During the past 90 years, hydrazine compounds have been studied in animal cells grown in the laboratory, in live animals, and in humans. Reviewed in [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). Reviewed in [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. Reviewed in [1] 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.[2,3] Reviewed in [1] 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. Reviewed in [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.[17,23] Reviewed in [14] Hydrazine compounds have been reported to cause mutations and chromosome damage in bacteria and in plant and animal cells. Reviewed in [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] Reviewed in [25-29] 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] Reviewed in [25-30] 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.[24] Reviewed in [25-30]

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. Reviewed in [31,32,34-36] Higher-than-normal TNF-alpha production has been observed in white blood cells obtained from cancer patients. Reviewed in [35-37] 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. Reviewed in [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. ¹ Last accessed May 19, 2008. 
    
    
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]
    
    

Glossary Terms

In chemistry, a substance that is similar, but not identical, to another.

An abnormal loss of the appetite for food. Anorexia can be caused by cancer, AIDS, a mental disorder (i.e., anorexia nervosa), or other diseases.

Describes a drug or effect that works against cachexia (loss of body weight and muscle mass).

A drug used to treat depression.

A substance that protects cells from the damage caused by free radicals (unstable molecules made by the process of oxidation during normal metabolism). Free radicals may play a part in cancer, heart disease, stroke, and other diseases of aging. Antioxidants include beta-carotene, lycopene, vitamins A, C, and E, and other natural and manufactured substances.

Describes a drug or effect that works against tuberculosis (a contagious bacterial infection that usually affects the lungs).

A large group of single-cell microorganisms. Some cause infections and disease in animals and humans. The singular of bacteria is bacterium.

Loss of body weight and muscle mass, and weakness that may occur in patients with cancer, AIDS, or other chronic diseases.

Cancer that begins in the skin or in tissues that line or cover internal organs.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Treatment with drugs that kill cancer cells.

Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes.

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called DNA.

In chemistry, a compound produced from or related to another.

A protein that speeds up chemical reactions in the body.

Initial treatment used to reduce a cancer. First-line therapy is followed by other treatments, such as chemotherapy, radiation therapy, and hormone therapy to get rid of cancer that remains. Also called induction therapy, primary therapy, and primary treatment.

A highly reactive chemical that often contains oxygen and is produced when molecules are split to give products that have unpaired electrons (a process called oxidation). Free radicals can damage important cellular molecules such as DNA or lipids or other parts of the cell.

The process of making glucose (sugar) from its own breakdown products or from the breakdown products of lipids (fats) or proteins. Gluconeogenesis occurs mainly in cells of the liver or kidney.

A type of sugar; the chief source of energy for living organisms.

A chemical that kills plants.

A cancer of the immune system that is marked by the presence of a type of cell called the Reed-Sternberg cell. The two major types of Hodgkin disease are classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Symptoms include the painless enlargement of lymph nodes, spleen, or other immune tissue. Other symptoms include fever, weight loss, fatigue, or night sweats. Also called Hodgkin lymphoma.

A chemical used in bleaches, dyes, cleansers, antiseptics, and disinfectants. In a concentrated form, it is toxic and irritating to tissues.

Invasion and multiplication of germs in the body. Infections can occur in any part of the body and can spread throughout the body. The germs may be bacteria, viruses, yeast, or fungi. They can cause a fever and other problems, depending on where the infection occurs. When the body’s natural defense system is strong, it can often fight the germs and prevent infection. Some cancer treatments can weaken the natural defense system.

Fat.

One of a pair of organs in the chest that supplies the body with oxygen, and removes carbon dioxide from the body.

A form of cancer that begins in melanocytes (cells that make the pigment melanin). It may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines.

An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms.

Any change in the DNA of a cell. Mutations may be caused by mistakes during cell division, or they may be caused by exposure to DNA-damaging agents in the environment. Mutations can be harmful, beneficial, or have no effect. If they occur in cells that make eggs or sperm, they can be inherited; if mutations occur in other types of cells, they are not inherited. Certain mutations may lead to cancer or other diseases.

A chemical compound (such as protein, fat, carbohydrate, vitamin, or mineral) contained in foods. These compounds are used by the body to function and grow.

The first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of the treatments being tested, phase I trials usually include only a small number of patients who have not been helped by other treatments.

The initial study examining a new method or treatment.

The active ingredient in a drug that is used to treat advanced Hodgkin lymphoma and is being studied in the treatment of other types of cancer. Procarbazine blocks cells from making proteins and damages DNA. It may kill cancer cells. It is a type of antineoplastic agent and a type of alkylating agent.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A treatment plan that specifies the dosage, the schedule, and the duration of treatment.

Looking back at events that have already taken place.

Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects.

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

A protein made by white blood cells in response to an antigen (substance that causes the immune system to make a specific immune response) or infection. Tumor necrosis factor can also be made in the laboratory. It may boost a person’s immune response, and also may cause necrosis (cell death) of some types of tumor cells. Tumor necrosis factor is being studied in the treatment of some types of cancer. It is a type of cytokine. Also called TNF.

A type of immune cell. Most white blood cells are made in the bone marrow and are found in the blood and lymph tissue. White blood cells help the body fight infections and other diseases. Granulocytes, monocytes, and lymphocytes are white blood cells. Also called leukocyte and WBC.

The transplant of an organ, tissue, or cells to an individual of another species.