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Hydrazine Sulfate (PDQ®)

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History

During the past 90 years, hydrazine compounds have been studied in animal cells grown in the laboratory, in live animals, and in humans.[1] More than 400 hydrazine analogs (related compounds) have been screened for their ability to kill tumors. In 1996, a retrospective review of scientific studies in which the anticancer activity of hydrazine analogs was investigated found that 65 of 82 evaluated compounds showed some anticancer activity in xenograft models (tumor cells of one species transplanted to another species).[1] Of the 82 tested compounds, seven showed activity against human tumor cells and were, therefore, selected for further testing in pilot studies and phase I clinical trials. Among these seven compounds, only procarbazine (a methylhydrazine derivative, also called ibenzmethyzin or natulan) completed preliminary testing in humans. Procarbazine exhibited anticancer activity in patients with Hodgkin disease, melanoma, and lung carcinoma, and it was ultimately used in several first-line treatment regimens in the 1960s.[1-3] In view of the initial success with procarbazine, hydrazine sulfate, which is similar in chemical composition, was investigated for anticancer activity beginning in the 1970s. During this period, investigation of hydrazine sulfate as a treatment for cancer-related cachexia was also initiated. Research on hydrazine sulfate both as a single agent and in combination with standard chemotherapy regimens continued through the mid-1990s.[4-9]

Although it was proposed in the early 1900s that hydrazine compounds are toxic to animals and to humans, they have been administered as antidepressant (e.g., iproniazid), chemotherapy (e.g., procarbazine), and antituberculosis (e.g., isoniazid) drugs. In addition to medicinal uses, hydrazine compounds have been used in industry and agriculture as components of rocket fuel, as herbicides, and as antioxidants in boiler and cooling-tower water.[10-12] Many scientists consider hydrazine sulfate and other hydrazine analogs to be cancer-causing agents, and they have expressed concern about the safety of these compounds.[1,10,12-21] In the 10th Report on Carcinogens, hydrazine and hydrazine sulfate are listed by the U.S. Department of Health and Human Services’ National Toxicology Program as “reasonably anticipated to be human carcinogens.”[22] When the antituberculosis drug isoniazid and hydrazine antidepressants are combined with purified DNA in the laboratory, they produce hydrogen peroxide and free radicals that can damage the DNA.[14,17,23] Hydrazine compounds have been reported to cause mutations and chromosome damage in bacteria and in plant and animal cells.[10]

Two mechanisms of action have been proposed for hydrazine sulfate to explain its potential antitumor and anticachexia properties. Both mechanisms involve the utilization of glucose (sugar), which tumors require as a main source of energy for growth. In one proposed mechanism, hydrazine sulfate blocks gluconeogenesis through inhibition of the enzyme phosphoenolpyruvate carboxykinase.[24-29] Gluconeogenesis is a process by which extra glucose (in addition to that obtained from the diet) can be formed in the liver and the kidneys from the breakdown products of sugars, lipids (fats), and proteins. It has been suggested that cachexia occurs because the body must use increasing amounts of energy and other resources, including its own protein, to meet the demand for glucose by tumors.[24-30] Blocking gluconeogenesis and interfering with the supply of nutrients to tumors has been proposed as one way to inhibit tumor growth and to prevent cachexia.

In the second proposed mechanism, hydrazine sulfate inhibits tumor necrosis factor (TNF)-alpha activity.[31-34] TNF-alpha, which is also known as cachectin, is one of a number of substances normally produced by white blood cells in the body in response to infection by microorganisms and in response to other stimuli such as tissue damage.[31,32,34-36] Higher-than-normal TNF-alpha production has been observed in white blood cells obtained from cancer patients. It has been suggested that higher-than-normal levels of TNF-alpha can cause the anorexia, increased energy expenditure, and increased muscle protein breakdown seen in cancer patients.[31,35-37] Some of the muscle protein breakdown products would become available for gluconeogenesis. Inhibition of TNF-alpha activity might, therefore, inhibit tumor growth and prevent cachexia.

References
  1. Toth B: A review of the antineoplastic action of certain hydrazines and hydrazine-containing natural products. In Vivo 10 (1): 65-96, 1996 Jan-Feb.  [PUBMED Abstract]

  2. DeVita VT, Serpick A, Carbone PP: Preliminary clinical studies with ibenzmethyzin. Clin Pharmacol Ther 7 (4): 542-6, 1966 Jul-Aug.  [PUBMED Abstract]

  3. Samuels ML, Leary WV, Alexanian R, et al.: Clinical trials with N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride in malignant lymphoma and other disseminated neoplasia. Cancer 20 (8): 1187-94, 1967.  [PUBMED Abstract]

  4. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer. J Clin Oncol 8 (1): 9-15, 1990.  [PUBMED Abstract]

  5. Kosty MP, Fleishman SB, Herndon JE 2nd, et al.: Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B. J Clin Oncol 12 (6): 1113-20, 1994.  [PUBMED Abstract]

  6. Loprinzi CL, Kuross SA, O'Fallon JR, et al.: Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer. J Clin Oncol 12 (6): 1121-5, 1994.  [PUBMED Abstract]

  7. Loprinzi CL, Goldberg RM, Su JQ, et al.: Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 12 (6): 1126-9, 1994.  [PUBMED Abstract]

  8. Filov VA, Gershanovich ML, Danova LA, et al.: Experience of the treatment with Sehydrin (Hydrazine Sulfate, HS) in the advanced cancer patients. Invest New Drugs 13 (1): 89-97, 1995.  [PUBMED Abstract]

  9. Tayek JA, Sutter L, Manglik S, et al.: Altered metabolism and mortality in patients with colon cancer receiving chemotherapy. Am J Med Sci 310 (2): 48-55, 1995.  [PUBMED Abstract]

  10. Kimball RF: The mutagenicity of hydrazine and some of its derivatives. Mutat Res 39 (2): 111-26, 1977.  [PUBMED Abstract]

  11. Nelson SD, Gordon WP: Metabolic activation of hydrazines. Adv Exp Med Biol 136 Pt B: 971-81, 1981.  [PUBMED Abstract]

  12. Vasudeva M, Vashishat RK: Mutagenic and recombinogenic activity of hydrazine sulphate in Saccharomyces cerevisiae. Mutat Res 155 (3): 113-5, 1985.  [PUBMED Abstract]

  13. Toth B: Synthetic and naturally occurring hydrazines as possible cancer causative agents. Cancer Res 35 (12): 3693-7, 1975.  [PUBMED Abstract]

  14. Rosenkranz HS, Carr HS: Hydrazine antidepressants and isoniazid: potential carcinogens. Lancet 1 (7713): 1354-5, 1971.  [PUBMED Abstract]

  15. Douglas GR, Gingerich JD, Soper LM: Evidence for in vivo non-mutagenicity of the carcinogen hydrazine sulfate in target tissues of lacZ transgenic mice. Carcinogenesis 16 (4): 801-4, 1995.  [PUBMED Abstract]

  16. Quintero-Ruiz A, Paz-Neri LL, Villa-Treviño S: Indirect alkylation of CBA mouse liver DNA and RNA by hydrazine in vivo. A possible mechanism of action as a carcinogen. J Natl Cancer Inst 67 (3): 613-8, 1981.  [PUBMED Abstract]

  17. Freese E, Sklarow S, Freese EB: DNA damage caused by antidepressant hydrazines and related drugs. Mutat Res 5 (3): 343-8, 1968 May-Jun.  [PUBMED Abstract]

  18. Bhide SV, D'Souza RA, Sawai MM, et al.: Lung tumour incidence in mice treated with hydrazine sulphate. Int J Cancer 18 (4): 530-5, 1976.  [PUBMED Abstract]

  19. Severi L, Biancifiori C: Hepatic carcinogenesis in CBA-Cb-Se mice and Cb-Se rats by isonicotinic acid hydrazide and hydrazine sulfate. J Natl Cancer Inst 41 (2): 331-49, 1968.  [PUBMED Abstract]

  20. Toth B: Lung tumor induction and inhibition of breast adenocarcinomas by hydrazine sulfate in mice. J Natl Cancer Inst 42 (3): 469-75, 1969.  [PUBMED Abstract]

  21. Menon MM, Bhide SV: Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 105 (3): 258-61, 1983.  [PUBMED Abstract]

  22. National Institute of Environmental Health Sciences.: 11th Report on Carcinogens. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, 2005. Available online. Last accessed February 4, 2014. 

  23. National Toxicology Program.: Hydrazine and hydrazine sulfate. Rep Carcinog 10: 138-9, 2002.  [PUBMED Abstract]

  24. Ray PD, Hanson RL, Lardy HA: Inhibition by hydrazine of gluconeogenesis in the rat. J Biol Chem 245 (4): 690-6, 1970.  [PUBMED Abstract]

  25. Gold J: Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology 25 (1): 66-71, 1971.  [PUBMED Abstract]

  26. Gold J: Inhibition by hydrazine sulfate and various hydrazides, of in vivo growth of Walker 256 intramuscular carcinoma, B-16 melanoma, Murphy-Sturm lymphosarcoma and L-1210 solid leukemia. Oncology 27 (1): 69-80, 1973.  [PUBMED Abstract]

  27. Gold J: Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate. Nutr Cancer 3 (1): 13-9, 1981.  [PUBMED Abstract]

  28. Gold J: Hydrazine sulfate: a current perspective. Nutr Cancer 9 (2-3): 59-66, 1987.  [PUBMED Abstract]

  29. Dills WL Jr: Nutritional and physiological consequences of tumour glycolysis. Parasitology 107 (Suppl): S177-86, 1993.  [PUBMED Abstract]

  30. Gold J: Proposed treatment of cancer by inhibition of gluconeogenesis. Oncology 22 (2): 185-207, 1968.  [PUBMED Abstract]

  31. Hughes TK, Cadet P, Larned CS: Modulation of tumor necrosis factor activities by a potential anticachexia compound, hydrazine sulfate. Int J Immunopharmacol 11 (5): 501-7, 1989.  [PUBMED Abstract]

  32. De SK, Silverstein R, Andrews GK: Hydrazine sulfate protection against endotoxin lethality: analysis of effects on expression of hepatic cytokine genes and an acute-phase gene. Microb Pathog 13 (1): 37-47, 1992.  [PUBMED Abstract]

  33. Johnson DC, Freudenberg MA, Jia F, et al.: Contribution of tumor necrosis factor-alpha and glucocorticoid in hydrazine sulfate-mediated protection against endotoxin lethality. Circ Shock 43 (1): 1-8, 1994.  [PUBMED Abstract]

  34. Jia F, Morrison DC, Silverstein R: Hydrazine sulfate selectively modulates the TNF response to endotoxin in mouse macrophages. Circ Shock 42 (2): 111-4, 1994.  [PUBMED Abstract]

  35. Parnes HL, Aisner J: Protein calorie malnutrition and cancer therapy. Drug Saf 7 (6): 404-16, 1992 Nov-Dec.  [PUBMED Abstract]

  36. Lowry SF, Moldawer LL: Tumor necrosis factor and other cytokines in the pathogenesis of cancer cachexia. Princ Pract Oncol Updates 4 (8): 1-12, 1990. 

  37. Bruera E: Current pharmacological management of anorexia in cancer patients. Oncology (Huntingt) 6 (1): 125-30; discussion 132, 137, 1992.  [PUBMED Abstract]