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

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