Abstract
Carcinogenesis involves inactivation or subversion of the normal controls of proliferation, differentiation, and apoptosis. However, these controls are robust, redundant, and interlinked at the gene expression levels, regulation of mRNA lifetimes, transcription, and recycling of proteins. One of the central systems of control of proliferation, differentiation and apoptosis is retinoid signaling. The hRARαnuclear receptor occupies a central position with respect to induction of gene transcription in that when bound to appropriate retinoid ligands, its homodimers and heterodimers with hRXRαregulate the transcription of a number of retinoid-responsive genes. These include genes in other signaling pathways, so that the whole forms a complex network. In this study we showed that simple, cause-effect interpretations in terms of hRARαgene transcription being the central regulatory event would not describe the retinoid-responsive gene network.
A set of cultured bladder-derived cells representing different stages of bladder tumorigenesis formed a model system. It consisted of 2 immortalized bladder cell lines (HUC-BC and HUC-PC), one squamous cell carcinoma cell line (SCaBER), one papilloma line (RT4), and 4 transitional cell carcinomas (TCC-Sup, 5637, T24, J82) of varying stages and grades. This set of cells were used to model the range of behaviors of bladder cancers. Relative gene expression before (constitutive) and after treatment with 10 µM all-trans- retinoic acid (aTRA) was measured for androgen and estrogen receptor; a set of genes involved with retinoid metabolism and action, hRAR α nd β, hRXR α and β CRBP, CRABP I and II; and for signaling genes that are known to be sensitive to retinoic acid, EGFR, cytokine MK, ICAM I and transglutaminase. The phenotype for inhibition of proliferation and for apoptotic response to both aTRA and the synthetic retinoid 4-HPR was determined. Transfection with a CAT-containing plasmid containing an aTRA-sensitive promoter was used to determine if the common retinoic acid responsive element (RARE)-dependent pathway for retinoid regulation of gene expression was active. Each of the genes selected is known from previous studies to react to aTRA in a certain way, either by up- or down-regulation of the message and protein.
A complex data set not readily interpretable by simple cause and effect was observed. While all cell lines expressed high levels of the mRNAs for hRXRαand β that were not altered by treatment with exogenous aTRA, constitutive and stimulated responses of the other genes varied widely among the cell lines. For example, CRABP I was not expressed by J82, T24, 5637 and RT4, but was expressed at low levels that did not change in SCaBER and at moderate levels that decreased, increased, or decreased sharply in HUC-BC, TCC-Sup and HUC-PC, respectively. The expression of hRARα, which governs the expression of many retinoid-sensitive genes, was expressed at moderate to high levels in all cell lines, but in some it was sharply upregulated (TCC-Sup, HUC-PC and J82), remained constant (5637 and HUC-BC), or was down-regulated (SCaBER, T24 and RT4). The phenotypes for inhibition of proliferation showed no obvious relationship to the expression of any single gene, but cell lines that were inhibited by aTRA (HUC-BC and TCC-Sup) were not sensitive to 4-HPR, and vice versa. One line (RT4) was insensitive to either retinoid. Transfection showed very little retinoid-stimulated transfection of the CAT reporter gene with RT4 or HUC-PC. About 2-fold enhancement transactivation was observed with SCaBER, HUC-BC, J82 and T24 cells and 3–8 fold with 5637, TCC-Sup cells. In HUC-BC, a G to T point mutation was found at position 606 of the hRARα gene. This mutation would substitute tyrosine for asparagine in a highly conserved domain.
These data indicate that retinoid signaling is probably a frequent target of inactivation in bladder carcinogenesis. However, it seems this inactivation is a random process, but the strongly interlinked nature of signaling pathways can lead to unexpected manifestations. The phenotype of a cell is probably determined more by a neural net type of calculation involving numerous inputs (risk factors) than it is by strict cause and effect, i.e. inactivation of a particular gene may lead to widespread alterations in the activities of genes linked to it. A novel perspective based upon complexity for the investigation of carcinogenesis is presented.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Kinzler, K. W. and Vogelstein, B.: Lessons from hereditary colorectal cancer. Cell, 87: 159, 1996.
Shackney, S. E. and Shankey, T. V.: Common patterns of genetic evolution in human solid tumors. Cytometry, 29: 1, 1997.
Prehn, R. T.: Cancers beget mutations versus mutations beget cancers. Cancer Res., 54: 5296, 1994.
Weaver, V. M., Petersen, O. W., Wang, F., Larabell, C. A., Briand, P., Damsky, C., and Bissell, M. J.: Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J. Cell Biol., 137: 231, 1997.
Wingo, P. A., Tong, T., and Bolden, S.: Cancer Statistics, 1995. CA Cancer J. Clin., 45: 8, 1995.
Whelan, S. L. and Ferlay, J.: Cancer Incidence in Five Continents. Age-specific and standardized incidence rates. IARC Sci. Publ. 178, 1992.
Cartwright, R. A.: Screening workers exposed to suspect bladder carcinogens. J. Occup. Med., 28: 1017, 1986.
Heney, N. M., Ahmed, S., Flanagan, M. J., Frable, W., Corder, M. P., Hafermann, M. D., and Hawkins, I. R.: Superficial bladder cancer: progression and recurrence. J. Urol., 130: 1083, 1983.
Weinberg, R.: Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res., 49: 3713, 1989.
Pientä, K., Partin, A., and Coffey, D. S.: Cancer as a disease of DNA organization and dynamic cell structure. Cancer Res., 49: 2525, 1989.
Tzen, C., Estervig, D. N., Minoo, P., Filipak, M., Maercklein, P., Hoerl, B., and Scott, R.: Differentiation, cancer, and anticancer activity. Biochem. Cell Biol., 66: 478, 1988.
Heldin, C., Betscholz, C., Claesson-Welsh, l., and Westermark, B.: Subversion of growth regulatory pathways in malignant transformation. Biochim. Biophys. Acta, 907: 219, 1987.
Couture, J. and Hansen, M.: Recessive genes in tumorigenesis. Cancer Bull., 43: 41, 1991.
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W.: Participation of p53 protein in the cellular response to DNA damage. Cancer Res., 51: 6304, 1991.
Ruoslahti, E. and Yamaguchi, Y.: Proteoglycans as modulators of growth factors. Cell, 64: 867, 1991.
Nathan, C. and Sporn, M.: Cytokines in context. J. Cell Biol. 113: 981, 1991.
Harris, C. C.: Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res., 51: 5023s, 1991.
Trosko, J. E., Chang, C. C., Madhukar, B. V., and Oh, S. Y.: Modulators of gap junction function: the scientific basis of epigenetic toxicology. In Vitro Toxicology, 3: 9, 1990.
Cuthill, S.: Cellular epigenetics and the origin of cancer. BioEssays, 16: 393, 1994.
Hemstreet, G. P., Rao, J. Y., Hurst, R. E., Bonner, R. B., Jones, P. L., Vaidya, A. M., Fradet, Y., Moon, R. C., and Kelloff, G. J.: Intermediate endpoint biomarkers for chemoprevention. J. Cell. Biochem., Suppl. 16l: 93, 1992.
Rao, J. Y., Hemstreet, G. P., Hurst, R. E., Bonner, R. B., Jones, P. L., Min, K. W., and Fradet, Y.: Alterations in phenotypic biochemical markers in bladder epithelium during tumorigenesis. Proc. Natl. Acad. Sci. USA., 90: 8287, 1993.
Koss, L. G.: Tumors of the urinary tract and prostate. In L.G. Koss (Ed.), Diagnostic cytology and its histologic basis. Philadelphia: J.B. Lippincott, 1979. Pp. 749.
Norming, U., Nyman, C., and Tribukait, B.: Comparative flow and cytometric deoxyribonucleic acid studies on exophytic tumor and random mucosal biopsies in untreated carcinoma of the bladder. J. Urol., 142: 1442, 1989.
Tsai, Y. C., Simoneau, A. R., Spruck, C. H. III, Nichols, P. W., Steven, K., Buckley, J. D., and Jones, P. A.: Mosaicism in human epithelium: Macroscopic monoclonal patches cover the urothelium. J. Urol., 153: 1697, 1995.
Spruck, C. H. III, Ohneseit, P. F., Gonzalez-Zulueta, M., Esrig, D., Miyao, N., Tsai, Y. C., Lerner, S. P., Schnitte, C., Yang, A. S., Cote, R., Dubeau, L., Nichols, P. W., Hermann, G. G., Steven, K., Horn, T., Skinner, D. G., and Jones, P. A.: Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res., 54: 784, 1994.
Hemstreet, G. P., Rao, J. Y., Hurst, R. E., Bonner, R. B., Mellott, J., and Rooker, G. M.: Biomarkers in monitoring for efficacy of immunotherapy and chemoprevention of bladder cancer with dimethylsulfoxide. Cancer Detec. Prev., 1998.(in press)
Presti, J. C. Jr., Reuter, V. E., Galan, T., Fair, W. R., and Cordon-Cardo, C.: Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res., 51: 5405, 1991.
Farrow, G. M.: Urine cytology in the detection of bladder cancer: a critical approach. J. Occup. Med., 32: 817, 1990.
Prehn, R. T.: Many growth factors may not be growth factors. Cancer Res., 52: 501, 1992.
Cohen, S. M. and Ellwein, L. B.: Genetic errors, cell proliferation, and carcinogenesis. Cancer Res., 51: 6493, 1991.
Elliott, B., Ostman, A., Westermark, B., and Rubin, K.: Modulation of growth factor responsiveness of murine mammary carcinoma cells by cell matrix interactions: correlation of cell proliferation and spreading. J. Cell. Physiol., 152: 292, 1992.
Gudas, L. J.: Retinoids, retinoid-responsive genes, cell differentiation, and cancer. Cell Growth Differ., 3: 655, 1992.
Greenwald, P., Kelloff, G., Whitman-Burch, C., and Kramer, B.: Chemoprevention. CA Cancer J. Clin., 45: 31, 1995.
Lipman, S., Heyman, R., Kurie, J., Benner, S., and Hong, K.: Retinoids and chemoprevention: Clinical and basic studies. J. Cell. Biochem., 22: 1, 1995.
McCormick, A. M. and Napoli, J. L.: Identification of 5,6-epoxyretinoic acid as an endogenous retinol metabolite. J. Biol. Chem., 257: 1730, 1982.
Napoli, J. L. and Race, K. R.: Biogenesis of retinoic acid from beta-carotene. Differences between the metabolism of beta-carotene and retinal. J. Biol. Chem., 263: 17372, 1988.
DeLuca, L. H. and Shapiro, S. S.: Modulation of cellular interactions by vitamin A and derivatives (retinoids). Ann. N. Y. Acad. Sci., 359: 14, 1981.
Ong, D. E., Crow, J. A., and Chytil, F.: Radioimmunochemical determination of cellular retinol- and cellular retinoic acid-binding proteins in cytosols of rat tissues. J. Biol. Chem., 257: 13385, 1982.
Sani, B. and Corbett, T.: Retinoic acid-binding protein in normal tissues and experimental tumors. Cancer Res., 27: 209, 1977.
Giguere, V., Lyn, S., Yip, P., Siu, C. H., and Amin, S.: Molecular cloning of cDNA encoding a second cellular retinoic acid-binding protein. Proc. Natl. Acad. Sci. USA., 87: 6233, 1990.
Adamson, P. C., Boylan, J. F., Balis, F. M., Murphy, R. F., Godwin, K. A., Gudas, L. J., and Poplack, D. G.: Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein. Cancer Res., 267: 21486, 1992.
Boylan, J. F. and Gudas, L. J.: The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells. J. Biol. Chem., 267: 21486, 1992.
Giguere, V.: Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocrine Reviews 15: 61, 1994.
Sporn, M. B. and Roberts, A. B.: Role of retinoids in differentiation and carcinogenesis. Cancer Res., 43: 3034, 1983.
Pfahl, M., Apfel, R., Bendik, I., Fanjul, A., Graupner, G., Lee, M. O., La-Vista, N., Lu, X. P., Piedrafita, J., Ortiz, M. A., and et al: Nuclear retinoid receptors and their mechanism of action. Vitamins & Hormones, 49: 327, 1994.
Chambon, P.: The retinoid signaling pathway: molecular and genetic analyses. Semin. Cell Biol., 5: 115, 1994.
Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., and et al: The nuclear receptor superfamily: the second decade. Cell, 83: 835, 1995.
Giguere, V., Ong, E. S., Segui, P., and Evans, R. M.: Identification of a receptor for the morphogen retinoic acid. Nature, 330: 624, 1987.
Benbrook, D., Lernhardt, E., and Pfahl, M.: A new retinoic acid receptor identified from a hepatocellular carcinoma. Nature, 333: 669, 1988.
Heyman, R. A., Mangelsdorf, D. J., Dyck, J. A., Stein, R. B., Eichele, G., Evans, R. M., and Thaller, C.: 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell, 68: 397, 1992.
Leid, M., Kastner, P., Lyons, R., Nakshatri, H., Saunders, M., Zacharewski, T., Chen, J. Y., Staub, A., Gamier, J. M., Mader, S., and et al: Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently [published erratum appears in Cell 1992 Nov 27;71(5): following 886]. Cell, 68: 377, 1992.
Mangelsdorf, D. J. and Evans, R. M.: The RXR heterodimers and orphan receptors. Cell, 83: 841, 1995.
Pfahl, M.: Vertebrate receptors: molecular biology, dimerization and response elements. Semin. Cell Biol., 5: 95, 1994.
Lehmann, J. M., Zhang, X. K., Graupner, G., Lee, M. O., Hermann, T., Hoffmann, B., and Pfahl, M.: Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching. Mol. Cell. Biol., 13: 7698, 1993.
Salbert, G., Fanjul, A., Piedrafita, F. J., Lu, X. P., Kim, S. J., Tran, P., and Pfahl, M.: Retinoic acid receptors and retinoid X receptor-alpha down-regulate the transforming growth factor-beta 1 promoter by antagonizing AP-1 activity. Mol. Endocrinol., 7: 1347, 1993.
Fanjul, A., Dawson, M. I., Hobbs, P. D., Jong, L., Cameron, J. F., Harlev, E., Graupner, G., Lu, X. P., and Pfahl, M.: A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature, 372: 107, 1994.
Graupner, G., Malle, G., Maignan, J., Lang, G., Prunieras, M., and Pfahl, M.: 6′-substituted naphthalene-2-carboxylic acid analogs, a new class of retinoic acid receptor subtype-specific ligands. Biochem. Biophys. Res. Commun., 179: 1554, 1991.
Mehta, K., McQueen, T., Neamati, N., Collins, S., and Andreeff, M.: Activation of retinoid receptors RARα and RXRα induces differentiation and apoptosis, respectively, in HL-60 cells. Cell Growth Differ., 7: 179, 1996.
Moon, R. C., McCormick, D. L., and Mehta, R. G.: Inhibition of carcinogenesis by retinoids. Cancer Res., 43: 2469s, 1983.
Ponzoni, M., Bocea, P., Chiesa, V., Decensi, A., Pistoia, V., Raffaghello, L., Rozzo, C., and Montaldo, P. G.: Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation. Cancer Res., 55: 853, 1995.
Delia, D., Aiello, A., Formelli, F., Fontaneila, E., Costa, A., Miyashita, T., Reed, J. C., and Pierotti, M. A.: Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. Blood, 85: 359, 1995.
Kim, Y. H., Dohi, D. F., Han, G. R., Zou, C. P., Oridate, N., Walsh, G. L., Nesbitt, J. C., Xu, X. C., Hong, W. K., Lotan, R., and et al.: Retinoid refractoriness occurs during lung carcinogenesis despite functional retinoid receptors. Cancer Res., 55: 5603, 1995.
Li, J. J., Dong, Z., Dawson, M. I., and Colburn, N. H.: Inhibition of tumor promoter-induced transformation by retinoids that transrepress AP-1 without transactivating retinoic acid response element. Cancer Res., 56: 483, 1996.
Shao, Z. M., Dawson, M. I., Li, X. S., Rishi, A. K., Sheikh, M. S., Han, Q. X., Ordonez, J. V., Shroot, B., and Fontana, J. A.: p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene, 11: 493, 1995.
Sheikh, M. S., Shao, Z. M., Li, X. S., Ordonez, J. V., Conley, B. A., Wu, S., Dawson, M. I., Han, Q. X., Chao, W. R., and Quick, T.: N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. Carcinogenesis, 16: 2477, 1995.
Moon, R. C., McCormick, D. L., Becci, P. J., Shealy, Y. F., Frickel, F., Paust, J., and Sporn, M. B.: Influence of 15 retinoic acid amides on urinary bladder carcinogenesis in the mouse. Carcinogenesis, 3: 1469, 1982.
Moon, R. C., Kelloff, G. J., Detrisac, C. J., Steele, V. E., Thomas, C. F., and Sigman, C. C.: Chemoprevention of OH-BBN-induced bladder cancer in mice by oltipraz, alone and in combination with 4-HPR and DFMO. Anticancer Res. 14: 5, 1994.
Moon, R. C., Detrisac, C. J., Thomas, C. F., and Kelloff, G. J.: Chemoprevention of experimental bladder cancer. J. Cell. Biochem. Suppl., 161: 134, 1992.
Studer, U. E., Biedermann, C., Chollet, D., Karrer, R., Kraft, R., Toggenburg, H., and Vonbank, F.: Prevention of recurrent superficial bladder tumors by oral etretinate: preliminary results of a randomized, double blind multicenter trial in Switzerland. J. Urol., 131: 47, 1984.
Studer, U. E., Jenzer, S., Biedermann, C., Chollet, D., Kraft, R., Von Toggenburg, H., and Vonbank, F.: Adjuvant treatment with a vitamin A analogue (etretinate) after transurethral resection of superficial bladder tumors — Final analysis of a prospective, randomized multicenter trial in Switzerland. Eur. Urol., 28: 284, 1995.
Decensi, A., Curotto, A., Bruno, S., Costantini, M., Torrisi, R., Gatteschi, B., Cussotto, M., Pizzorno, R., Quattrini, S., Repetto, U., and et al.: DNA flow cytometry as a surrogate end-point in patients with superficial bladder cancer treated with 4-HPR. Eur. J. Cancer Prev., 3: 377, 1994.
Lamm, D. L., Riggs, D. R., Shriver, J. S., VanGilder, P. F., Rach, J. F., and DeHaven, J. I.: Megadose vitamins in bladder cancer: A double-blind clinical trial. J. Urol., 151: 21, 1994.
Bookland, E., Reznikoff, C. A., Lindstrom, M., and Swaminathan, S.: Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxyderivatives. Cancer Res., 52: 1615, 1992.
Mosmann, T.: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 65: 55, 1983.
Glover, J. F., Irwin, J. T., and Darbre, P. D.: Interaction of phenol red with estrogenic and antiestrogenic action on growth of human breast cancer cells ZR-75-1 and T-47-D. Cancer Res., 48: 3693, 1988.
Chomczynski, P. and Sacchi, N.: Single-step method of RNA isolation by acid guanidinium thiocyanatephenol- chloroform extraction. Anal. Biochem., 162: 156, 1987.
Maniatis, T., Fritsch, E. F., and Sambrook, J.: Molecular cloning: a laboratory manual, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory, 1990.
Rao, J. Y., Bonner, R. B., Hurst, R. E., Qiu, W. R., Reznikoff, C. A., and Hemstreet, G. P.: Quantitative changes in cytoskeletal and nuclear actin levels during cellular transformation. Int. J. Cancer, 70: 423, 1997.
Shibata, H., Spencer, T. E., Onate, S. A., Jenster, G., Tsai, S. Y., Tsai, M. J., and O’Malley, B. W.: Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action. Recent Progress in Hormone Research, 52: 141, 1997.
Leid, M., Kastner, P., and Chambon, P.: Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem. Sci., 17: 427, 1992.
Forman, B. M., Umesono, K., Chen, J., and Evans, R. M.: Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell, 81: 541, 1995.
Zhang, X. K. and Pfahl, M.: Hetero- and homodimeric receptors in thyroid hormone and vitamin A action. Receptor 3: 183, 1993.
Lufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., LeMeur, M., and Chambon, P.: High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc. Natl. Acad. Sci. USA., 90: 7225, 1993.
Sun, S.-Y., Yue, P., Dawson, M., Shroot, B., Michel, S., Lamph, W., Heyman, R., Teng, M., Chandraratna, R., Shudo, K., Hong, W., and Lotan, R.: Differential Effects of Synthetic Nuclear Retinoid Receptor-selective Retinoids on the Growth of Human Non-Small Cell Lung Carcinoma Cells. Cancer Res., 57: 4931, 1997.
Hemstreet, G. P., Rao, J. Y., Hurst, R. E., Bonner, R. B., Waliszewski, P., Grossman, H. B., Liebert, M., and Bane, B. L.: G-actin as a risk factor and modulatable endpoint for cancer chemoprevention trials. J. Cell. Biochem. Suppl., 25S: 197, 1996.
Hemstreet, G. P., Bonner, R. B., Hurst, R. E., and O’Dowd, G. A.: Cytology of bladder cancer. In N.J. Vogelzang, P.T. Scardino, W.U. Shipley, and D.S. Coffey (Eds.), Comprehensive Textbook of Genitourinary Oncology. Baltimore, MD: Williams & Wilkins, 1996. Pp. 338–350.
Rao, J. Y., Hemstreet, G. P., Bonner, R. B., Hurst, R. E., Qiu, W. R., and Reznikoff, C. A.: Nuclear actin as a biomarker for bladder cancer risk assessment. J. Urol., 151: 349A, 1994.(Abstract)
Rao, J. Y., Hemstreet, G. P., Hurst, R. E, Bonner, R. B., Min, K. W., and Jones, P. L.: Cellular F-actin levels as a marker for cellular transformation: correlation with bladder cancer risk. Cancer Res., 51: 2762, 1991.
Rao, J. Y., Hurst, R. E., Bales, W. D., Jones, R L., Bass, R. A., Archer, L. T., and Hemstreet, G. P.: Cellular f-actin levels as a marker for cellular transformation: relationship to cell division and differentiation. Cancer Res., 50: 2215, 1990.
Jones, P. A.: DNA Methylation Errors and Cancer. Cancer Res., 56: 2463, 1996.
Cairns, J.: The cancer problem. Sci. Am. 233: 64, 1975.
Rothman, N., Bhatnagar, V. K., Hayes, R. B., Zenser, T. V., Kashyap, S. K., Butler, M. A. X., Bell DA, Lak-shmi, V., Jaeger, M., Kashyap, R., and et al: The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers. Proc. Natl. Acad. Sci. USA., 93: 5084, 1996.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Science+Business Media New York
About this chapter
Cite this chapter
Hurst, R.E. et al. (1999). Complexity, Retinoid-Responsive Gene Networks, and Bladder Carcinogenesis. In: Baskin, L.S., Hayward, S.W. (eds) Advances in Bladder Research. Advances in Experimental Medicine and Biology, vol 462. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4737-2_35
Download citation
DOI: https://doi.org/10.1007/978-1-4615-4737-2_35
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7147-2
Online ISBN: 978-1-4615-4737-2
eBook Packages: Springer Book Archive