) Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. Cancer Res 52: 6567
Nelson DR, Kamataki T, Waxman D, Guengerich FP, Estabrook RW, Feyereisen R, Gonzalez FJ, Coon MJ, Gunsalus IC, Gotoh O, Okuda K, Nebert DW (1993) The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1: 1
Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70: 158
Satoh K, Kitahara A, Soma Y, Inaba Y, Hatayama I, Sato K (1985) Purification, induction, and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis. Proc Natl Acad Sci USA 82: 3964
Shimada T, Misono KS, Guengerich FP (1986) Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative metabolism. J Biol Chem 261: 909
Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150: 76
Soma Y, Satoh K, Sato K (1986) Purification and subunit structural and immunological characterization of five glutathione-S-transferases in human liver, and the acidic form as a hepatic tumor marker. Biochim Biophys Acta 869: 247
Tidefelt U, Elmhorn-Rosenborg A, Paul C, Hao X-Y, Mannervick B, Eriksson LC (1992) Expression of glutathione transferase π as a predictor for treatment results at different stages of acute nonlymphoblastic leukemia. Cancer Res 52: 3281
Wolf CR, Lewis AD, Carmichael J, Adams DJ, Hickson IJ, Harris A, Balkwill FR, Griffin DB, Hayes JD (1987) Glutathione-S-transferase expression in normal and tumour cells resistant to cytotoxic drugs. In: Mantle TJ, Pichett CB, Hayes JD (eds) Glutathione-S-transferases in carcinogenesis. Taylor and Francis, London, p 199
Yoo JSH, Ning SM, Patten CJ, Yang CS (1987) Metabolism and activation ofN-nitrosodimethylamine by hamster and rat microsomes: comparative study with weanling and adult animals. Cancer Res 47: 992
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This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Association pour la Recherche sur le Cancer (ARC, Villejuif)
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Massaad, L., Chabot, G.G., Toussaint, C. et al. Influence of tumor size on the main drug-metabolizing enzyme systems in mouse colon adenocarcinoma Co38. Cancer Chemother. Pharmacol. 34, 497–502 (1994). https://doi.org/10.1007/BF00685661
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DOI: https://doi.org/10.1007/BF00685661