Metabolism of Cancer Chemotherapeutic Agents via Pathways Utilized by Xenobiotics

  • A. M. Guarino
  • C. L. Litterst
Part of the Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology book series (HEP, volume 38 / 1)


The main factors which affect the duration and intensity of drug action are absorption, distribution, excretion, and metabolism; in this chapter attention will be focused on one important factor, the metabolism of antineoplastic agents. The metabolism of a drug can lead to an increase, a decrease, or no change in the pharmacologic or toxicologic activity of that drug. The catabolic reactions which are usually directed toward enhancing the elimination of a drug are emphasized in this and the preceding chapter. The anabolic processes by which conversion of drugs to more complex forms, and, in some cases, incorporation into body constituents occurs, have been discussed (Johns, Chapt. 14, this volume). In the latter case assimilation can occur only when the enzymes involved in intermediary anabolism cannot distinguish the antineoplastic compound from endogenous substrates because of a close resemblance in structural and/or physicochemical properties. Such a substitution of a drug for a natural metabolite is defined by the term “parametabolite” where substitution in a morphological, as well as a functional sense can occur. When the drug substitutes for the natural metabolite only in a morphological sense, with a resultant blockage in the normal biochemical process, the drug is called an antimetabolite.


Liver Microsome Glucuronic Acid Antineoplastic Agent Microsomal Enzyme Antineoplastic Drug 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alvares, A.P., Schilling, G.R., Kttntzman, R.: Differences in the kinetics of benzpyrene hydroxylation by hepatic drug-metabolizing enzymes from phenobarbital and 3-methyl-cholanthrene-treated rats. Biochem. biophys. Res. Commun. 30, 588–593 (1968).PubMedGoogle Scholar
  2. Axelrod, J.: Biochemical factors in the activation and inactivation of drugs. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 238, 24–35 (1960).Google Scholar
  3. Axelrod, J., Inscoe, J.K., Tomkins, G.M.: Enzymatic synthesis of N-glucuronic acid conjugates. Nature (Lond.) 179, 538–539 (1957).Google Scholar
  4. Bailey-Wood, R., Dodgson, K.S., Rose, F.A.: A rat liver sulphohydrolase enzyme acting on adenylyl sulphate. Biochem. J. 112, 257–258 (1969).PubMedGoogle Scholar
  5. Baron, J., Tephly, T.R.: Effect of 3-amino-l, 2,4-triazole on the stimulation of hepatic microsomal heme synthesis and induction of hepatic microsomal oxidases produced by pheno-barbital. Molec. Pharmacol. 5, 10–20 (1969).Google Scholar
  6. Beraud, T., Vannotti, A.: Comportement métabolique du rat hepatectomise. Acta Endocrinol. 35, 324–333 (1960).Google Scholar
  7. Bollman, J.L., Mendez, F. L.: Separation of bile pigments by column chromatography. Fed. Proc. 14, 399–400 (1955).Google Scholar
  8. Booth, J., Boyland, E.: The biochemistry of aromatic amines. 10. Enzymic N-hydroxylation of arylamines and conversion of arylhydroxylamines into o-aminophenols. Biochem. J. 91, 362–369 (1964).PubMedGoogle Scholar
  9. Boyland, E., Manson, D., Orr, S.F.D.: The biochemistry of aromatic amines. 2. The conversion of arylamines into arylsulfamic acids and arylamine-iglucuronic acids. Biochem. J. 65, 417–423 (1957).PubMedGoogle Scholar
  10. Boyland, E., Nery, R.: The metabolism of urethane and related compounds. Biochem. J. 94, 198–208 (1965).PubMedGoogle Scholar
  11. Bray, D.A., Devita, V.T., Adamson, R.H., Oliverio, V.T.: Effects of l-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037) and its degradation products on progression of L1210 cells through the cell cycle. Cancer Chemother. Rep. 55, 215–220 (1971).PubMedGoogle Scholar
  12. Bridges, J.W., Williams, R.T.: N-Glucuronide formation in vivo and in vitro. Biochem. J. 83, 27P (1962).Google Scholar
  13. Bridges, J.W., Kibby, M.R., Walker, S.R., Williams, R.T.: Species differences in the metabolism of sulphadimethoxine. Biochem. J. 109, 851–856 (1968).PubMedGoogle Scholar
  14. Bridges, J. W., Kibby, M.R., Walker, S.R., Williams, R.T.: Structure and species as factors affecting the metabolism of some methoxy-6-sulphanilamidopyrimidines. Biochem. J. III, 167–172 (1969a).Google Scholar
  15. Bridges, J.W., Walker, S.R., Williams, R.T.: Species differences in the metabolism and excretion of sulphasomidine and sulphamethomidine. Biochem. J. III, 173–179 (1969b).Google Scholar
  16. Brock, N., Hohorst, H.J.: Metabolism of cyclophosphamide. Cancer 20, 900–904 (1967).PubMedGoogle Scholar
  17. Brodie, B.B., Gillette, J.R., LaDu, B.N.: Enzymatic metabolism of drugs and other foreign compounds. Ann. Rev. Biochem. 27, 427–454 (1958).PubMedGoogle Scholar
  18. Brown, H.D., Chattopadhyay, S.K., Pennington, S.N., Spratt, J.S., Morris, H.P.: Mixed-function oxidation in tumors. Brit. J. Cancer 25, 135–141 (1971).PubMedGoogle Scholar
  19. Cantoni, G.L.: S-adenosylmethionine: a new intermediate formed enzymatically from L-methionine and adenosine triphosphate. J. biol. Chem. 204, 403–416 (1953).Google Scholar
  20. Castro, J.A., Gillette, J.R.: Species and sex differences in the kinetic constants for the N-demethylation of ethylmorphine by liver microsomes. Biochem. biophys. Res. Commun. 28, 426–430 (1967).PubMedGoogle Scholar
  21. Claude, A.: The constitution of protoplasm. Science 97, 451–456 (1943).PubMedGoogle Scholar
  22. Cohen, J.L., Jao, J.Y.: Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. J. Pharmacol, exp. Ther. 174, 206–210 (1970).Google Scholar
  23. Cohn, R.: Über das Verhalten einiger Pyridin- und Naphthalinderivate im thierischen Stoff-wechsel. Hoppe-Seylers Z. physiol. Chem. 18, 112–113 (1894).Google Scholar
  24. Colvin, M., Bono, V.H., Jr.: The enzymatic reduction of hydroxyurea to urea by mouse liver. Cancer Res. 30, 1516–1519 (1970).PubMedGoogle Scholar
  25. Conney, A.H., Gilman, A.G.: Puromycin inhibition of enzyme induction by 3-methyl-cholanthrene and phenobarbital. J. biol. Chem. 238, 3682–3685 (1963).PubMedGoogle Scholar
  26. Conney, A.H., Schneidman, K., Jacobson, M., Kuntzman, R.: Drug-induced changes in steroid metabolism. Ann. N. Y. Acad. Sci. 123, 98–109 (1965).PubMedGoogle Scholar
  27. Craig, A.W., Jackson, H.: The mechanism of 32P-labelled triethylene-phosphoramide in relation to its anti-tumor activity. Brit. J. Pharmacol. 10, 321–325 (1955).PubMedGoogle Scholar
  28. Dahm, V.K., Breuer, H.: Enzymatische Untersuchungen über die Glucuronidierung von Östriol beim Menschen. Z. klin. Chem. 4, 153–157 (1966).Google Scholar
  29. Danielli, J.F., Montagu, K.A., Bernard, P.J., Pye, A., Price, F.W., Hamerton, J.L., Courtney, W.A.M., A. R. Brit. Empire Cancer Campaign 37, 575–576 (1959).Google Scholar
  30. Davies, D.S., Gigon, P.L., Gillette, J.R.: Sex differences in the kinetic constants for the N-demethylation of ethylmorphine by rat liver microsomes. Biochem. Pharmacol. 17, 1865–1872 (1968).PubMedGoogle Scholar
  31. Devita, V.T., Denham, C., Davidson, J. D., Oliverio, V.T.: Physiological disposition of the carcinostatic l, 3-bis(2-chloroethyl)-l-nitrosourea (BCNU) in man and animals. Clin. Pharmacol. Ther. 8, 566–577 (1967).PubMedGoogle Scholar
  32. Dewaide, J.H.: Metabolism of Xenobiotics. Ph. D. Thesis, Univ. of Nijmegen, Nijmegen, Netherlands (1971).Google Scholar
  33. Dixon, R.L.: Effect of chloramphenicol on the metabolism and lethality of cyclophosphamide in rats. Proc. Soc. exp. Biol. (N. Y.) 127, 1151–1155 (1968).Google Scholar
  34. Dixon, R.L., Shultice, R. W., Fouts, J.R.: Factors affecting drug metabolism by liver micro-somes. IV. Starvation. Proc. Soc. exp. Biol. (N. Y.) 103, 333–335 (1960).Google Scholar
  35. Dodgson, K.S., Rose, F.A.: Sulfoconjugation and sulfobydrolysis. In: Metabolic conjugation and metabolic hydrolysis (Fishman, W.H., Ed.) p. 240. New York: Academic Press 1970.Google Scholar
  36. Donelll, M.G., Garattinij S.: Drug metabolism after repeated treatments with cytotoxic agents. Europ. J. Cancer 7, 361–364 (1971).Google Scholar
  37. Dost, F.N., Reed, D. J.: Methane formation in vivo from N-isopropyl α(2-methylhydrazino)-p-toluamide hydrochloride, a tumor-inhibiting methylhydrazine derivative. Biochem. Pharmacol. 16, 1741–1746 (1967).PubMedGoogle Scholar
  38. Dring, L.G., Smith, R.L., Williams, R.T.: The fate of amphetamine in man and other mammals. J. pharm. Pharmacol. 18, 402–404 (1966).PubMedGoogle Scholar
  39. Duncan, G.G., Cristofori, F.C., Yue, J.K., Murthy, M.S.J.: The control of obesity by intermittent fasts. Med. Clin. N. Amer. 48, 1359–1372 (1964).Google Scholar
  40. Dutton, G.J., Storey, I.D.E.: The isolation of a compound of uridine diphosphate and glucuronic acid from liver. Biochem. J. 53, XXXVII (1953).PubMedGoogle Scholar
  41. Ellison, T.L., Gutzait, L., Van Loon, E. J.: The comparative metabolism of d-amphetamine-C14 in the rat, dog, and monkey. J. Pharmacol. exp. Ther. 152, 383–387 (1966).PubMedGoogle Scholar
  42. Everett, J.L., Ross, W.C.J.: Aryl-2-halogenoalkylamines. Part II. J. chem. Soc. 1972–1983 (1949).Google Scholar
  43. Farber, S., Toch, R., Sears, E.M., Pinkel, D.: Advances in chemotherapy of cancer in man. Adv. Cancer Res. 4, 1–71 (1956).PubMedGoogle Scholar
  44. Field, R.B., Gang, M., Kline, I., Vendttti, J.M., Waravdekar, V.S.: The effect of pheno-barbital or 2-diethylaminoethyl-2, 2-diphenyl-valerate on the activation of cyclophos-phamide in vivo. J. Pharmacol. exp. Ther. 180, 475–483 (1972).PubMedGoogle Scholar
  45. Fouts, J.R.: Interaction of drugs and hepatic microsomes. Fed. Proc. 21, 1107–1111 (1962).PubMedGoogle Scholar
  46. Fouts, J.R., Brodie, B.B.: The enzymatic reduction of chloramphenicol, p-nitrobenzoic acid and other aromatic nitro compounds in mammals. J. Pharmacol. exp. Ther. 119, 197–207 (1957).PubMedGoogle Scholar
  47. Fox, B.W., Craig, A. W., Jackson, H.: The comparative metabolism of myleran-85S in the rat, mouse, and rabbit. Biochem. Pharmacol. 5, 27–29 (1960).PubMedGoogle Scholar
  48. Franchi, G., Rosso, R.: Metabolic fate of zoxazolamine in tumor bearing rats. Biochem. Pharmacol. 18, 236–238 (1969).PubMedGoogle Scholar
  49. French, A.P., Warren, J. C.: Properties of steroid sulphatase and aryl sulphatase activities of human placenta. Biochem. J. 105, 233–241 (1967).PubMedGoogle Scholar
  50. Frezza, M., Desandre, G., Perona, G., Coericher, R.: Bilirubin inhibition of 4-methyl-umbelliferone glucuro conjugation in vitro by the human liver. Clin. chim. Acta 21, 509–512 (1968).PubMedGoogle Scholar
  51. Friedman, O.M., Papanastassiou, Z.N., Levi, R.S., Till, H.R., Jr., Whaley, W.M.: Potential carcinolytic agents related to cyclophosphamide. J. med. Chem. 6, 82–85 (1963).PubMedGoogle Scholar
  52. Fujiwara, T., Spencer, B.: Adenyl deaminase of Helix pomatia. Biochem. J. 85, 19P (1962).Google Scholar
  53. Gaudette, L.E., Brodie, B.B.: Relationship between the lipid solubility of drugs and their oxidation by liver microsomes. Biochem. Pharmacol. 2, 89–96 (1959).PubMedGoogle Scholar
  54. Gillette, J.R.: Factors affecting drug metabolism. Ann. N. Y. Acad. Sci. 179, 43–66 (1971).PubMedGoogle Scholar
  55. Gillette, J.R., Gram, T.E.: Cytochrome P-450 reduction in liver microsomes and its relationship to drug metabolism. In: Microsomes and drug oxidations. (Gillette, J.R., Conney, A.H., Cosmides, G.J., Estabrook, R. W., Fouts, J.R., Mannering, G. J., Eds.,) pp. 133–150. New York: Academic Press 1969.Google Scholar
  56. Goldenthal, E.I., Nadkarni, M.V., Smith, P.K.: The excretion of radioactivity following administration of tri-C14-ethylenimino-s-triazine in normal mice. J. Pharmacol, exp. Ther. 122, 431–441 (1958).Google Scholar
  57. Gram, T.E., Hansen, A. R., Fouts, J.R.: The submicrosomal distribution of hepatic UDP-glucuronyl transferases in the rabbit. Biochem. J. 106, 587–591 (1968).PubMedGoogle Scholar
  58. Grelm, H., Remmer, H.: Abbauhemmung und Synthesesteigerung bei der Vermehrung mikro-somaler Cytochrome durch Phenobarbital. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 264, 238–239 (1969).Google Scholar
  59. Grunicke, H., Liersch, M., Holzer, H., Arnold, H.: Untersuchungen zum Wirkungsmechanismus von Endoxan. Biochem. Pharmacol. 14, 1485–1490 (1965).PubMedGoogle Scholar
  60. Guarino, A.M., Fales, H.M.: Gas chromatography-mass spectrometry. Handbook exp. Pharmacol. XXVIII-2, 178–208 (1971).Google Scholar
  61. Guarino, A.M., Gram, T.E., Gigon, P.L., Greene, F. E., Gillette, J. R.: Changes in Michaelis and spectral constants for aniline in hepatic microsomes from phenobarbital-treated rats. Molec. Pharmacol. 5, 131–136 (1969).Google Scholar
  62. Halac, E., Jr., Frank, S.: Glucuronyl transferase and glycogen deficiency in liver of Gunn rats. Biochem. biophys. Res. Commun. 2, 379–383 (1960).Google Scholar
  63. Hansen, W.J., Giles, W.G., Nadler, S.B.: Metabolism of 9-ethyl-e-MP-S36 and 9-butyl-6-MP-S35 in humans. Proc. Soc. exp. Biol. (N. Y.) 113, 163–165 (1963).Google Scholar
  64. Harper, N.J.: Drug latentiation. J. med. pharm. Chem. 1, 467–500 (1959).PubMedGoogle Scholar
  65. Henderson, J.F., Mazel, P.: Demethylation of purine analogs by microsomal enzymes from mouse liver. Biochem. Pharmacol. 13, 207–210 (1964).PubMedGoogle Scholar
  66. Hill, D.L., Laster, W.R., Jr., Struck, R.F.: Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res. 32, 658–665 (1972).PubMedGoogle Scholar
  67. Holtzman, J.L., Gdllette, J.R.: The effect of phenobarbital on the turnover of microsomal phospholipid in male and female rats. J. biol. Chem. 243, 3020–3028 (1968).PubMedGoogle Scholar
  68. Imamura, H.: Studies on carcinostatic substances. XXVIII. Activation of the derivatives of 2-chloroethylamine with latent activity. Chem. pharm. Bull. 8, 449–454 (1960).Google Scholar
  69. Irving, C.L.: Enzymatic N-hydroxylation of the carcinogen 2-acetylaminofluorene and the metabolism of N-hydroxy-2-acetylaminofluorene-9-14C in vitro, J. biol. Chem. 239, 1589–1596 (1964).PubMedGoogle Scholar
  70. Iring, C.L., Wiseman, R., Jr., Hull, J.T.: Biliary excretion of the O-glucuronide of N-hydroxy-2-acetylaminofluorene by the rat and rabbit. Cancer Res. 27, 2309–2317 (1967).Google Scholar
  71. Iyer, V.N., Szybalski, W.: Mitomycins and porfiromycin: chemical mechanism of activation and cross-linking of DNA. Science 145, 55–58 (1964).PubMedGoogle Scholar
  72. Jayle, M.F., Pasqualini, J.R.: In: Glucuronic acid: free and combined. Chemistry, biochemistry, pharmacology, and medicine, p. 507. (Dutton, G. J., Ed.). New York: Academic Press 1966.Google Scholar
  73. Kamil, I. A., Smith, J.K., Williams, R.T.: Studies in detoxication. 50. The isolation of methyl and ethyl glucuronides from the urine of rabbits receiving methanol and ethanol. Biochem. J. 54, 390–392 (1953).PubMedGoogle Scholar
  74. Kampffmeyer, H., Kiese, M.: The effect of carbon monoxide on the hydroxylation of aniline and N-ethylaniline by microsomal enzymes. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 250, 1–8 (1965).Google Scholar
  75. Kandaswamy, T.S., Henderson, J.F.: The metabolism of ethidium bromide in normal and neoplastic tissues. Cancer Res. 23, 250–253 (1963).Google Scholar
  76. Kaslander, J.: Formation of an S-glucuronide from tetraethylthiuram disulfide (Antabuse®) in man. Biochem. biophys. Acta (Amst.) 71, 730–732 (1963).Google Scholar
  77. Kato, R., Frontino, G., Vassanelli, P.: Decreased activities of liver microsomal drug-metabolizing enzymes in the rats bearing Walker carcinosarcoma. Experientia (Basel) 19, 31–32 (1963).Google Scholar
  78. Kato, R., Gillette, J.R.: Effect of starvation on NADPH-dependent enzymes in liver micro-somes of male and female rats. J. Pharmacol, exp. Ther. 150, 279–284 (1965).Google Scholar
  79. Kato, R., Jondorf, W.R., Loeb, L.A., Ben, T., Gelboin, H.V.: Studies on the mechanism of drug-induced microsomal enzyme activities. V. Phenobarbital stimulation of endogenous messenger RNA and polyuridylic acid-directed L-[14C]-phenylalanine incorporation. Molec. Pharmacol. 2, 171–186 (1966).Google Scholar
  80. Kato, R., Oshima, T., Takanaka, A.: Studies on the mechanism of nitroreduction by rat liver. Molec. Pharmacol. 5, 487–498 (1969a).Google Scholar
  81. Kato, R., Takanaka, A., Shoji, H.: Inhibition of drug-metabolizing enzymes of liver micro-somes by hydrazine derivatives in relation to their lipid solubility. Jap. J. Pharmacol. 19, 315–322 (1969b).PubMedGoogle Scholar
  82. Kiese, M., Uehleke, H.: Der Ort der N-oxydation des Anilins im höheren Tier. Naunyn-Schmiedebergs Arch. exp. Phar. Pharmak. 242, 117–129 (1961).Google Scholar
  83. Koizumi, T., Suematsu, T., Kawasaki, A., Hiramatsu, K., Iwabori, N.: Synthesis and degradation of active sulfate in liver. Biochem. biophys. Acta (Amst.) 184, 106–113 (1969).Google Scholar
  84. Kreis, W.: Metabolism of an antineoplastic methylhydrazine derivative in a P815 mouse neoplasm. Cancer Res. 30, 82–89 (1970).PubMedGoogle Scholar
  85. Kuntzman, R., Jacobson, M., Schneidman, K., Conney, A.H.: Similarities between oxidative drug-metabolizing enzymes and steroid hydroxylases in liver microsomes. J. Pharmacol. exp. Ther. 146, 280–285 (1964).PubMedGoogle Scholar
  86. Kuntzman, R., Levin, W., Jacobson, M., Conney, A.H.:Studies on microsomal hydroxylation and the demonstration of a new carbon monoxide binding pigment in liver microsomes. Life Sci. 7, 215–224 (1968).Google Scholar
  87. Lang, N.: Steroid hormones and enzyme induction. In: The biochemistry of steroid hormone action. (Smellie, R.M.S., Ed.) pp. 85–100. New York: Academic Press 1971.Google Scholar
  88. Lange, G.: Verschiedene Induktion der mikrosomalen N- und p-Hydroxylierung von Anilin und N-Äthylanilin bei Kaninchen. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 257, 230–256 (1967).Google Scholar
  89. Lavin, P., Koss, L.G.: Effects of a single dose of cyclophosphamide on various organs in the rat. III. Electron microscopic study of the liver. Amer. J. Path. 62, 159–168 (1971).PubMedGoogle Scholar
  90. Lee, R.M., Livett, B.H.: A method for the colorimetric estimation of local anaesthetics containing an ester link, and its use in the determination of esterase activity. Biochem. Pharmacol. 16, 1757–1765 (1967).PubMedGoogle Scholar
  91. Leibman, K.C., McAllister, W.J., Jr.: Metabolism of trichloroethylene in liver microsomes. III. Induction of the enzymic activities and its effect on excretion of metabolites. J. Pharmacol. exp. Ther. 157, 574–580 (1967).PubMedGoogle Scholar
  92. Levin, W., Kuntzman, R.: Biphasic decrease of radioactive hemoprotein from liver microsomal CO-binding particles. J. biol. Chem. 244, 3671–3676 (1969).PubMedGoogle Scholar
  93. Lippel, K., Olson, J.A.: Biosynthesis of β-glucuronides of retinal and of retinoic acid in vivo and in vitro. J. Lipid Res. 9, 168–175 (1968).PubMedGoogle Scholar
  94. Lotlikar, P.D., Enomoto, M., Miller, J. A., Miller, E.C.: Species variation in the N- and ring-hydroxylation of 2-acetylaminofluorene and effects of 3-methylcholanthrene pretreatment. Proc. Soc. exp. Biol. (N. Y.) 125, 341–346 (1967).Google Scholar
  95. Lu, I., Larson, R.E.: Hepatic oxidative metabolism of pentobarbital following intoxication with l, 3-bis(2-chloroethyl)-l-nitrosourea (BCNU). Proc. Western Pharmacol. Soc. 13, 78–82 (1970).Google Scholar
  96. Maddock, C.L., Handler, A.H., Friedman, O.M., Foley, G.E., Farber, S.: Primary evaluation of alkylating agent cyclohexylamine salt of N,N-bis(2-chloroethyl)phosphorodiamidic acid (NSC-69945; OMF-59) in experimental antitumor assay systems. Cancer Chemother. Rep. 50, 629–639 (1966).Google Scholar
  97. Maller, R.K., Heidelberger, C.: Studies on OPSPA. II. Distribution and excretion of radioactivity following administration of OPSPA-C14 and OPSPA-P32 to the rat. Cancer Res. 17, 284–290 (1957).PubMedGoogle Scholar
  98. Mandel, H.G.: The physiological disposition of some anticancer agents. Pharmacol. Rev. 11, 743–838 (1959).PubMedGoogle Scholar
  99. Marsh, J.B., James, A.T.: The conversion of stearic to oleic acid by liver and yeast preparations. Biochim. biophys. Acta (Amst.) 60, 320–328 (1962).Google Scholar
  100. Mason, H.S.: In: Advances in enzymology. (Nord, F.F., Ed.), p. 1979. New York: Interscience 1957.Google Scholar
  101. Mattes, L., Kruger, S., Schueler, F.W.: The effect of Ehrlich ascites tumor on the sleeping time of mice. Arch. int. Pharmacodyn. 87, 166–172 (1962).Google Scholar
  102. Mazel, P., Henderson, J.F., Axelrod, J.: S-demethylation by microsomal enzymes. J. Pharmacol. exp. Ther. 143, 1–6 (1964).PubMedGoogle Scholar
  103. Mazel, P., Kerza-Kwiatecki, A., Simanis, J.: Studies on the demethylation of puromycin and related compounds by liver microsomal enzymes. Biochim. biophys. Acta (Amst.) 114, 72–82 (1966).Google Scholar
  104. Mellett, L.B., Hodgson, P.E., Woods, L.A.: Absorption and fate of C14 labeled N, N′, N″- triethylenethiophosphoramide (thio-TEPA) in humans and dogs. J. Lab. clin. Med. 60, 818–825 (1962).PubMedGoogle Scholar
  105. Mlettinen, T.A., Leskinen, E.: Enzyme levels of glucuronic acid metabolism in the liver, kidney and intestine of normal and fasted rats. Biochem. Pharmacol. 12, 565–575 (1963).Google Scholar
  106. Miller, J.A., Cramer, J.W., Miller, E.C.: The N- and ring-hydroxylation of 2-acetylamino-fluorene during carcinogenesis in the rat. Cancer Res. 20, 950–962 (1960).PubMedGoogle Scholar
  107. Milsom, S.W., Rose, F.A., Dodgson, K.S.: Assay of a microsomal marker enzyme: Rat liver aryl sulfatase. Biochem. J. 109, 40P (1968).PubMedGoogle Scholar
  108. Montgomery, J.A., James, R., McCaleb, G.S.: The modes of decomposition of 1, 3-bis(2-chloroethyl)-l-nitrosourea and related compounds. J. med. Chem. 10, 668–674 (1967).PubMedGoogle Scholar
  109. Moy, R.H.: Studies of the pharmacology of o, p’-DDD in man. J. Lab. clin. Med. 58, 296–304 (1961).PubMedGoogle Scholar
  110. Nadkarni, M.V., Trams, E.G., Smith, P.K.: Preliminary studies on the distribution and fate of TEM, TEPA, and myleran in the human. Cancer Res. 19, 713–718 (1959).PubMedGoogle Scholar
  111. Nebert, D.W., Gelboin, H. V.: Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture. I. Assay and properties of induced enzyme. J. biol. Chem. 243, 6242–6249 (1968).PubMedGoogle Scholar
  112. Nelson, A. A., Woodward, G.: Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2, 2-bis(parachlorophenyl)-l, l-dichloroethane (DM) or TDE). Arch. Path. 48, 387–394 (1949).PubMedGoogle Scholar
  113. Oliverio, V.T., Vietzke, W.M., Williams, M.K., Adamson, R.H.: The absorption, distribution, excretion and biotransformation of the carcinostatic l-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in animals. Cancer Res. 30, 1330–1337 (1970).PubMedGoogle Scholar
  114. Omura, T., Sato, R., Cooper, D.Y., Rosenthal, O., Estabrook, R.W.: Function of cytochrome P-450 of microsomes. Fed. Proc. 24, 1181–1189 (1965).PubMedGoogle Scholar
  115. Otsuka, S.: Studies on nitro-reducing enzymes of swine liver. Properties and cofactor requirements of nitro and nitroso reductases. J. Biochem. (Tokyo) 50, 85–94 (1961).Google Scholar
  116. Parke, D.V.: Studies in detoxication. 84. The metabolism of [14C] aniline in the rabbit and other animals. Biochem. J. 77, 493–503 (1960).PubMedGoogle Scholar
  117. Parke, D.V.: Cited in: Detoxication mechanisms, 2nd ed. (Williams, R.T., Ed.) p. 492. Chapman and Hall 1952.Google Scholar
  118. Preussmann, R., Vonhodenberg, A., Hengy, H.: Mechanism of carcinogenesis with 1-aryl-3, 3-dialkyltriazenes. Enzymatic dealkylation by rat liver microsomal fraction in vitro. Biochem. Pharmacol. 18, 1–13 (1969).PubMedGoogle Scholar
  119. Prough, R.A., Wittkop, J.A., Reed, D.J.: Further evidence on the nature of microsomal metabolism of procarbazine and related alkylhydrazines. Arch. Biochem. Biophys. 140, 450–458 (1970).PubMedGoogle Scholar
  120. Quinn, G.P., Axelrod, J., Brodie, B.B.: Species, strain, and sex differences in metabolism of hexobarbitone, amidopyrine, antipyrine, and aniline. Biochem. Pharmacol. 1, 152–159 (1958).Google Scholar
  121. Rakieten, N., Rakieten, M.L., Nadkarni, M.V.: Studies on the diabetogenic action of Streptozotocin (NSC-37917). Cancer Chemother. Rep. 29, 91–98 (1963).Google Scholar
  122. Rall, D.P.: Pharmacologic aspects of selective chemotherapy of leukemia and Burkitt’s tumor. Combination chemotherapy: advertent and inadvertent. Cancer Res. 27, 2650–2655 (1967).PubMedGoogle Scholar
  123. Remy, C.N.: Metabolism of thiopyrimidines and thiopurines. S-methylation with S-adenosyl-methionine transmethylase and catabolism in mammalian tissues. J. biol. Chem. 238, 1078–1084 (1963).PubMedGoogle Scholar
  124. Roberts, R.J., Warwick, G.P.: Mode of action of alkylating agents: formation of S-ethyl-cysteine from ethyl methanesulphonate in vivo. Nature (Lond.) 179, 1181–1182 (1957).Google Scholar
  125. Roberts, R.J., Warwick, G.P.: Studies on the mode of action of alkylating agents. A. R. Brit. Empire Cancer Campaign. 37, 40–43 (1959).Google Scholar
  126. Roberts, R.J., Plaa, G.L.: Effect of phénobarbital on the excretion of an exogenous bilirubin load. Biochem. Pharmacol. 16, 827–835 (1967).PubMedGoogle Scholar
  127. Ross, W.C.J., Warwick, G.P.: Aryl-2-halogenoalkylamines. Part XVIII. The rates of reduction of substituted 4-di-(2-chloroethyl) aminoazobenzenes by stannous chloride, hydrazine, and the xanthine oxidase-xanthine system. J. chem. Soc. 1724–1732 (1956).Google Scholar
  128. Ross, W.C.J., Wilson, J.G.: Some N,N-di-2-chloroalkyl derivatives of carboxyamides and sulphonamides. J. chem. Soc. 3616–3622 (1959).Google Scholar
  129. Rosso, R., Dolfini, L., Donelli, M.G.: Prolonged effect of pentobarbital in tumor bearing rats. Europ. J. Cancer 4, 133–135 (1968a).Google Scholar
  130. Rosso, R., Dolfini, L., Franchi, G.: Metabolism of amphetamine in tumor bearing rats. Biochem. Pharmacol. 17, 633–634 (1968b).PubMedGoogle Scholar
  131. Rubin, A., Tephly, T.R., Mannering, G.J.: Kinetics of drug metabolism by hepatic microsomes. Biochem. Pharmacol. 13, 1007–1016 (1964).PubMedGoogle Scholar
  132. Sarcione, E. J., Sokal, J.E.: Detoxication of thiouracil by S-methylation. J. biol. Chem. 231, 605–608 (1958).PubMedGoogle Scholar
  133. Scheline, R.R.: Drug metabolism by intestinal microorganisms. J. pharm. Sci. 57, 2021–2037 (1968).PubMedGoogle Scholar
  134. Schmid, R., Hammaker, L., Axelrod, J.: The enzymatic formation of bilirubin glucuronide. Arch. biochem. Biophys. 70, 285–288 (1957).PubMedGoogle Scholar
  135. Schmid, R., Lester, R.: In: Glucuronic acid: free and combined. Chemistry, biochemistry, pharmacology, and medicine, p. 493 (Dutton, G. J., Ed.). New York: Academic Press 1966.Google Scholar
  136. Schumacher, H., Smith, R.L., Williams, R.T.: The metabolism of thalidomide: the spontaneous hydrolysis of thalidomide in solution. Brit. J. Pharmacol. 25, 324–337 (1965a).PubMedGoogle Scholar
  137. Schumacher, H., Smith, R.L., Williams, R.T.: The metabolism of thalidomide: the fate of thalidomide and some of its hydrolysis products in various species. Brit. J. Pharmacol. 25, 338–351 (1965b).PubMedGoogle Scholar
  138. Schwartz, H.S.: Pharmacology of mitomycin C. III. In vitro metabolism by rat liver. J. Pharmacol, exp. Ther. 136, 250–258 (1962).Google Scholar
  139. Schwartz, H.S., Philips, F.S.: Pharmacology of mitomycin C. II. Renal excretion and metabolism by tissue homogenates. J. Pharmacol. exp. Ther. 133, 335–342 (1961).PubMedGoogle Scholar
  140. Schwartz, H.S., Sodergren, J.E., Philips, F.S., Mitomycin C.: Chemical and biological studies on alkylation. Science 142, 1181–1183 (1963).PubMedGoogle Scholar
  141. Skibba, J.L., Beal, D.D., Ramirez, G., Bryan, G.T.: N-demethylation of the antineoplastic agent 4(5)-(3, 3-dimethyl-l-triazeno)imidazole-5(4)-carboxamide in rats and man. Cancer Res. 30, 147–150 (1970).PubMedGoogle Scholar
  142. Skipper, H.E., Bennett, L.L., Jr., Bryan, C.E., White, L., Jr., Newton, M.A., Simpson, L.: Carbamates in the chemotherapy of leukemia. VIII. Overall tracer studies on carbonyllabeled urethane, methylene-labeled urethane and methylene-labeled ethyl alcohol. Cancer Res. 11, 46–51 (1951).PubMedGoogle Scholar
  143. Sladek, N.E.: Therapeutic efficacy of cyclophosphamide as a function of its metabolism. Cancer Res. 32, 535–542 (1972).PubMedGoogle Scholar
  144. Smith, P.K., Nadkarni, M. V., Trams, E.G., Davison, C.: Distribution and fate of alkylating agents. Ann. N. Y. Acad. Sci. 68, 834–850 (1958).PubMedGoogle Scholar
  145. Steinberg, A.D., Plotz, P.H., Wolff, S.M., Wong, V.G., Agus, S.G., Decker, J.L.: Cytotoxic drugs in treatment of nonmalignant diseases. Ann. intern. Med. 76, 619–642 (1972).Google Scholar
  146. Stevenson, I.H., Dutton, G.J.: Glucuronide synthesis in kidney and gastrointestinal tract. Biochem. J. 82, 330–340 (1962).PubMedGoogle Scholar
  147. Strominger, J.L., Kalckar, H.M., Axelrod, J., Maxwell, E.S.: Enzymatic oxidation of uridine diphosphate glucose to uridine diphosphate glucuronic acid. J. Amer. chem. Soc. 76, 6411–6412 (1954).Google Scholar
  148. Struck, R.F., Kirk, M.C., Mellett, L.B., Dareer, S.E., Hill, D.L.: Urinary metabolites of the antitumor agent cyclophosphamide. Molec. Pharmacol. 7, 519–529 (1971).Google Scholar
  149. Tardiff, R.G., Dubois, K.P.: Inhibition of hepatic microsomal enzymes by alkylating agents. Arch. int. Pharmacodyn. 177, 445–456 (1969).PubMedGoogle Scholar
  150. Thompson, G.R., Laeson, R.E.: The hepatotoxicity of l, 3-bis(2-chloroethyl)-l-nitrosourea (BCNU) in rats. J. Pharmacol. exp. Ther. 166, 104–112 (1969).PubMedGoogle Scholar
  151. Teams, E.G., Nadkaeni, M.V.: Studies on the N-dealkylation of nitrogen mustard and trie-thylenemelamine by liver homogenates. Cancer Res. 16, 1069–1075 (1956).Google Scholar
  152. Teams, E.G., Nadkabni, M.V., Dequateo, V., Maengwyn-Davies, G.C., Smith, P.K.: Di-methane-sulphonoxybutane (myleran). Preliminary studies on distribution and metabolic fate in the rat. Biochem. Pharmacol. 2, 7–16 (1959).Google Scholar
  153. Umae, M.T., Mitchaed, M.: The competitive inhibition of nitroreductase by some analogues of nitrofurantoin. Biochem. Pharmacol. 17, 2057–2060 (1968).Google Scholar
  154. Viala, R., Gianetto, R.: The binding of sulfatase by rat-liver particles as compared to that of acid phosphatase. Can. J. Biochem. Physiol. 33, 839–844 (1955).PubMedGoogle Scholar
  155. Wada, F., Hieata, K., Nakao, K., Sakamoto, Y.: Participation of P-450 in 7-α hydroxylation of cholesterol. J. Biochem. 64, 415–417 (1968a).PubMedGoogle Scholar
  156. Wada, F., Shibata, H., Gotto, M., Sakamoto, Y.: Participation of the microsomal electron transport system involving cytochrome P-450 in co-oxidation of fatty acids. Biochim. biophys. Acta (Amst.) 162, 518–524 (1968b).Google Scholar
  157. Williams, R.T.: Patterns of excretion of drugs in man and other species. Ciba Found. Symp. drug Resp. in Man, 71–91 (1967).Google Scholar
  158. Williamson, C.E., Kieby, J.G., Millee, J.L., Sass, S., Keamee, S.P., Seligman, A.M., Witten, B.: Enzyme-alterable alkylating agents. IX. The enzymatic transformation of some nitrogen mustards in the presence of carbon dioxide: implications in respiration. Cancer Res. 26, 323–330 (1966).PubMedGoogle Scholar
  159. Wittkop, J.A., Pbough, R.A., Reed, D.J.: Oxidative demethylation of N-methylhydrazines by rat liver microsomes. Arch. Biochem. Biophys. 134, 308–315 (1969).PubMedGoogle Scholar
  160. Zahaeko, D.S., Beucknee, H., Oltveeio, V.T.: Antibiotics alter methotrexate metabolism and excretion. Science 166, 887–888 (1969).Google Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1974

Authors and Affiliations

  • A. M. Guarino
  • C. L. Litterst

There are no affiliations available

Personalised recommendations