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Biologic and Therapeutic Effects of Dehydroepiandrosterone and Structural Analogs

  • Arthur G. Schwartz
  • Laura L. Pashko
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Dehydroepiandrosterone (DHEA) is a major adrenal cortical steroid in humans (1, 2). The plasma levels of DHEA and its sulfated ester rise early in life, reaching a maximum in the second decade, and decline thereafter throughout adult life, whereas cortisol levels rise linearly with age (3). DHEA and related steroids are potent, non-competitive inhibitors of mammalian glucose-6 phosphate dehydrogenase (G6PDH), the rate-limiting enzyme of the pentose phosphate pathway, which is a major source of fivecarbon sugars as well as nicotinamide adenine dinucleotide phosphate (NADPH), a critical modulator of cellular redox potential. NADPH supplies reducing equivalents for several reactions that generate oxygenfree radicals, which, in addition to their mutagenicity, act as intermediate messengers that stimulate mitogenesis and upregulate inflammation.

Keywords

West Nile Virus Pentose Phosphate Pathway Nicotinamide Adenine Dinucleotide Phosphate Leydig Cell Tumor Reduce Weight Gain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    VandeWiele RL, MacDonald PC, Gurpide E, Lieberman S. Studies on the secretion and interconversion of the androgens. Recent Prog Horm Res 1963;19:275–310.PubMedGoogle Scholar
  2. 2.
    Parker CR Jr. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids 1999;64:640–647.PubMedCrossRefGoogle Scholar
  3. 3.
    Orentreich N, Brind JL, Rizer RL. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551–555.PubMedCrossRefGoogle Scholar
  4. 4.
    Lauglin GA, Barrett-Connor E. Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo study. J Clin Endocrinol Metab 2000;85:3561–3568.CrossRefGoogle Scholar
  5. 5.
    Marks PA, Banks J. Inhibition of mammalian glucose-6-phosphate dehydrogenase by steroids. Proc Nall Acad Sci USA 1960;46:447–452.CrossRefGoogle Scholar
  6. 6.
    Raineri R, Levy HR. On the specificity of steroid interaction with mammary gland glucose-6-phosphate dehydrogenase. Biochemistry 1970;9:2233–2243.PubMedCrossRefGoogle Scholar
  7. 7.
    Gordon GB, MacKow MC, Levy HR. On the mechanism of interaction of steroids with human glucose-6-phosphate dehydrogenase. Arch Biochem Biophys 1995;318:25–29.PubMedCrossRefGoogle Scholar
  8. 8.
    Kletzien RF, Harris PK, Foellmi LA. Glucose-6-phosphate dehydrogenase: a “housekeeping” enzyme subject to tissuespecific regulation by hormones, nutrients, and oxidant stress. FASEB J 1994;8:174–181.PubMedGoogle Scholar
  9. 9.
    Schwartz AG, Perantoni A. Protective effect of dehydroepiandrosterone against aflatoxin B1- and 7,12-dimethylbenz(a)anthracene-induced cytotoxicity and transformation in cultured cells. Cancer Res 1975;35:2482–2487.PubMedGoogle Scholar
  10. 10.
    Lee T- C, Lai G-J, Kao S-L, et al. Protection of a rat tracheal epithelial cell line from paraquat toxicity by inhibition of glucose-6-phosphate dehydrogenase. Bibchem Pharmacol 1993;45:1143–1147.CrossRefGoogle Scholar
  11. 11.
    Misra, HP, Gorsky LD. Paraquat and NADPH-dependent lipid peroxidation in lung microsomes. J Biol Chem 1981;256:9994–9998.PubMedGoogle Scholar
  12. 12.
    Babior BM. NADPH-oxidase: an update. Blood 1999;93:1464–1476.PubMedGoogle Scholar
  13. 13.
    Suh Y- A, Arnold RS, Lasegue B. et al. Cell transformation by the superoxide-generating oxidase, MOX 1. Nature 1999;401:79–82.PubMedCrossRefGoogle Scholar
  14. 14.
    Marietta MA. Nitric acid synthase: aspects concerning structure and catalysis. Cell 1994;78:927–930.CrossRefGoogle Scholar
  15. 15.
    Imlay JA, Linn S. DNA damage and oxygen radical toxicity. Science 1988;240:1302–1309.PubMedCrossRefGoogle Scholar
  16. 16.
    Dworkin CR, Gorman SD, Pashko LL, et al. Inhibition of growth of HeLa and WI-38 cells by dehydroepiandrosterone and its reversal by ribo- and deoxyribonucleosides. Life Sci 1988;38:1451–1457.CrossRefGoogle Scholar
  17. 17.
    Gordon GB, Shantz LM, Talalay P. Modulation of growth, differentiation and carcinogenesis by dehydroepiandrosterone. Adv Enzyme Regul 1987;26:355–382.PubMedCrossRefGoogle Scholar
  18. 18.
    Shantz LM, Talalay P, Gordon GB. Mechanism of inhibition of growth of 3T3-L1 fibroblasts and their differentiation to adipocytes by dehydroepiandrosterone and related steroids: role of glucose-6-phosphate dehydrogenase. Proc Nall Acad Sci USA 1989;86:3852–3856.CrossRefGoogle Scholar
  19. 19.
    Tian WN, Braunstein LD, Pang J, et al. Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J Biol Chem 1998;273:10,609–10,617.Google Scholar
  20. 20.
    Dashtaki R, Wharton AR, Murphy TM, et al. Dehydroepiandrosterone and analogs inhibit DNA binding of AP-1 and airway smooth muscle proliferation. J Pharmacol Exp Ther 1998;285:876–883.PubMedGoogle Scholar
  21. 21.
    Irani K, Xi Y, Zweier JL, et al. Mitogenic signaling mediated by oxidants in ras-transformed fibroblasts. Science 1997;275:1649–1652.PubMedCrossRefGoogle Scholar
  22. 22.
    Whitcomb JM, Schwartz AG. Dehydroepiandrosterone and 16α-Br epiandrosterone inhibit 12-O-tetradecanoylphorbol13-acetate stimulation of superoxide radical production by human polymorphonuclear leukocytes. Carcinogenesis 1985;6:333–335.PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz AG, Pashko LL. Suppression of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and inflammation by the dehydroepiandrosterone analog 16a-fluoro-5-androsten-17-one and its reversal by NADPH-liposomes. Cancer Lett 2001;168:7–14.PubMedCrossRefGoogle Scholar
  24. 24.
    Schwartz AG. Inhibition of spontaneous breast cancer formation in female C3H-Av Y/A mice by long-term treatment with dehydroepiandrosterone. Cancer Res 1979;39:1129–1132.PubMedGoogle Scholar
  25. 25.
    Schwartz A, Hard G, Pashko L, et al. Dehydroepiandrosterone: an anti-obesity and anti-carcinogenic agent. Nutr Cancer 1981;3:46–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Inano H, Ishii-Ohba H, Suzuki K, et al. Chemoprevention by dietary dehydroepiandrosterone against promotion/progres-sion phase of radiation-induced mammary tumorigenesis in rats. J Steroid Biochem Mol Biol 1995;54:47–53.PubMedCrossRefGoogle Scholar
  27. 27.
    Ratko TA, Detrisac CJ, Mehta RG, et al. Inhibition of rat mammary gland chemical carcinogenesis by dietary dehydroepiandrosterone or a fluorinated analog of dehydroepiandrosterone. Cancer Res 1991;51:481–486.PubMedGoogle Scholar
  28. 28.
    Simile M, Pascale RM, DeMiglio MR, et al. Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis. Int J Cancer 1995;62:210–215.PubMedCrossRefGoogle Scholar
  29. 29.
    Schwartz AG, Tannen RH. Inhibition of 7,12-dimethylbenz(a)anthracene- and urethan-induced lung tumor formation in A/J mice by long-term treatment with dehydroepiandrosterone. Carcinogenesis 1981;2:1335–1338.PubMedCrossRefGoogle Scholar
  30. 30.
    Nyce JW, Magee PN, Hard GC, Schwartz AG. Inhibition of 1,2-dimethylhydrazine-induced colon tumorigenesis in Balb/c mice by dehydroepiandrosterone. Carcinogenesis 1984;5:57–62.PubMedCrossRefGoogle Scholar
  31. 31.
    Rao KV, Johnson WD, Bosland MC, et al. Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone. Cancer Res 1999;59:3084–3089.PubMedGoogle Scholar
  32. 32.
    Hursting SD, Perkins SN, Phang JM. Chemoprevention of spontaneous tumorigenesis in p53-knockout transgenic mice. Proc Am Assoc Cancer Res 1995;36:588.Google Scholar
  33. 33.
    Rao MS, Subbarao V, Yeldani AV, Reddy JK. Inhibition of spontaneous testicular Leydig cell tumor development in F-344 rats by dehydroepiandrosterone. Cancer Lett 1992;65:123–126.PubMedCrossRefGoogle Scholar
  34. 34.
    Pashko LL, Rovito RJ, Williams JR, et al. Dehydroepiandrosterone (DHEA) and 3β-methylandrost-5-en-17-one: inhibitors of 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin papilloma formation in mice. Carcinogenesis 1984;5:463–466.PubMedCrossRefGoogle Scholar
  35. 35.
    Pashko LL, Hard GC, Rovito RJ, et al. Dehydroepiandrosterone and 3 ß-methylandrost-5-en-17-one inhibit 7,12-dimethylbenz(a)anthracene-induced skin papillomas and carcinomas in mice. Cancer Res 1985;45:164–166.PubMedGoogle Scholar
  36. 36.
    Pashko LL, Lewbart ML, Schwartz AG. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-promoted skin tumor formation in mice by 16α-fluoro-5-androsten-17-one and its reversal by deoxyribonucleosides. Carcinogenesis 1991;12:2189–2192.PubMedCrossRefGoogle Scholar
  37. 37.
    Lee WY, Locknisar MF, Fischer SM. Interleukin- 1a mediates phorbol-ester-induced inflammation and epidermal hyperplasia. FASEB J 1994;8:1081–1087.PubMedGoogle Scholar
  38. 38.
    Schwartz AG, Lewbart ML, Pashko LL. Novel dehydroepiandrosterone analogues with enhanced biological activity and reduced side-effects in mice and rats. Cancer Res 1988;48:4817–4822.PubMedGoogle Scholar
  39. 39.
    Garcea R, Daino L, Frassetto S, et al. Reversal by ribo- and deoxyribonucleosides of dehydroepiandrosterone-induced inhibition of enzyme altered foci in the liver of rats subjected to the initiation-selection process of experimental carcinogenesis. Carcinogenesis 1988;9:931–938.PubMedCrossRefGoogle Scholar
  40. 40.
    Pallman J, Ackerman LJ. 28-Day Oral Toxicity Study in Rats, Pharmakon, USA.Google Scholar
  41. 41.
    Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in activation of NFKB transcription factor and HIV-1. EMBO J 1991;10:2247–2258.PubMedGoogle Scholar
  42. 42.
    Satriano JA, Shuldiner M, Hora K, et al. Oxygen radicals as second messengers for expression of the monocyte chemoattract protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-a and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Investig 1993;92:1564–1571.PubMedCrossRefGoogle Scholar
  43. 43.
    Gordon GB, Bush DE, Weisman HF. Reduction of atherosclerosis by administration of dehydroepiandrosterone. J Clin Invest 1988;82:712–720.PubMedCrossRefGoogle Scholar
  44. 44.
    Arad Y, Badimon JJ, Badimon L, et al. Dehydroepiandrosterone: feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit. Arteriosclerosis 1989;9:159–166.PubMedCrossRefGoogle Scholar
  45. 45.
    Eich DM, Nestler JE, Johnson DE, et al. Inhibition of accelerated atherosclerosis with dehydroepiandrosterone in the heterotropic rabbit model of cardiac transplantation. Circulation 1993;87:261–269.PubMedCrossRefGoogle Scholar
  46. 46.
    Mao SJ, Rates MT, Parker RA, et al. Attenuation of atherosclerosis in a modified strain of hypercholesterolemic Watanabe rabbits with use of a probucol analog (MDL 29,311) that does not lower serum cholesterol. Arterioscler Thromb 1991;11:1266–1275.PubMedCrossRefGoogle Scholar
  47. 47.
    Schuh JR, Blehm DJ, Frierdich GE, et al. Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. J Clin Invest 1993;91:1453–1458.PubMedCrossRefGoogle Scholar
  48. 48.
    Munzel T, Keaney JF Jr. Are ACE inhibitors a “magic bullet” against oxidative stress. Circulation 2001;104:1571–1574.PubMedCrossRefGoogle Scholar
  49. 49.
    Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–153.PubMedCrossRefGoogle Scholar
  50. 50.
    Luzzato L, Mehta A. Glucose-6-phosphate dehydrogenase deficiency, in The Metabolic Basis of Inherited Diseases, 6th ed. Scriver CR, Baudot AL, Sly WS, Valle D, eds McGraw Hill, New York 1989, pp.2237, 4517.Google Scholar
  51. 51.
    Siniscalo M, Bernini L, Latte B, Motulski AG. Favism and thalassemia and the relationship to malaria. Nature 1961;190:1179–1180.CrossRefGoogle Scholar
  52. 52.
    Beutler E. G6PD deficiency. Blood 1994;84:3613–3636.PubMedGoogle Scholar
  53. 53.
    Feo F, Pirisi L, Pascale R, et al. Modulatory effect of glucose-6-phosphate dehydrogenase deficiency on benzo(a)pyrene toxicity and transforming activity for in vitro-cultured human skin fibroblasts. Cancer Res 1984;44:3419–3425.PubMedGoogle Scholar
  54. 54.
    Feo F, Pirisi L, Pascale R, et al. Modulatory mechanisms of chemical carcinogenesis: the role of the NADPH pool in benzo(a)pyrene activation. Toxicol Pathol 1984;12:261–268.PubMedCrossRefGoogle Scholar
  55. 55.
    Pascale R, Garcea R, Ruggiu ME, et al. Decreased stimulation by 12-O-tetradecanoylphorbol-13-acetate of superoxide radical production by polymorphonuclear leukocytes carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase. Carcinogenesis 1987;8:1567–1570.PubMedCrossRefGoogle Scholar
  56. 56.
    Dessi S, Batetta B, Cherchi R, et al. Hexose monophosphate shunt enzymes in lung tumors from normal and glucose-6-phosphate-dehydrogenase-deficient subjects. Oncology 1988;45:287–291.PubMedCrossRefGoogle Scholar
  57. 57.
    Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis 2000;361–370.Google Scholar
  58. 58.
    Cerutti P. Oxy-radicals and cancer. Lancet 1994;344:862–863.PubMedCrossRefGoogle Scholar
  59. 59.
    Barry-Lane PA, Patterson C, van der Merwe M, et al. P47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice. J Clin Investig 2001;108:1513–1522.PubMedGoogle Scholar
  60. 60.
    Jenner P. Oxidative damage in neurodegenerative disease. Lancet 1994;344:796–798.PubMedCrossRefGoogle Scholar
  61. 61.
    Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Nall Acad Sci USA 1988;85:2706–2708.CrossRefGoogle Scholar
  62. 62.
    Cocco P, Todde P, Fornera S, et al. Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency. Blood 1998;91:706–709.PubMedGoogle Scholar
  63. 63.
    Koenig R. Sardinia’s mysterious male Methusalehs. Science 2001;291:2074–2076.PubMedCrossRefGoogle Scholar
  64. 64.
    Passarino G, Underhill PA, Cavalli-Sforza LL, et al. Y chromosome binary markers to study the high prevalence of males in Sardinian centenarians and the genetic structure of the Sardinian population. Hum Hered 2001;52:136–139.PubMedCrossRefGoogle Scholar
  65. 65.
    Cavalli-Sforza L, De Benedictis G. Personal communication.Google Scholar
  66. 66.
    Yen TT, Allan JV, Pearson DV, et al. Prevention of obesity in AvY/a mice by dehydroepiandrosterone. Lipids 1977;12:401–413.CrossRefGoogle Scholar
  67. 67.
    Coleman DL, Schwizer RW, Leiter EH. Effect of the genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice. Diabetes 1984;33:26–32.PubMedCrossRefGoogle Scholar
  68. 68.
    Gansler TS, Muller S, Cleary MP. Chronic administration of dehydroepiandrosterone reduces pancreatic β-cell hyperplasia and hyperinsulinemia in genetically obese Zucker rats. Proc Soc Exp Biol Med 1985;180:155–162.PubMedGoogle Scholar
  69. 69.
    Kalimi M, Shafagoj Y, Loria R, et al. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell Biochem 1994;131:99–104.PubMedCrossRefGoogle Scholar
  70. 70.
    Blauer KL, Poth M, Rogers WM, Benton EW. Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology 1991;129:3174–3179.PubMedCrossRefGoogle Scholar
  71. 71.
    Loria RM, Inge TH, Cook SS, et al. Protection against acute lethal viral infections with the native steroid dehydroepiandrosterone (DHEA). J Med Virol 1988;26:301–314.PubMedCrossRefGoogle Scholar
  72. 72.
    Ben-Nathan D, Lachmi B, Lustig S, Feuerstein G. Protection by dehydroepiandrosterone in mice infected with viral encephalitis. Arch Virol 1991;120:263–271.PubMedCrossRefGoogle Scholar
  73. 73.
    Araneo B, Daynes R. Dehydroepiandrosterone functions as more than an antiglucocorticoid in preserving immunocompetence after thermal injury. Endocrinology 1995;136:393–401.PubMedCrossRefGoogle Scholar
  74. 74.
    Sapolsky RM. A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J Neurosci 1985;5:1228–1232.PubMedGoogle Scholar
  75. 75.
    Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998;1:69–73.PubMedCrossRefGoogle Scholar
  76. 76.
    Kimonides VG, Khatibi NH, Svendsen CN, et al. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci USA 1998;95:1852–1857.PubMedCrossRefGoogle Scholar
  77. 77.
    Pecke PM, Chrousos GP. Hypercortisolism and obesity. Ann NY Acad Sci 1995;771:665–676.CrossRefGoogle Scholar
  78. 78.
    Sprecher DL, Pearce GL. How deadly is the “Deadly Quartet”? A post-CABG evaluation. J Am Coll Cardiol 2000;36:1159–1165.PubMedCrossRefGoogle Scholar
  79. 79.
    Freedman MR, Horwitz BA, Stern JS. Effect of adrenalectomy and glucocorticoid replacement on development of obesity. Am J Physiol 1986;250:R595—R607.PubMedGoogle Scholar
  80. 80.
    Edwards CRW, Stewart PM, Burt D, et al. Localisation of 11β-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor. Lancet 1988;ii:986–989.CrossRefGoogle Scholar
  81. 81.
    Kotelevtsev Y, Holmes MC, Burchell A, et al. 11betaHydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia obesity or stress. Proc Natl Acad Sci USA 1997;94:14,924–14,929.CrossRefGoogle Scholar
  82. 82.
    Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001;294:2166–2170.PubMedCrossRefGoogle Scholar
  83. 83.
    Pashko LL, Schwartz AG. Antihyperglycemic effect of the dehydroepiandrosterone analogue 16a-fluoro-5-androsten17-one in diabetic mice. Diabetes 1993;42:1105–1108.PubMedCrossRefGoogle Scholar
  84. 84.
    Coleman, DL, Leiter EH, Schwizer RW. Therapeutic effects of dehydroepiandrosterone (DHEA) on diabetic mice. Diabetes 1982;31:830–833.PubMedCrossRefGoogle Scholar
  85. 85.
    Whorwood CB, Donovan SJ, Wood PJ, Phillips DI. Regulation of glucocorticoid receptor alpha and beta isoforms and type I 1 1beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? J Clin Endocrinol Metab 2001;86:2296–2308.PubMedCrossRefGoogle Scholar
  86. 86.
    Svec F, Porter JF. The actions of exogenous dehydroepiandrosterone in experimental animals and humans. Proc Soc Exp Biol Med 1998;218:174–191.PubMedGoogle Scholar
  87. 87.
    Freireich EJ, Gehan EA, Rall DP, et al. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemother Rep 1966;50:219–244.PubMedGoogle Scholar
  88. 88.
    Mortola JF, Yen SSC. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990;71:696–704.PubMedCrossRefGoogle Scholar
  89. 89.
    Frenkel RA, Slaughter CA, Orth K, et al. Peroxisome proliferation and induction of peroxisomal enzymes in mouse and rat liver by dehydroepiandrosterone feeding. J Steroid Biochem 1990;35:333–342.PubMedCrossRefGoogle Scholar
  90. 90.
    Rao MS, Subbarao V, Yeldani AV, Reddy JK. Hepatocarcinogenicity of dehydroepiandrosterone in the rat. Cancer Res 1992;52:2977–2979.PubMedGoogle Scholar
  91. 91.
    Perkins SN, Hursting SD, Haines DC, et al. Chemoprevention of spontaneous tumorigenesis in nullizygous p53-deficient mice by dehydroepiandrosterone and its analog, 16a-fluoro5-androsten-17-one. Carcinogenesis 1997;18:989–994.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  • Arthur G. Schwartz
  • Laura L. Pashko

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