Purpose of This PDQ Summary
Overview
General Information
History
Laboratory/Animal/Preclinical Studies
Human/Clinical Studies
Adverse Effects
Overall Level of Evidence for Hydrazine Sulfate
Changes to This Summary (05/20/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of hydrazine sulfate as a treatment for cancer. The summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board.

Information about the following is included in this summary:

• A brief history of hydrazine sulfate research.
• The results of clinical studies of hydrazine sulfate.
• Possible side effects of hydrazine sulfate use.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level of evidence designation. These designations are intended to help the readers assess the strength of the evidence supporting the use of specific interventions or treatment strategies. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system in developing its level of evidence designations. These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language.

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Overview

This complementary and alternative medicine (CAM) information summary provides an overview of the use of hydrazine sulfate as a treatment for cancer. The summary includes a brief history of hydrazine sulfate research, results of clinical trials, and possible side effects of hydrazine sulfate use.

This summary contains the following key information:

• Hydrazine sulfate is a chemical that has been studied as a treatment for cancer and as a treatment for the body wasting (i.e., cachexia) associated with this disease.
• It has been claimed that hydrazine sulfate limits the ability of tumors to obtain glucose, which is a type of sugar used by cells to create energy.
• Hydrazine sulfate has been shown to increase the incidence of lung, liver, and breast tumors in laboratory animals, suggesting it causes cancer.
• There is only limited evidence from animal studies that hydrazine sulfate has anticancer activity.
• Hydrazine sulfate has shown no anticancer activity in randomized clinical trials, and data concerning its effectiveness in treating cancer-related cachexia are inconclusive.
• Hydrazine sulfate has been marketed in the United States as a dietary supplement or a nutraceutical by some companies; however, its use as an anticancer drug outside of clinical trials has not been approved by the U.S. Food and Drug Administration.

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Web site Dictionary, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.

Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.

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General Information

Hydrazine sulfate has been investigated as an anticancer treatment for more than 30 years. It has been studied in combination with established treatments as a chemotherapy agent. It has also been studied as a treatment for cancer-related anorexia (loss of appetite) and cachexia (loss of muscle mass and body weight). Similar to other hydrazine compounds, it has a core chemical structure that consists of two nitrogen atoms and four hydrogen atoms.

Hydrazine sulfate is marketed in the United States as a dietary supplement /nutraceutical by some companies. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. The FDA can, however, remove from the market dietary supplements that it deems unsafe. The use of hydrazine sulfate as an anticancer treatment outside of clinical trials has not been approved by the FDA. The FDA has not approved the use of hydrazine sulfate for any medical condition.

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. To date, the FDA has granted IND status to at least three groups of researchers to study hydrazine sulfate as a treatment for cancer.[1-3]

In animal studies, hydrazine sulfate has been added to the drinking water or the food supply, or it has been given by injection. In clinical trials involving cancer patients, hydrazine sulfate has been administered in pills or capsules. Reviewed in [4] In the clinical studies conducted thus far, the dose and the duration of hydrazine sulfate administration have varied.

References

1. 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]
   
   
2. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3 (2): 121-4, 1979.  [PUBMED Abstract]
   
   
3. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32 (1): 1-10, 1975.  [PUBMED Abstract]
   
   
4. 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]
   
   

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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. 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. 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]
    
    

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Laboratory/Animal/Preclinical Studies

Hydrazine compounds have been studied both as potential anticancer drugs and as cancer-causing agents. Early studies of hydrazines, including hydrazine sulfate, were conducted to determine whether these compounds could cause cancer in healthy laboratory animals.[1-9] Reviewed in [10,11] Substantial increases in tumor incidence were observed in most studies that used rats, mice, or hamsters.[1-5,7-9] Hydrazine administration was associated with increases in lung, liver, and breast tumors in rats,[2,5] increases in lung and liver tumors in mice,[1-4,8] and increases in liver tumors in hamsters.[7,9] In one study, hydrazine sulfate increased the incidence of lung tumors in both males and females of the mouse strain C3H, but reduced the incidence of breast adenocarcinomas in C3H females.[3]

Animal studies of hydrazine sulfate as a treatment for cancer have investigated this compound as a single agent and in combination with established chemotherapy drugs.[12-18] In studies conducted in one laboratory, hydrazine sulfate alone was found to cause dose-dependent inhibition of tumor growth in rats bearing Walker 256 carcinosarcoma or Murphy-Sturm lymphosarcoma tumors and in mice bearing B-16 melanoma tumors.[12-14] Hydrazine sulfate alone had no effect on solid tumors formed from L-1210 leukemia cells in mice.[13] In work performed in another laboratory, hydrazine sulfate alone inhibited the growth of FBCa bladder cancer tumors in one of two experiments in rats, but it had no effect on the growth of 13762NF mammary adenocarcinomas in rats.[17] Findings from a third laboratory demonstrated that hydrazine sulfate alone had no effect on the growth of Dunning prostate cancer tumors in rats.[18]

It is important to note that the best tumor responses to hydrazine sulfate as a single agent (i.e., tumor reductions of approximately 50% or more) were accompanied by substantial losses in animal body weight.[12-14] This finding appears to be inconsistent with the proposed use of hydrazine sulfate as an anticachexia agent.

In other experiments, hydrazine sulfate was combined with individual chemotherapy drugs (cyclophosphamide, mitomycin C, methotrexate, bleomycin, fluorouracil [5-FU], carmustine [BCNU], or neocarcinostatin) to treat Walker 256 carcinosarcoma tumors in rats and solid L-1210 leukemia tumors in mice.[13-15] For both tumor types, enhanced anticancer effects were observed. In the experiments with L-1210 tumors, cyclophosphamide and mitomycin C were more effective when combined with hydrazine sulfate than they were when used alone.[13] As indicated previously, hydrazine sulfate alone had no effect against solid L-1210 tumors.[13]

Addition of the drug clofibrate to the hydrazine sulfate plus chemotherapy drug combinations was reported to produce even greater antitumor effects.[15] Clofibrate lowers blood lipid levels and has the potential to inhibit gluconeogenesis by limiting the availability of lipid breakdown products for the synthesis of glucose. Reviewed in [15] This three drug treatment regimen, however, was tested against only one type of tumor (Walker 256 carcinosarcomas in rats).[15]

Hydrazine sulfate has also been tested in combination with drugs that affect the uptake of glucose by cells. The combination of hydrazine sulfate and phloretin, a drug that blocks glucose uptake, showed greater activity against FBCa bladder cancer tumors in rats than was found with hydrazine sulfate alone; however, this combination did not exhibit enhanced antitumor activity against 13762NF mammary adenocarcinomas in rats.[17] When hydrazine sulfate was combined with the drug phloridzin, which is similar to phloretin, using the same two tumor models, no increase in anticancer activity was observed.[17] When hydrazine sulfate was combined with the drug phenformin, which increases glucose uptake by cells (and lowers blood glucose levels), enhanced antitumor activity against Walker 256 carcinosarcomas in rats was observed.[16]

In the 1980s, the National Cancer Institute (NCI) conducted preclinical studies of hydrazine sulfate as a single agent, using many of the animal tumor models described above. With the exception of borderline activity against Walker 256 carcinosarcomas in rats, no evidence of antitumor activity was found. Reviewed in [19] In view of these results, NCI recommended against further evaluation of hydrazine sulfate as an anticancer agent. Reviewed in [19] However, clinical investigation of this compound continued, largely because of its potential as a treatment for cancer-related anorexia and cachexia.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. Menon MM, Bhide SV: Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 105 (3): 258-61, 1983.  [PUBMED Abstract]
   
   
5. Biancifiori C, Giornelli-Santilli FE, Milia U, et al.: Pulmonary tumours in rats induced by oral hydrazine sulphate. Nature 212 (60): 414-5, 1966.  [PUBMED Abstract]
   
   
6. Toth B: Tumorigenesis studies with 1,2-dimethylhydrazine dihydrochloride, hydrazine sulfate, and isonicotinic acid in golden hamsters. Cancer Res 32 (4): 804-7, 1972.  [PUBMED Abstract]
   
   
7. Shimizu H, Toth B: Effect of lifetime administration of 2-hydroxyethylhydrazine on tumorigenesis in hamsters and mice. J Natl Cancer Inst 52 (3): 903-6, 1974.  [PUBMED Abstract]
   
   
8. Maru GB, Bhide SV: Effect of antioxidants and antitoxicants of isoniazid on the formation of lung tumours in mice by isoniazid and hydrazine sulphate. Cancer Lett 17 (1): 75-80, 1982.  [PUBMED Abstract]
   
   
9. Bosan WS, Shank RC, MacEwen JD, et al.: Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine. Carcinogenesis 8 (3): 439-44, 1987.  [PUBMED Abstract]
   
   
10. Toth B: Synthetic and naturally occurring hydrazines as possible cancer causative agents. Cancer Res 35 (12): 3693-7, 1975.  [PUBMED Abstract]
    
    
11. National Toxicology Program.: Hydrazine and hydrazine sulfate. Rep Carcinog 10: 138-9, 2002.  [PUBMED Abstract]
    
    
12. Gold J: Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology 25 (1): 66-71, 1971.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. Gold J: Enhancement by hydrazine sulfate of antitumor effectiveness of cytoxan, mitomycin C, methotrexate and bleomycin, in walker 256 carcinosarcoma in rats. Oncology 31 (1): 44-53, 1975.  [PUBMED Abstract]
    
    
15. Gold J: Potentiation by clofibrate of in-vivo tumor inhibition by hydrazine sulfate and cytotoxic agents, in Walker 256 carcinosarcoma. Cancer Biochem Biophys 3 (1): 41-5, 1978.  [PUBMED Abstract]
    
    
16. Dilman VM, Anisimov VN: Potentiation of antitumor effect of cyclophosphamide and hydrazine sulfate by treatment with the antidiabetic agent, 1-phenylethylbiguanide (phenformin). Cancer Lett 7 (6): 357-61, 1979.  [PUBMED Abstract]
    
    
17. Nelson JA, Falk RE: The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res 13 (6A): 2287-92, 1993 Nov-Dec.  [PUBMED Abstract]
    
    
18. Kamradt JM, Pienta KJ: The effect of hydrazine sulfate on prostate cancer growth. Oncol Rep 5 (4): 919-21, 1998 Jul-Aug.  [PUBMED Abstract]
    
    
19. Henney JE: Unproven methods of cancer treatment. In: DeVita VT, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 2nd ed. Philadelphia, Pa: JB Lippincott Company, 1985, pp 2333-44. 
    
    

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Human/Clinical Studies

Most of the information presented here is summarized in a table located at the end of this section.

Hydrazine sulfate has been studied extensively in patients with advanced cancer. These studies have evaluated the following: a) tumor response and/or survival among patients with various types of cancer,[1-13] b) changes in body weight,[1-6,8,10-12,14] c) carefully measured quality of life,[4-6,15] and d) changes in nutritional or metabolic status.[1,4,12,13,16,17] Clinical studies of hydrazine sulfate have been funded by a pharmaceutical company,[3] the Russian government,[7,9,10,18] and by grants from the National Cancer Institute (NCI).[1,2,4-6,8,11,12,15,16] They have also been sponsored by the North Central Cancer Treatment Group (NCCTG) [5,6] and the Cancer and Leukemia Group B (CALGB).[4,15]

The first clinical tests of hydrazine sulfate as a treatment for cancer were conducted in the mid-1970s by a pharmaceutical company.[3] In an uncontrolled study of 158 patients with advanced disease, it was found that 45 of 84 evaluable patients had subjective improvements (i.e., the patients reported an increase in appetite, a decrease in weight loss, an increase in strength, or a decrease in pain) and that 14 had objective improvements (i.e., there was measurable tumor regression, stable disease, or improvement in a cancer-related disorder) in response to treatment with hydrazine sulfate. Among the patients with objective responses, two had long-term (17 and 18 months) stabilization of their disease and seven had measurable tumor regression, although the extent and duration of these regressions were not specified. Major weaknesses of this study included the absence of a control (i.e., comparison) group and the fact that 74 of the 158 initially recruited patients could not be evaluated because of poor prognosis, missing documentation, insufficient duration of treatment, and/or concurrent therapy (i.e., therapy given at the same time) with other anticancer drugs.[3]

In 1976, Russian investigators reported findings from 95 patients with advanced cancer who had been treated with hydrazine sulfate after all previous therapy (surgery, chemotherapy, and/or radiation therapy) had failed.[9] Three partial responses (i.e., reductions in tumor size of greater than 50% observed for a period of 4 weeks or more) and no complete responses were noted after 1 to 5 months of treatment. Tumor regressions of 50% or less and stable disease (i.e., cessation of tumor growth for a period of 1.5 to 2.0 months or more) were reported for 16 and 20 patients, respectively.

In 1981, the same investigators published findings from 225 patients with advanced disease who had been treated with hydrazine sulfate after all previous therapy had failed.[10] It appears that the 225 patients described in this second report [10] included the 95 patients described in the first report.[9] Partial responses and stable disease were reported for 4 and 95 patients, respectively, after 1 to 6 months of treatment. No patient experienced a complete response. Subjective improvements in appetite, weight stabilization or gain, pain, fever, breathing, and/or mental outlook were reported by 147 patients.

In 1995, the same Russian investigators published findings from 740 patients with advanced cancer.[7] Once again, it appears that 225 of these 740 patients were described in the earlier reports.[9,10] Partial responses and stable disease were reported for 25 and 263 patients, respectively. Complete responses were noted for six patients. Subjective improvements in cancer-related symptoms were reported by 344 patients.

In 1994, the same investigators reported findings from a clinical series involving 46 patients with malignant brain tumors (38 with glioblastomas, four with astrocytomas, and four with meningiomas) and six patients with benign brain tumors.[18] These patients were not described in the other reports.[7,9,10] All patients in this series appear to have been treated with surgery in addition to hydrazine sulfate therapy, and at least some of the patients were also treated with radiation therapy. Complete or partial regression of neurologic symptoms (e.g., seizures, headaches, sensory and motor disorders, and hallucinations) was reported for 73% of the patients. In addition, longer-than-average survival was reported for most patients. Among the patients with glioblastomas, the increase in average survival time was from 6 months to more than 13 months.[18]

Evaluation of the findings from these Russian clinical series [7,9,10,18] is made difficult by the limited information provided about the patients and their treatment histories. In addition, insufficient information was given about study design and methodology. The absence of control groups; the receipt of prior or concurrent surgery, chemotherapy, and/or radiation therapy by all patients; and the reliance on subjective measures of quality of life are major study weaknesses. Therefore, it is difficult to ascribe any of the positive findings to treatment with hydrazine sulfate. In contrast with the previously described clinical series, three NCI-funded clinical series found no complete responses or partial responses among a total of 79 patients treated with hydrazine sulfate.[2,8,11] In addition, only temporary, minor improvements in appetite, pain, and weight stabilization or gain were reported by the patients in these series. A weakness in these three clinical series was the absence of control groups.

Findings from four placebo-controlled, randomized clinical trials, however, also fail to support the effectiveness of hydrazine sulfate as a cancer treatment in humans.[1,4-6,15] In these trials, survival,[1,4-6,15] objective tumor response,[1,4,15] and carefully measured quality of life [4-6,15] were major endpoints.

One of the trials involved 65 patients with advanced nonsmall cell lung cancer and examined the effects of hydrazine sulfate on survival and nutritional status.[1]. In this trial, patients received either hydrazine sulfate or placebo in addition to a multiple-drug chemotherapy regimen. When all patients were evaluated, no improvement in survival was found with hydrazine sulfate therapy. In addition, no differences were noted in objective tumor response between the hydrazine sulfate group and the placebo group. However, on the basis of caloric intake and the maintenance of serum albumin levels, the nutritional status of the patients in the hydrazine sulfate group was judged better than that of the patients in the placebo group. However, the moderate increases in body weight associated with hydrazine sulfate use did not achieve statistical significance.

A CALGB-sponsored trial also evaluated the use of hydrazine sulfate as a treatment for patients with advanced nonsmall cell lung cancer.[4,15] In this trial, 266 patients received either hydrazine sulfate or placebo in addition to a multiple-drug chemotherapy regimen. No differences in survival, objective tumor response, anorexia, weight gain or loss, or nutritional status were observed between the hydrazine sulfate group and the placebo group. However, the quality of life of the patients who received hydrazine sulfate was found to be statistically significantly worse than that of the patients who received placebo.

The use of hydrazine sulfate as a treatment for patients with nonsmall cell lung cancer was also evaluated in an NCCTG-sponsored trial.[6] In this trial, 243 patients were randomly assigned to receive either hydrazine sulfate or placebo in addition to a multiple-drug chemotherapy regimen. No statistically significant differences were found between the hydrazine sulfate group and the placebo group with respect to either survival or quality of life.

Another NCCTG-sponsored trial tested hydrazine sulfate alone versus placebo in the treatment of 127 patients with metastatic colorectal cancer.[5] In this trial, the patients who received hydrazine sulfate had, on average, shorter survival than the patients who received placebo, a finding that was statistically significant. There were no statistically significant differences between the hydrazine sulfate group and the placebo group with respect to weight gain or loss, anorexia, or quality of life.

Four other clinical trials did find some objective evidence of benefit with hydrazine sulfate therapy.[12,13,16,17] These trials had either nutritional status or metabolic status as the primary endpoint. In a placebo-controlled, randomized trial involving 38 patients with advanced disease, hydrazine sulfate was found to improve the abnormal glucose metabolism seen in cancer patients.[13] In another placebo-controlled, randomized trial that involved 101 patients with advanced cancer and weight loss, the use of hydrazine sulfate was associated with statistically significant improvements in appetite and either weight increase or weight maintenance.[12] However, the higher average caloric intake observed in this study for patients treated with hydrazine sulfate compared with patients treated with placebo was not statistically significant.[12] Two other clinical studies involving a total of 34 patients with either lung cancer or colon cancer found that hydrazine sulfate was able to reduce the body protein breakdown associated with cancer cachexia.[16,17] In view of the totality of evidence, the overall importance of the findings from these four clinical trials is not clear.

A search of the PDQ clinical trials database indicates that no clinical trials of hydrazine sulfate as a therapy for cancer are being conducted at this time.

References

1. 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]
   
   
2. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3 (2): 121-4, 1979.  [PUBMED Abstract]
   
   
3. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32 (1): 1-10, 1975.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. Lerner HJ, Regelson W: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 60 (7): 959-60, 1976.  [PUBMED Abstract]
   
   
9. Gershanovich ML, Danova LA, Kondratyev VB, et al.: Clinical data on the antitumor activity of hydrazine sulfate. Cancer Treat Rep 60 (7): 933-5, 1976.  [PUBMED Abstract]
   
   
10. Gershanovich ML, Danova LA, Ivin BA, et al.: Results of clinical study antitumor action of hydrazine sulfate. Nutr Cancer 3 (1): 7-12, 1981.  [PUBMED Abstract]
    
    
11. Ochoa M Jr, Wittes RE, Krakoff IH: Trial of hydrazine sulfate (NSC-150014) in patients with cancer. Cancer Chemother Rep 59 (6): 1151-4, 1975 Nov-Dec.  [PUBMED Abstract]
    
    
12. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience. Cancer 59 (3): 406-10, 1987.  [PUBMED Abstract]
    
    
13. Chlebowski RT, Heber D, Richardson B, et al.: Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 44 (2): 857-61, 1984.  [PUBMED Abstract]
    
    
14. Gold J: Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate. Nutr Cancer 3 (1): 13-9, 1981.  [PUBMED Abstract]
    
    
15. Herndon JE 2nd, Fleishman S, Kosty MP, et al.: A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931. Control Clin Trials 18 (4): 286-300, 1997.  [PUBMED Abstract]
    
    
16. 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]
    
    
17. Tayek JA, Heber D, Chlebowski RT: Effect of hydrazine sulphate on whole-body protein breakdown measured by 14C-lysine metabolism in lung cancer patients. Lancet 2 (8553): 241-4, 1987.  [PUBMED Abstract]
    
    
18. Filov VA, Gershanovich ML, Ivin BA, et al.: [Therapy of primary brain tumors with segidrin] Vopr Onkol 40 (7-12): 332-6, 1994.  [PUBMED Abstract]
    
    

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Adverse Effects

The side effects associated with hydrazine sulfate use have been mainly gastrointestinal and neurologic.[1-12] Nausea and/or vomiting, dizziness, and sensory and motor neuropathies have been reported.[1-12] The sensory and motor neuropathies have included paresthesias (abnormal touch sensations, such as burning or prickling, in the absence of external stimuli) of the upper and lower extremities (i.e., the arms and the legs, including the hands and the feet), polyneuritis (simultaneous inflammation of several peripheral nerves), and impaired fine motor function (e.g., an impaired ability to write).[2,5,7-9] Other side effects have included dry skin and/or itching, insomnia, and hypoglycemia.[1,2,7,9] One case of fatal liver and kidney failure and one case of severe encephalopathy (an injury to the brain) have been associated with the use of hydrazine sulfate.[13,14] The former case involved a man aged 55 years with squamous cell carcinoma of the maximillary sinus who purchased hydrazine sulfate from a source found on the Internet and proceeded to take it without medical advice or supervision. After 4 months he presented with evidence of renal and liver toxicity, which eventually resulted in death. This case highlights the danger of accessing materials and medical information on the Internet and proceeding with self- medication without seeking proper medical advice and supervision.[15]

The side effects of hydrazine sulfate have been described as mild to moderate in severity, and their incidence appears to have been low. Most side effects are reported to resolve when treatment is stopped. However, limited evidence from animal studies suggests that hydrazine sulfate is highly toxic when combined with either alcohol or barbiturates.[16-18] Reviewed in [19]

References

1. Spremulli E, Wampler GL, Regelson W: Clinical study of hydrazine sulfate in advanced cancer patients. Cancer Chemother Pharmacol 3 (2): 121-4, 1979.  [PUBMED Abstract]
   
   
2. Gold J: Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 32 (1): 1-10, 1975.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. Lerner HJ, Regelson W: Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 60 (7): 959-60, 1976.  [PUBMED Abstract]
   
   
7. Gershanovich ML, Danova LA, Kondratyev VB, et al.: Clinical data on the antitumor activity of hydrazine sulfate. Cancer Treat Rep 60 (7): 933-5, 1976.  [PUBMED Abstract]
   
   
8. Gershanovich ML, Danova LA, Ivin BA, et al.: Results of clinical study antitumor action of hydrazine sulfate. Nutr Cancer 3 (1): 7-12, 1981.  [PUBMED Abstract]
   
   
9. Ochoa M Jr, Wittes RE, Krakoff IH: Trial of hydrazine sulfate (NSC-150014) in patients with cancer. Cancer Chemother Rep 59 (6): 1151-4, 1975 Nov-Dec.  [PUBMED Abstract]
   
   
10. Chlebowski RT, Bulcavage L, Grosvenor M, et al.: Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience. Cancer 59 (3): 406-10, 1987.  [PUBMED Abstract]
    
    
11. Chlebowski RT, Heber D, Richardson B, et al.: Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 44 (2): 857-61, 1984.  [PUBMED Abstract]
    
    
12. Herndon JE 2nd, Fleishman S, Kosty MP, et al.: A longitudinal study of quality of life in advanced non-small cell lung cancer: Cancer and Leukemia Group B (CALGB) 8931. Control Clin Trials 18 (4): 286-300, 1997.  [PUBMED Abstract]
    
    
13. Hainer MI, Tsai N, Komura ST, et al.: Fatal hepatorenal failure associated with hydrazine sulfate. Ann Intern Med 133 (11): 877-80, 2000.  [PUBMED Abstract]
    
    
14. Nagappan R, Riddell T: Pyridoxine therapy in a patient with severe hydrazine sulfate toxicity. Crit Care Med 28 (6): 2116-8, 2000.  [PUBMED Abstract]
    
    
15. Black M, Hussain H: Hydrazine, cancer, the Internet, isoniazid, and the liver. Ann Intern Med 133 (11): 911-3, 2000.  [PUBMED Abstract]
    
    
16. Masaki H, Arai H, Torii K: Newly developed animal model with alcoholic liver damage induced by an inhibitor for gluconeogenesis, hydrazine sulfate. Gastroenterol Jpn 24 (5): 584, 1989.  [PUBMED Abstract]
    
    
17. Suzuki H, Tominaga T, Mizuno H, et al.: Ethanol and hydrazine sulfate induced chronic hepatic injury in rats: the curative effect of administration of glucogenic amino acids. Alcohol Alcohol Suppl 1A: 111-7, 1993.  [PUBMED Abstract]
    
    
18. Gold J: Incompatibility of hydrazine sulfate and pentobarbital in the treatment of tumor bearing animals. [Abstract] Proc Am Assoc Cancer Res 18: A-999, 250, 1977. 
    
    
19. U.S. General Accounting Office.: Cancer Drug Research: Contrary to Allegation, NIH Hydrazine Sulfate Studies Were Not Flawed. Washington, DC: U.S. General Accounting Office, 1995, GAO-HEHS-95-141. Also available online. Last accessed May 19, 2008. 
    
    

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Overall Level of Evidence for Hydrazine Sulfate

Several clinical case series conducted by Russian investigators have indicated that hydrazine sulfate has marginal anticancer activity, but these results are considered inconclusive due to the lack of control groups and insufficient information provided about study methodology. Well-controlled clinical studies conducted in the United States have shown no evidence of anticancer activity. In addition, evidence concerning the effectiveness of hydrazine sulfate as a treatment for cancer-related cachexia and anorexia is inconclusive. Furthermore, hydrazine sulfate has been shown to increase the incidence of several types of tumors in animals, and it has been classified as a potential carcinogen by the National Toxicology Program of the U.S. Department of Health and Human Services. The use of hydrazine sulfate as an anticancer drug outside the context of clinical trials has not been approved by the U.S. Food and Drug Administration and, thus, cannot be recommended.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

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Changes to This Summary (05/20/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Adverse Effects

Added text about a man aged 55 years with squamous cell carcinoma of the maximillary sinus who purchased hydrazine sulfate from a source found on the Internet and proceeded to take it without medical advice or supervision (cited Black et al. as reference 15).

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More Information

Additional Information about CAM Therapies

• The National Center for Complementary and Alternative Medicine (NCCAM).
• The National Cancer Institute Office of Cancer Complementary and Alternative Medicine (OCCAM).
• CAM on PubMed, a special subset of the PubMed scientific literature database created through a partnership between NCCAM and the National Library of Medicine.

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  Full description of the NCI PDQ database.

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  Treatment options for adult cancers.

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  Treatment options for childhood cancers.

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• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

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  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

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• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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