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N-Methyl antitumour agents

A distinct class of anticancer drugs?

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  • N-Methyl Antitumour Agents, Anticancer Drugs
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Summary

This article reviews the structure-activity characteristics, mode of action, pharmacokinetics and clinical utility of a group of chemically dissimilar antitumour agents which have as a common structural feature the N-methyl moiety. The importance of this feature is shown by the fact that molecules without a substituent on the nitrogen or compounds with N-alkyl groups other than methyl are usually inactive in experimental systems. This observation is supported by structure-activity studies with N-alkyl derivatives of s-triazines, triazenes, formamides, hydrazines and nitrosoureas. Representatives of these structural types which have found clinical application are, respectively, hexamethylmelamine, dacarbazine, N-methylformamide, procarbazine and streptozotocin. Mode of action studies have shown that dacarbazine, procarbazine and streptozotocin can give rise to species capable of methylating nucleic acid. This may be the lesion which produces antitumour activity. The mechanism of action of N-methylmelamines and N-methylformamide remains unclear. There is good evidence that, with the exception of N-methylnitrosoureas, host metabolism is prerequisite for activity with these agents.

Although not pronounced, the clinical activity of N-methyl antitumour agents is useful, particularly as activity is not associated with severe haematological toxicity. Furthermore, responses may be observed in patients resistant to bifunctional alkylating agents. It is concluded that the drugs reviewed herein show a degree of coincidence in terms of their biological properties which may warrant a common classification. The term N-methyl antitumour agent is proposed.

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References

  1. Ahmann DL, Hahn RG, Bisel HF (1972) A comparative study of 1(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037) and imidazole carboxamide (NSC 45388) with vincristine (NSC 67574) in the palliation of disseminated malignant melanoma. Cancer Res 32:2432

    Google Scholar 

  2. Ahmann DL, Hahn RG, Bisel HF (1974) Evaluation of 1-(2-chloroethyl-3-4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU, NSC 95441) versus combined imidazole carboxamide (NSC 45388) and vincristine (NSC 67574) in palliation of disseminated malignant melanoma. Cancer 33:615

    Google Scholar 

  3. Ajani JA, Cabanillas FF, Bodey GP (1982) Phase I trial of pentamethylmelamine. Cancer Treat Rep 66:1227

    Google Scholar 

  4. Ames MM, Powis G, Kovach JS, Eagan RT (1979) Disposition and metabolism of pentamethylmelamine and hexamethylmelamine in rabbits and humans. Cancer Res 39:5016

    Google Scholar 

  5. Ames MM, Sanders ME, Tiede WS (1981) Metabolic activation of hexamethylmelamine and pentamethylmelamine by liver microsomal preparations. Life Sci 29:1591

    Google Scholar 

  6. Ames MM, Sanders ME, Tiede WS (1983) Role of N-methylolpentamethylmelamine in the metabolic activation of hexamethymelamine. Cancer Res 43:500

    Google Scholar 

  7. Audette RCS, Connors TA, Mandel HG, Merai K, Ross WCJ (1973) Studies on the mechanism of action of the tumour inhibitory triazenes. Biochem Pharmacol 22:1855

    Google Scholar 

  8. Baggiolini M, Dewald B, Aebi H (1969) Oxidation of p-(N-methylhydrazinomethyl)-N-isopropylbenzamide (procarbazine) to the methylazo derivative and oxidative cleavage of the N-C bond in isolated perfused rat liver. Biochem Pharmacol 18:2187

    Google Scholar 

  9. Barcley RK, Garfinkel E (1954) The influence of N-methylformamide on formate-14C incorporation. I. In nucleic acids of rat liver. J Biol Chem 208:875

    Google Scholar 

  10. Berd D, Cornog J, De Conti RC, Levitt M, Bertino JR (1975) Long term remission in diffuse histiocytic lymphoma treated with combination sequential chemotherapy. Cancer 35:1050

    Google Scholar 

  11. Blum RH, Livingstone RB, Carter SK (1973) Hexamethylmelamine — a new drug with activity in solid tumours. Eur J Cancer 9:195

    Google Scholar 

  12. Bolis G, D'Incalci M, Belloni C, Mangioni C (1979) Hexamethylmelamine in ovarian cancer resistant to cyclophosphamide and adriamycin. Cancer Treat Rep 63:1375

    Google Scholar 

  13. Bollag W., Grunberg E (1963) Tumour inhibitory effects of a new class of cytotoxic agents: methylhydrazine derivatives. Experientia 19:130

    Google Scholar 

  14. Bollag W, Kaiser A, Langemann A, Zeller P (1964) Methylazo and methylazoxy compounds: new types of antitumour agents. Experientia 20:503

    Google Scholar 

  15. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C (1975) Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine and imidazole carboxamide versus MOPP. Cancer 36:252

    Google Scholar 

  16. Bonomi PD, Mladineo J, Morrin B, Willbanks G, Slayton RE (1979) Phase II trial of hexamethylmelamine in ovarian carcinoma resistant to alkylating agents. Cancer Treat Rep 63:137

    Google Scholar 

  17. Borden EC, Larson P, Ansfield FJ (1977) Hexamethylmelamine treatment of sarcomas and lymphomas. Med Pediatr Oncol 3:401

    Google Scholar 

  18. Borm PJA, Mingels M-JJ, Frankhuijzen-Sierevogel AC, Van Graft M, Hulshoff A, Noordhoek J (1984) Cellular and subcellular studies of the biotransformation of hexamethylmelamine in rat isolated hepatocytes and intestinal epithelial cells. Cancer Res 44:2820

    Google Scholar 

  19. Breithaupt H, Dammann A, Aigner K (1982) Pharmacokinetics of dacarbazine (DTIC) and its metabolite 5-aminoimidazole-4-carboxamide (AIC) following different dose schedules. Cancer Chemother Pharmacol 9:103

    Google Scholar 

  20. Brindley CJ (1982) Investigation of the metabolism of N-alkyl agents with antineoplastic activity, PhD thesis, University of Aston, Birmingham

  21. Brindley C, Gescher A, Langdon SP, Broggini M, Colombo T, D'Incalci M (1982a) Studies on the mode of action of antitumour triazenes and triazines—III. Metabolism studies on hexamethylmelamine. Biochem Pharmacol 31:625

    Google Scholar 

  22. Brindley C, Gescher A, Harpur ES, Ross D, Slack JA, Threadgill M, Whitby H (1982b) Studies of the pharmacology of N-methylformamide in mice. Cancer Treat Rep 66:1957

    Google Scholar 

  23. Broder LE, Carter SK (1973) Pancreatic islet cell carcinoma. II. Results of therapy with Streptozotocin in 52 patients. Ann Int Med 79:109

    Google Scholar 

  24. Brookes P (1965) Studies on the mode of action of Ibenzymethyzin. In: Jelliffe AM, Marks J (eds) Natulan (ibenzmethyzin) Wright, Bristol, p 9

    Google Scholar 

  25. Bryan GT, Worzalla JF, Gorska RL, Ramirez G (1968) Plasma levels and urinary excretion of hexamethylmelamine following oral administration to human subjects with cancer. Clin Pharmacol Ther 9:777

    Google Scholar 

  26. Casper ES, Gralla RJ, Lynch GR, Jones BR, Woodcock TM, Gordon C, Kelsen DP, Young CW (1981) Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion. Cancer Res 41: 1402

    Google Scholar 

  27. Chabner BA, Sponso R, Hubbard S, Canellos GP, Young RC, Schein PS, DeVita VT (1973) High-dose intermittent intravenous infusion of procarbazine (NSC-77213). Cancer Chemother Rep 57: 361

    Google Scholar 

  28. Clarke DA, Philips FS, Sternberg SS, Barcley RK, Stock CC (1953) Effects of N-methylformamide and related compounds in mouse sarcoma 180. Proc Soc Exp Biol Med 84: 203

    Google Scholar 

  29. Clarke DA, Barcley RK, Stock CC, Rondestvedt CS (1955) Triazenes as inhibitors of mouse sarcoma 180. Proc Soc Exp Biol Med 90: 484

    Google Scholar 

  30. Colombo T, D'Incalci M (1984) Comparison of the antitumour activity of DTIC and 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt on murine transplantable tumours and their haematological toxicity. Cancer Chemother Pharmacol 13: 139

    Google Scholar 

  31. Comis RL (1976) DTIC (NSC 45388) in malignant melanoma: a perspective. Cancer Treat Rep 60: 165

    Google Scholar 

  32. Connors TA, Goddard PM, Merai K, Ross WCJ, Wilman DEV (1976) Tumour inhibitory triazenes: structural requirements for an active metabolite. Biochem Pharmacol 25: 241

    Google Scholar 

  33. Connors TA, Cumber AJ, Ross WCJ, Clarke SA, Mitchley BCV (1977) Regression of human lung tumour xenografts induced by water-soluble analogues of hexamethylmelamine. Cancer Treat Rep 61: 927

    Google Scholar 

  34. Cooksey PG, Gate EN, Gescher A, Hickman JA, Langdon SP, Stevens MFG (1983) The formation and metabolism of N-hydroxymethyl compounds. IV. Cytotoxicity and antitumour activity of N-hydroxymethylformamide, a putative metabolite of N-methylformamide (NSC 3051). Biochem Pharmacol 32: 3037

    Google Scholar 

  35. Cummings SW, Guengerich FP, Prough RA (1982) The characterisation of N-isopropyl-p-hydroxymethylbenzamide formed during the oxidative metabolism of azoprocarbazine. Drug Metab Dispos 10: 459

    Google Scholar 

  36. D'Incalci M, Bolis G, Mangioni C, Morasca L, Garattini S (1978) Variable oral absorption of hexamethylmelamine in man. Cancer Treat Rep 62: 2117

    Google Scholar 

  37. D'Incalci M, Erba E, Balconi G, Morasca L, Garattini S (1980) Time dependence of the in vitro cytotoxicity of hexamethylmelamine and its metabolites. Br J Cancer 41: 630

    Google Scholar 

  38. D'Incalci M, Beggiolin G, Sessa C, Mangioni C (1981) Influence of ascites on the pharmacokinetics of hexamethylmelamine and N-demethylated metabolites in ovarian cancer patients. Eur J Cancer Clin Oncol 17: 1331

    Google Scholar 

  39. D'Incalci M, Farina P, Sessa C, Mangiun C, Garattini S (1982) Hexamethylmelamine distribution in patients with ovarian and other pelvic cancers. Cancer Treat Rep 66: 231

    Google Scholar 

  40. Dawson WB (1965) Ibenzmethyzin in the management of late Hodgkin's disease. In: Jelliffe AM, Marks J (eds) Natulan (ibenzmethyzin) Wright, Bristol, p 31

    Google Scholar 

  41. De Milo AB, Borkovec AB (1968) Insect chemosterilants. VII. Oxidative degradation of hexamethylmelamine. J Med Chem 11: 961

    Google Scholar 

  42. DeVita VT, Hahn MA, Oliverio VT (1965) Monoamine oxidase inhibition by a new carcinostatic agent, N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (MIH). Proc Soc Exp Biol Med 120: 561

    Google Scholar 

  43. DeVita VT, Serpick AA, Carbone PP (1970) Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 73: 881

    Google Scholar 

  44. DeVita VT, Canellos GP, Chabner B, Schein P, Hubbard SP, Young RC (1975) Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1: 248

    Google Scholar 

  45. Dexter DL, Spremulli EN, Matook GM, Diamond I, Calabresi P (1982) Inhibition of the growth of human colon cancer xenografts by polar solvents. Cancer Res 42: 5018

    Google Scholar 

  46. Dost FN, Reed DJ (1967) Methane formation in vivo from N-isopropyl-α-(2-methylhydrazino)-p-toluamide hydrochloride, a tumour-inhibiting methylhydrazine derivative. Biochem Pharmacol 16: 1741

    Google Scholar 

  47. Dunn DL, Lubet RA, Prough RA (1979) Oxidative metabolism of N-isopropyl-α-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine) by rat liver microsomes. Cancer Res 39: 4555

    Google Scholar 

  48. Eidinoff ML, Knoll JE, Marano BJ, Klein D (1961) Pyrimidine studies II. Effect of several compounds with antitumour activity on utilisation of precursors for synthesis of nucleic acid pyrimidines. Cancer Res 21: 1377

    Google Scholar 

  49. Emanuel NM, Vermel EM, Ostrovskaya LA, Korman NP (1974) Experimental and clinical studies of the antitumour activity of 1-methyl-1-nitrosourea (NSC 23909). Cancer Chemother Rep 58: 135

    Google Scholar 

  50. Ettinger DS, Orr DW, Rice AP, Donehower RC (1985) Phase I study of N-methylformamide in patients with advanced cancer. Cancer Treat Rep 69: 489

    Google Scholar 

  51. Evans JS, Gerritsen GC, Mann KM, Owen SP (1965) Antitumour and hyperglycemic activity of streptozotocin (NSC 37917) and its cofactor, U-15,774. Cancer Chemother Rep 48: 1

    Google Scholar 

  52. Fabian CJ, Rasmussen S, Stephens R, Haut A, Smith F, Balcerzak S, Tranum B (1979) Phase II evaluation of hexamethylmelamine in advanced breast cancer: a Southwest Oncology Group study. Cancer Treat Rep 63: 1359

    Google Scholar 

  53. Finklestein JZ, Albo V, Ertel I, Hammond D (1975) 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (NSC 45388) in the treatment of solid tumours in children. Cancer Chemother Rep 59: 351

    Google Scholar 

  54. Frei E, Luce JK, Talley RW, Vaitkevicius VK, Wilson HE (1972) 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (NSC 45388) in the treatment of lymphoma. Cancer Chemother Rep 56: 667

    Google Scholar 

  55. Furst A, Cutting WC, Gross H (1955) Retardation of growth of Ehrlich ascites tumour by formamides and related compounds. Cancer Res 15: 294

    Google Scholar 

  56. Gad-El-Mawla N, Ziegler JL, Hamza R, Elserafi M, Khaled H (1984) Randomized phase II trial of hexamethylmelamine versus pentamethylmelamine in carcinoma of the bilharzial bladder. Cancer Treat Rep 68: 793

    Google Scholar 

  57. Garattini E, Broggini M, Coccia I, Colombo T, Rossi C, D'Incalci M (1984) Biochemical studies of the ability of pentamethylmelamine to interact in vivo with DNA and proteins in a sensitive murine reticular cell sarcoma. Biochem Pharmacol 33: 2715

    Google Scholar 

  58. Gerulath AH, Loo TL (1972) Mechanism of action of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide in mamalian cells in culture. Biochem Pharmacol 21: 2335

    Google Scholar 

  59. Gescher A, D'Incalci M, Fanelli R, Farina P (1980) N-Hydroxymethylpentamethylmelamine, a major in vitro metabolite of hexamethylmelamine. Life Sci 26: 147

    Google Scholar 

  60. Gescher A, Hickman JA, Simmonds RJ, Stevens MFG, Vaughan K (1981) Studies of the mode of action of antitumour triazenes and triazines. II. Investigation of the selective toxicity of 1-aryl-3,3-dimethyltriazenes. Biochem Pharmacol 30: 89

    Google Scholar 

  61. Gescher A, Gibson NW, Hickman JA, Langdon SP, Ross D, Atassi G (1982) N-Methylformamide: antitumour activity and metabolism in mice. Br J Cancer 45: 843

    Google Scholar 

  62. Gersel Pedersen A, Sorenson S, Aabo K, Dombernowsky P, Hansen HH (1982) Phase II study of procarbazine in small cell carcinoma of the lung. Cancer Treat Rep 66: 273

    Google Scholar 

  63. Giraldi T, Houghton PJ, Taylor DM, Nisi C (1978) Antimetastatic action of some triazene derivatives against the Lewis lung carcinoma in mice. Cancer Treat Rep 62: 721

    Google Scholar 

  64. Giraldi T, Sava G, Cuman R, Nisi C, Lassiani L (1981) Selectivity of the antimetastatic and cytotoxic effects of 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt, (±)1,2-di(3,5-dioxopiperazin-1-yl) propane, and cyclophosphamide in mice bearing Lewis lung carcinoma. Cancer Res 41: 2524

    Google Scholar 

  65. Goldberg RS, Griffin JP, McSherry JW, Krakoff IH (1980) Phase I study of pentamethylmelamine. Cancer Treat Rep 64: 1319

    Google Scholar 

  66. Goldin A, Venditti JM, MacDonald JS, Muggia FM, Henney JE, De Vita VT (1981) Current results of the screening programme at the Division of Cancer Treatment, National Cancer Institute. Eur J Cancer 17: 129

    Google Scholar 

  67. Gorsen RM, Weiss AJ, Manthei RW (1980) Analysis of procarbazine and metabolites by gas chromatography-mass spectrometry. J Chromatog (Biomed Appl) 221: 309

    Google Scholar 

  68. Gottlieb JA et al (1976) Role of DTIC (NSC 45388) in the chemotherapy of sarcomas. Cancer Treat Rep 60: 199

    Google Scholar 

  69. Gutterman J, Huang A, Hochstein P (1969) The mode of action of N-isopropyl-α(2-methylhydrazine)p-toluamide. Exp Biol Med 130: 797

    Google Scholar 

  70. Hansch C, Hatheway GJ, Quinn FR, Greenberg N (1978) Antitumour 1-(x-aryl)-3,3-dialkyltriazenes. 2. On the role of correlation analysis in decision making in drug modification. Toxicity quantitative structure activity relationships of 1-(x-phenyl)-3,3-dialkyltriazenes in mice. J Med Chem 21: 574

    Google Scholar 

  71. Hendry JA, Rose FL, Walpole AL (1951) Cytotoxic agents: I, Methylolamides with tumour inhibitory activity, and related inactive compounds. Br J Pharmacol 6: 201

    Google Scholar 

  72. Hickman JA (1978) Investigation of the mechanism of action of antitumour dimethyltriazenes. Biochimie 60: 997

    Google Scholar 

  73. Hill DL (1975) Microsomal metabolism of triazenylimidazoles. Cancer Res 35: 3106

    Google Scholar 

  74. Hope-Stone HF (1965) Ibenzmethyzin in the treatment of reticuloses. In: Natulan (ibenzmethyzin), Marks J Jelliffe AM (eds), Wright, Bristol p 15

    Google Scholar 

  75. Householder GE, Loo TL (1969) Elevated urinary excretion of >4-aminoimidazole-5-carboxamide in patients after intravenous injection of 4-(3,3-dimethyl-1-triazeno)imidazole-5-carboxamide. Life Sci 8: 533

    Google Scholar 

  76. Householder GE, Loo TL (1971) Disposition of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide, a new antitumour agent. J Pharmacol Exp Ther 179: 386

    Google Scholar 

  77. IARC Monograph (1978 a) N-Nitroso-N-ethylurea. In: Evaluation of the carcinogenic risk of chemicals to humans, volume 17. Some N-nitroso compounds. IARC, Lyon, p 191

    Google Scholar 

  78. IARC Monograph (1978 b) N-Nitroso-N-methylurea. In: Evaluation of the carcinogenic risk of chemicals to humans, volume 17. Some N-nitroso compounds. IARC, Lyon p 227

    Google Scholar 

  79. IARC Monograph (1981) Dacarbazine and procarbazine hydrochloride. In: Evaluation of the carcinogenic risk of chemicals to humans, volume 26. Some antineoplastic and immunosuppressive agents. IARC, Lyon, p 203 and p 311

    Google Scholar 

  80. Ihde DC, Dutcher JS, Young RC, Cordes RS, Barlock AL, Hubbard SM, Jones RB, Boyd MR (1981) Phase 1 trial of pentamethylmelamine: a clinical and pharmacologic study. Cancer Treat Rep 65: 755

    CAS  PubMed  Google Scholar 

  81. Johnson BL, Fisher RI, Bender RA, DeVita VT, Chabner BA, Young RC (1978) Hexamethylmelamine in alkylating agent-resistant ovarian carcinoma. Cancer 42: 2157

    Google Scholar 

  82. Johnston TP, McCaleb GS, Montgomery JA (1963) The synthesis of antineoplastic agents. XXXII. N-nitrosoureas 1. J Med Chem 6: 669

    Google Scholar 

  83. Judson IR, Rutty CJ, Abel G, Gumbrell L, Harrap KR, Calvert AH (1985) Phase I trial of N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine (Trimelamol), a new antitumour s-triazine. Proc Am Soc Clin Oncol 4: 31

    Google Scholar 

  84. Kaye SB, Juttner CA, Smith IE, Barrett A, Austin DE, Peckham MJ, McElwain TJ (1979) Three years' experience with Ch1VPP (a combination of drugs of low toxicity) for the treatment of Hodgkin's disease. Br J Cancer 39: 168

    Google Scholar 

  85. Kestell P, Gescher A, Slack JA (1985) The fate of N-methylformamide in mice. Routes of elimination and characterisation of metabolites. Drug Metab Dispos 13: 587

    Google Scholar 

  86. Kestell P, Gledhill AP, Threadgill MD, Gescher A (1986) S-(N-Methylcarbamoyl)-N-acetylcysteine: a urinary metabolite of the hepatotoxic experimental antitumour drug N-methylformamide (NSC 3051) in mouse, rat and man. Biochem Pharmacol 35: 2283

    Google Scholar 

  87. Klippert PJM, Hulshoff A, Mingels M-JJ, Hofman G, Noordhoek J (1983) Low oral bioavailability of hexamethylmelamine in the rat due to simultaneous hepatic and gastrointestinal metabolism. Cancer Res 43: 3160

    Google Scholar 

  88. Kohn KW (1977) Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas. Cancer Res 37: 1450

    Google Scholar 

  89. Kolar GF, Carubelli R (1979) Urinary metabolite of 1-(2,4,6-trichlorophenyl)-3,3-dimethyltriazene, with an intact diazoamino structure. Cancer Lett 7: 209

    Google Scholar 

  90. Kolar GF, Maurer M, Wildschütte M (1980) 5-(3-Hydroxymethyl-3-methyltriazeno)imidazole-4-carboxamide is a metabolite of 5(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DIC, DTIC, NSC 45388). Cancer Lett 10: 235

    Google Scholar 

  91. Kreis W (1970) Metabolism of an antineoplastic methylhydrazine derivative in a P815 mouse neoplasm. Cancer Res 30: 82

    Google Scholar 

  92. Kushner BS, Lazar M, Furman M (1969) Resistance of rabbits and guinea pigs to the diabetogenic effect of streptozotocin. Diabetes 18: 542

    Google Scholar 

  93. Kuttab SH, Tanglerpaibul S, Vouros P (1982) Studies on the metabolism of procarbazine by mass spectrometry. Biomed Mass Spectrom 9: 78

    Google Scholar 

  94. Lake LM, Grunden EE, Johnson BM (1975) Toxicity and antitumour activity of hexamethylmelamine and its N-demethylated metabolites in mice with transplantable tumours. Cancer Res 35: 2858

    Google Scholar 

  95. Langdon SP (1983) The synthesis and antitumour evaluation of methyl amino compounds PhD thesis, University of Aston, Birmingham

  96. Lawley PD (1980) DNA as a target for alkylating carcinogens. Br Med Bull 36: 19

    Google Scholar 

  97. Legha SS, Slavik M, Carter SK (1976) Hexamethylmelamine. An evaluation of its role in the therapy of cancer. Cancer 38: 27

    Google Scholar 

  98. Legha SS, Buzdar AU, Hortobagyi GN, DiStefano A, Wiseman CL, Yap H-Y, Blumenschein GR, Bodey EGP, (1979) Phase II study of hexamethylmelamine alone and in combination with mitomycin C and vincristine in advanced breast carcinoma. Cancer Treat Rep 63: 2053

    Google Scholar 

  99. Livingstone RB, Carter SK (1971) In: Carter SK (ed) Proceedings of the Chemotherapy Conference on Procarbazine: Development and Application. U.S. Goverment Printing Office, Washington, p 329

    Google Scholar 

  100. Loo TL, Luce JK, Jardine JH, Frei E (1968) Pharmacologic studies of the antitumour agent 5-(dimethyltriazeno)imidazole-4-carboxamide. Cancer Res 28: 2448

    Google Scholar 

  101. Louis J, Louis NB, Linman JW (1967) The clinical pharmacology of hexamethylmelamine: a phase I study. Clin Pharmacol Ther 8: 55

    Google Scholar 

  102. Luce JK, Thurman WG, Isaacs BL, Talley RW (1970) Clinical trials with the antitumour agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC 45388). Cancer Chemother Rep 54: 119

    Google Scholar 

  103. Luce JK, Gamble JF, Wilson HE, Monto RW, Isaacs BL, Palmer RL, Coltman CA, Hewlett JS, Gehan EA, Frei E (1971) Combined cyclophosphamide, vincristine and prednisone therapy of malignant lymphoma. Cancer 28: 306

    Google Scholar 

  104. Mathe G, Schweisguth O, Schneider M, Amiel JL, Berumen L, Brule G, Cattan A, Schwarzenberg L (1963) Methyl hydrazine in the treatment of Hodgkin's disease. Lancet 2: 1077

    Google Scholar 

  105. McVie JG, ten Bokkel Huinick WW, Simonetti G, Dubbelman R (1984) Phase I trial of N-methylformamide. Cancer Treat Rep 68: 607

    Google Scholar 

  106. Mizuno NS, Decker RW (1976) Alteration of DNA by 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (NSC 407347). Biochem Pharmacol 25: 2643

    Google Scholar 

  107. Mizuno NS, Humphrey EW (1972) Metabolism of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC 45388) in human and animal tumour tissue. Cancer Chemother Rep 56: 465

    Google Scholar 

  108. Moertel CG, Hanley JA, Johnson LA (1980) Streptozotocin alone compared with streptozotocin plus fluorouracil in the treatment of advanced islet cell carcinoma. N Engl J Med 303: 1189

    Google Scholar 

  109. Moertel CG (1975) Clinical management of advanced gastrointestinal cancer. Cancer 36: 675

    Google Scholar 

  110. Molony SJ, Prough RA (1983) Studies on the pathway of methane formation from procarbazine, a 2-methylbenzyl hydrazine derivative, by rat liver microsomes. Arch Biochem Biophys 221: 577

    Google Scholar 

  111. Morimoto M, Green D, Rahman A, Goldin A, Schein PS (1980) Comparative pharmacology of pentamethylmelamine and hexamethylmelamine in mice. Cancer Res 40: 2762

    Google Scholar 

  112. Morkhansen M, Hertz H, Videbaek A (1966) Use of a methyl hydrazine derivative (Natulan) especially in Hodgkin's disease. Acta Med Scand 18: 211

    Google Scholar 

  113. Morrison SS, Higgins GM (1956) An attempt to block sources of methyl groups in the therapy of mouse leukaemia. Cancer Res 16: 292

    Google Scholar 

  114. Muindi JRF, Rutty CJ, Harrap KR (1981) DNA cross-linking induced by pentamethylmonomethylolmelamine in vitro. Br J Cancer 44: 281

    Google Scholar 

  115. Muindi JRF, Newell DR, Smith IE, Harrap KR (1983) Pentamethylmelamine (PMM): phase I clinical and pharmacokinetic studies. Br J Cancer 47: 27

    Google Scholar 

  116. Murray-Lyon IM, Eddleston A, Williams R, Brown M, Hogbin BM, Bennett A, Edwards JC, Taylor KW (1968) Treatment of multiple-hormone-producing malignant islet cell tumours with streptozotocin. Lancet 2: 895

    Google Scholar 

  117. Myers WPL, Karnofsky DA, Burchenal JH (1956) The hepatotoxic action of N-methylformamide in man. Cancer 9: 949

    Google Scholar 

  118. Nagasawa HT, Shirota FN, Mizuno NS (1974) The mechanism of alkylation of DNA by 5-(3-methyl-1-triazeno)-imidazole-4-carboxamide (MIC), a metabolite of DIC (NSC 45388). Non-involvement of diazomethane. Chem Biol Interact 8: 403

    Google Scholar 

  119. Newbold RF, Warren W, Medcalf ASC, Amos J (1980) Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification. Nature 283: 596

    Google Scholar 

  120. Nicholson WM, Beard MEJ, Crowther D (1970) Combination chemotherapy in generalised Hodgkin's disease. Br Med J 3: 7

    Google Scholar 

  121. O'Dwyer PJ, Donehower M, Sigman LM, Fortner CL, Aisner J, Van Echo DA (1985) Phase I trial of N-Methylformamide (NMF, NSC 3051). J Clin Oncol 3: 853

    Google Scholar 

  122. Oliverio VT, Denham C, DeVita VT, Kelly MG (1964) Some pharmacologic properties of a new antitumour agent, N-isopropyl-α-(2-methylhydrazino)-p-toluamide, hydrochloride (NSC 77213). Cancer Chemother Rep 42: 1

    Google Scholar 

  123. Omura GA, Greco FA, Brich R (1981) Hexamethylmelamine in mustard-resistant ovarian adenocarcinoma. Cancer Treat Rep 65: 530

    Google Scholar 

  124. Omura GA, Broun GO, Papps J, Birch R (1981) Phase II study of hexamethylmelamine in refractory Hodgkin's disease, other lymphomas and chronic lymphocytic leukaemia. Cancer Treat Rep 65: 1027

    Google Scholar 

  125. Palmer RL, Kroening PM (1978) Comparison of low dose radiation therapy alone or combined with procarbazine (NSC-77213) for unresectable epidermoid carcinoma of the lung, stage T3, N1, N2 or M1. Cancer 42: 424

    Google Scholar 

  126. Panasci LC, Fox PA, Schein PS (1977) Structure activity studies of methylnitrosourea antitumour agents with reduced murine bone marrow toxicity. Cancer Res 37: 3321

    Google Scholar 

  127. Preussman R, Ivankovic S, Landschultz C, Gimmy J, Flohr E, Friesbach U (1974) Karzinogene Wirkung von 13 Aryldialkyltriazenen an BD-Ratten. Z Krebsforsch 81: 285

    Google Scholar 

  128. Prough RA, Brown MI, Dannan GA, Guengerich FP (1984) Major isozymes of rat liver microsomal cytochrome P-450 involved in the N-oxidation of N-isopropyl-alpha-(2-methylazo-p-toluamide), the azo derivative of procarbazine. Cancer Res 44: 543

    Google Scholar 

  129. Prough RA, Brown MI, Moloney SJ, Wiebkin P, Cummings SW, Spearman ME, Guengerich FP (1985) The activation of hydrazines to reactive intermediates. In: Boobis AR, Caldwell J, De Mattis F, Elcombe CR (eds) Microsomes and drug oxidations, Taylor and Francis, London, p 330

    Google Scholar 

  130. Raaflaub J, Schwartz DE (1965) Über den Metabolismus eines cytostatisch wirksamen Methylhydrazin-Derivates (Natulan). Experientia 21: 44

    Google Scholar 

  131. Ross WCJ (1962) In: Biological alkylating agents. Butterworth, London

    Google Scholar 

  132. Ross WE, McMillan DR, Ross CF (1981) Comparison of DNA damage by methylmelamines and formaldehyde. J Natl Cancer Inst 67: 217

    Google Scholar 

  133. Rutty CJ, Abel G (1980) In vitro cytotoxicity of the methylmelamines. Chem Biol Interact 29: 235

    Google Scholar 

  134. Rutty CJ, Connors TA (1977) In vitro studies with hexamethylmelamine. Biochem Pharmacol 26: 2385

    Google Scholar 

  135. Rutty CJ, Connors TA, Nam NH, Thang DC, Hoellinger H (1978) In vivo studies with hexamethylmelamine. Eur J Cancer 14: 713

    Google Scholar 

  136. Rutty CJ, Abel G, Harrap KR (1979) In vitro cytotoxicity of hexamethylmelamine and its analogues. Br J Cancer 40: 317

    Google Scholar 

  137. Rutty CJ, Newell DR, Munidi JRF, Harrap KR (1982) The comparative pharmacokinetics of pentamethylmelamine in man, rat and mouse. Cancer Chemother Pharmacol 8: 105

    Google Scholar 

  138. Rutty CJ, Newell DR, Vincent RB, Abel G, Goddard PM, Harland SJ, Calvert AH (1983) The species dependent pharmacokinetics of DTIC. Br J Cancer 48: 140

    Google Scholar 

  139. Sartorelli AC, Le Page GA (1958) The development and biochemical characterisation of resistance to azaserine in a TA3 ascites carcinoma. Cancer Res 18: 457

    Google Scholar 

  140. Sava G, Giraldi T, Lassiani L, Nisi C (1979) Mechanism of the antimetastatic action of dimethyl triazenes. Cancer Treat Rep 63: 93

    Google Scholar 

  141. Sava G, Giraldi T, Lassiani L, Nisi C (1982) Metabolism and mechanism of action of the antileukemic action of isomeric aryldimethyltriazenes. Cancer Treat Rep 66: 1751

    Google Scholar 

  142. Sava G, Giraldi T, Nisi C, Bertoli G (1983) Prophylactic antimetastatic treatment with aryldimethyl triazenes as adjuvants to surgical tumour removal in mice bearing Lewis lung carcinoma. Cancer Treat Rep 66: 115

    Google Scholar 

  143. Schwartz DE, Bollag W, Obrecht P (1967) Distribution and excretion studies of procarbazine in animals and man. Arzneimittelforsch 17: 1389

    Google Scholar 

  144. Schein PS, Cooney DA, Vernon ML (1967) The use of nicotinamide to modify the toxicity of streptozotocin diabetes without loss of antitumour activity. Cancer Res 27: 2324

    Google Scholar 

  145. Schein PS, Kahn R, Gordon P (1973) Steptozotocin for malignant insulinomas and carcinoid tumour. Report of eight cases and review of the literature. Arch Int Med 132: 555

    Google Scholar 

  146. Schein PS, O'Connell MJ, Blom J, Hubbard S, Magrath IT, Bergevin P, Wiernik PH, Ziegler JL, DeVita VT (1974) Clinical antitumour activity and toxicity of streptozotocin (NSC-85998). Cancer 34: 993

    Google Scholar 

  147. Schein PS, DeVita VT, Hubbard S, Chabner BA, Canellos GP, Berard C, Young RC (1976) Bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histocytic lymphoma. Ann Intern Med 85: 417

    Google Scholar 

  148. Selawry OS (1973) Monochemotherapy of bronchogenic carcinoma with special reference to cell type. Cancer Chemother Rep Pt [3] 4:177

    Google Scholar 

  149. Shealy YF, Struck RF, Holum LB, Montgomery JA (1961) Synthesis of potential anticancer agents. XXIX. 5-Diazoimidazole-4-carboxamide and 5-diazo-v-triazole-4-carboxamide. J Org Chem 26: 2396

    Google Scholar 

  150. Shealy YF, Krauth CA, Montgomery JA (1962) Imidazoles. I. Coupling reactions of 5-diazoimidazole-4-carboxamide. J Org Chem 27: 2150

    Google Scholar 

  151. Shealy YF, Montgomery JA, Laster WR (1962) Antitumour activity of triazenoimidazoles. Biochem Pharmacol 11: 674

    Google Scholar 

  152. Shiba DA, Weinkam RJ (1983) The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukaemia cells of CDF1 mice and the effects of pretreatment with procarbazine, phenobarbital, diphenylhydantoin, and methylprednisolone upon in vivo procarbazine activity. Cancer Chemother Pharmacol 11: 124

    Google Scholar 

  153. Shiba DA, Weinkam RJ (1982) Quantitative analysis of procarbazine, procarbazine metabolites and chemical degradation products with application to pharmacokinetic studies. J Chromatogr Biomed Appl 229: 397

    Google Scholar 

  154. Shiloh Y, Becker Y (1981) Kinetics of O6-methylguanine repair in human normal and ataxia telangiectaria cell lines and correlation of repair capacity with cellular sensitivity to methylating agents. Cancer Res 41: 5114

    Google Scholar 

  155. Sicher K (1965) Short report: In: Jelliffe AM, Marks J (eds) Natulan (ibenzmethyzin). Wright, Bristol, p 40

    Google Scholar 

  156. Sinha BK (1984) Metabolic activation of procarbazine. Evidence for carbon-centred free-radical intermediates. Biochem Pharmacol 33: 2777

    Google Scholar 

  157. Skibba JL, Ramirez G, Beal DD, Bryan GT (1969) Preliminary clinical trial and the physiological disposition of 4(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)-carboxamide in man. Cancer Res 29: 1944

    Google Scholar 

  158. Skibba JL, Ramirez G, Beal DD, Bryan GT (1970) Metabolism of 4(5)-(3,3-dimethyl-1-triazeno)imidazole-5-carboxamide to 4(5)-amino-imidazole-5(4)-carboxamide in man. Biochem Pharmacol 19: 2043

    Google Scholar 

  159. Skibba JL, Beal DD, Ramirez G, Bryan GT (1970) N-De-methylation methylation of the antineoplastic agent 4(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)-carboxamide by rats and man. Cancer Res 30: 147

    Google Scholar 

  160. Skibba JL, Bryan GT (1971) Methylation of nucleic acids and urinary excretion of 14C-labelled 7-methylguanine by rats and man after administration of 4(5)-(3,3-dimethyl-1-triazeno)-imidazole 5(4)-carboxamide. Toxicol Appl Pharmacol 18: 707

    Google Scholar 

  161. Skipper HE, Schabel FM Jr, Binns V, Thomson JR, Wheeler GP (1955) Studies on the mechanism of action and anticancer activity of N-methylformamide. Cancer Res 15: 143

    Google Scholar 

  162. Smulson ME, Schein P, Mullins DW, Sudhakar S (1977) A putative role for nicotinamide adenine dinucleotide — promoted nuclear protein modification in the antitumour activity of N-methyl-N-nitrosourea. Cancer Res 37: 3006

    Google Scholar 

  163. Spivack SD (1974) Procarbazine. Ann Intern Med 81: 795

    Google Scholar 

  164. Spremulli EN, Dexter DL (1984) Polar solvents: a novel class of antineoplastic agents. J Clin Oncol 2: 227

    Google Scholar 

  165. Stevens MFG, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, Newton CG (1984) Antitumour imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl) imidazo (5,1-d)-1,2,3,5-tetrazin-4(3H)-one, a novel broad-spectrum antitumour agent. J Med Chem 27: 196

    Google Scholar 

  166. Stolinsky D, Sadoff L, Braunwald J, Bateman J (1972) Streptozotocin in the treatment of cancer: phase II study. Cancer 30: 61

    Google Scholar 

  167. Tauer K, Kemeny N, Hollander P (1985) Phase II trial of N-methylformamide (NMF) in patients with advanced colorectal carcinoma. Proc Am Ass Cancer Res 26: 169

    Google Scholar 

  168. Takeuchi M, Ogiu T, Nakadate M, Odashima S (1980) Induction of doudenal tumours and thymomas in Fischer rats by continuous oral administration of 1-propyl-1-nitrosourea. Gann 71: 231

    Google Scholar 

  169. Todd IDH (1965) Further experience with ibenzmethyzin: In: Jelliffe AM, Marks J (eds) Natulan (ibenzmethyzin), Wright Bristol, p 20

    Google Scholar 

  170. Van Echo DA, Chiuten DF, Whitacre M, Aisner J, Lichtenfeld JL, Wiernik PH (1980) Phase I trial of pentamethylmelamine in patients with previously treated malignancies. Cancer Treat Rep 64: 1335

    Google Scholar 

  171. Vavra JJ, de Boer C, Dietz A, Hanka LJ, Sokolski WT (1959–60) Streptozotocin, a new antibacterial antibiotic. Antibiot Ann 230

  172. Vogel CL, Primack A, Owor R, Kyalwazi SK (1973) Effective treatment of Kaposi's sarcoma with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC 45388). Cancer Chemother Rep 57:65

    Google Scholar 

  173. Vogl SE, Pagano M, Davis TE, Einhorn N, Tunca JC, Kaplan BH, Arseneau JC (1982) Hexamethylmelamine and cisplatin in advanced ovarian cancer after failure of alkylating agent therapy. Cancer Treat Rep 66: 1285

    Google Scholar 

  174. Wagner DE, Ramirez G, Weiss AJ (1972) Combination Phase I–II study of imidazole carboxamide (NSC 45388). Oncology 26: 310

    Google Scholar 

  175. Weinkam RJ, Shiba DA (1978) Metabolic activation of procarbazine. Life Sci 22: 937

    Google Scholar 

  176. Weinkam RJ, Shiba DA, Chabner BA (1982) Nonclassical alkylating agents. In: Chabner B (ed) Pharmacologic principles of cancer treatment. Saunders, Philadelphia, p 340

    Google Scholar 

  177. Wharton JT, Rutledge F, Smith JP, Herson J, Hodge MP (1979) Hexamethylmelamine: an evaluation of its role in the treatment of ovarian cancer. Am J Obstet Gynecol 133: 833

    Google Scholar 

  178. Wheeler GP, Grammer MG (1960) Prevention of the inhibitory effects of urethan, formamide and N-methylformamide on the growth of Escherichia Coli. Biochem Pharmacol 3: 316

    Google Scholar 

  179. Wiebkin P, Prough RA (1980) Oxidative metabolism of N-isopropyl-alpha-(2-methylazo)-p-toluamide (Azoprocarbazine) by rodent liver microsomes. Cancer Res 40: 3524

    Google Scholar 

  180. Wiemann MC, Cummings FJ, Posner MR, Weens JH, Crabtree GW, Birmingham BK, Moore A, Calabresi P (1985) Phase I clinical and pharmacological trial of oral N-methylformamide. Proc Am Soc Clin Oncol 4: 38

    Google Scholar 

  181. Wilson WL, De La Garza JG (1965) Phase I study of hexamethylmelamine (NSC 13875). Cancer Chemother Rep 48: 49

    Google Scholar 

  182. Worzalla JF, Johnson BM, Ramirez G, Bryan GT (1973) N-Demethylation of the antineoplastic agent hexamethylmelamine by rats and man. Cancer Res 33: 2810

    Google Scholar 

  183. Worzalla JF, Kaiman BD, Johnson BM, Ramirez G, Bryan GT (1974) Metabolism of hexamethylmelamine-ring-14C in rats and man. Cancer Res 34: 2669

    Google Scholar 

  184. Zeller P, Gutmann H, Hegedus B, Kaiser A, Langemann A, Muller M (1963) Methylhydrazine derivatives, a new class of cytotoxic agents. Experientia 19: 129

    Google Scholar 

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Authors and Affiliations

  1. Department of Biochemical Pharmacology, Institute of Cancer Research, Belmont, Sutton, Surrey, United Kingdom

    David Newell, Stephen Harland & Christine Rutty

  2. Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom

    Andreas Gescher

  3. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Colorado, Boulder, Colorado, USA

    David Ross

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  1. David Newell
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  4. David Ross
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Newell, D., Gescher, A., Harland, S. et al. N-Methyl antitumour agents. Cancer Chemother. Pharmacol. 19, 91–102 (1987). https://doi.org/10.1007/BF00254559

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