Unconventional therapies for cancer:
4. Hydrazine sulfate

Elizabeth Kaegi, MB, ChB, MSc, on behalf of the Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative

CMAJ 1998;158:1327-30

The Canadian Breast Cancer Research Initiative does not endorse the use of any particular unconventional therapy. It urges patients to evaluate all evidence carefully and to consult their caregiver in order to make thoughtful and fully informed personal decisions.

This article has been peer reviewed.

Reprint requests to: Dr. Marilyn Schneider, Director of Research, Canadian Breast Cancer Research Initiative, 200–10 Alcorn Ave., Toronto ON M4V 3B1; tel 416 961-7223; fax 416 961-4189

© 1998 Canadian Medical Association (full text)

• Letter: Alternative views on alternative therapies

• Safety
• Laboratory and clinical evidence
• Conclusion
• References

This article, on hydrazine sulfate, is fourth in the series that reviews the safety and effectiveness of 6 unconventional therapies commonly used by Canadian cancer patients. The purpose and methodology of the review appear in part 1 (CMAJ 1998;158[7]:897-902 [full text / résumé]). Annotated bibliographies providing more detailed references are available in print from the Canadian Breast Cancer Research Initiative (CBCRI; address appears at end of article). The reference lists and the lay summaries of the findings (published in 1997) can be found on the CBCRI's Web site (www.breast.cancer.ca). The following article adapts the lay summary on hydrazine sulfate for clinicians and provides references for the key findings.

Unlike most unconventional therapies, hydrazine sulfate was developed in a way that more closely parallels the development of conventional therapies: a probable mechanism of action was identified and some research using animal models was conducted before the product was made available to patients.

The principal proponent and developer of hydrazine sulfate is Dr. Joseph Gold, an American research oncologist now at the Syracuse Cancer Research Institute, a private, nonprofit institute that performs cancer research, including studies of hydrazine sulfate alone or in combination with other chemotherapeutic agents. In developing hydrazine sulfate, Gold was influenced by the research of Dr. Otto Warburg, a 1931 Nobel prize winner who had proposed that an important distinguishing feature of cancer cells is their propensity to obtain energy through the anaerobic, rather than the aerobic, metabolism of glucose.¹ This difference between cancer cells and normal cells was confirmed by Gold and other investigators.^2,3 Gold, noting that gluconeogenesis (the process whereby the products of anaerobic metabolism are reconstituted into glucose) required a great deal of energy, postulated that excessive gluconeogenesis was a major determinant of cancer-related cachexia. As a result of further experimentation, Gold concluded that the enzyme phosphoenol pyruvate carboxykinase (PEP-CK) played an important role in gluconeogenesis and proposed that inhibition of this enzyme would impede gluconeogenesis and reduce the severity of cachexia.⁴

Gold tested a number of substances thought to interfere with gluconeogenesis, including L-tryptophan^5–7 and hydrazine sulfate,^8–10 in an effort to identify an agent that would inhibit PEP-CK. He found that hydrazine sulfate was the most effective for this purpose.^8,10 He reported that, in clinical studies, the use of hydrazine sulfate resulted in improved appetite and reduced weight loss,^11,12 and he proposed that it be used as an adjuvant therapy to prevent cachexia.

In addition to its effects on gluconeogenesis, Gold also reported that hydrazine sulfate administered to rats with transplanted tumours inhibited tumour growth and increased survival.⁸ In the past, Gold has advised the use of hydrazine sulfate in patients with breast cancer, sarcomas, Hodgkin's disease and other lymphomas, and neuroblastomas. He now recommends its use for all forms of cancer.¹³

Gold recommends that hydrazine sulfate be used in conjunction with conventional therapeutic agents. He believes that combining these agents may result in an enhanced effect, a position for which there is some support.^14,15

Hydrazine sulfate is usually administered orally, with food or immediately before eating. It may also be given by injection. The usual cycle of treatment is 60 mg 3 times daily for 30–45 days followed by a rest period of 2–6 weeks. The cycle can be repeated as many times as desired. Each 60-mg dose is available in capsule form or in 15-mL vials for injection.

The product is available legally in Canada, and physicians can obtain information about its availability by contacting the Health Protection Branch of Health Canada. The Health Protection Branch does not object to the use of hydrazine sulfate as long as the patient is under medical supervision. Although the product is not expensive, its costs are not covered by public or private health insurance plans. In the US, hydrazine sulfate is available to physicians through the Investigational New Drug (IND) program of the Food and Drug Administration. Hydrazine sulfate is more widely used in Europe, especially Russia, where it is known as Sehydrin. Further information about the availability of hydrazine sulfate can be obtained by contacting Dr. Gold directly (Syracuse Center Research Institute, 600 E Genesse St., Syracuse NY 13202 [www.ngen.com/hs-cancer]).

Hydrazine sulfate and its parent chemical hydrazine are well known industrial chemicals used in refining certain metals and in the production of some rocket fuels, insecticides and rust-prevention agents. Industrial-quality hydrazine sulfate can be obtained from industrial sources for laboratory research.

[ Contents ]

The side effects have been reported as mild and transient when hydrazine sulfate is taken as recommended by Gold.^11,16 However, nausea, pruritis, dizziness, drowsiness, excitation and peripheral neuropathies (motor and sensory) may develop in 5% to 10% of patients.^16,17 Hydrazine, a metabolite of hydrazine sulfate, has been reported to have cytotoxic effects on hepatocyte cell cultures.¹⁸

Although the scientific literature reporting serious adverse interactions between hydrazine sulfate and alcohol, barbiturates and tranquillizers (particularly benzodiazepines) is limited,^19,20 Gold insists that these combinations are contraindicated. Gold believes that these combinations may lead to increased toxicity and decreased effectiveness. He also cautions that because hydrazine and hydrazine sulfate are monoamine oxidase inhibitors, people using hydrazine sulfate should avoid foods that are rich in tyramine (e.g., certain cheeses).^21,22

In animal studies, hydrazine sulfate and other related compounds have been shown to be carcinogens or co-carcinogens in some species.^23–26 No human studies indicating such findings were found. Although no evidence was found that hydrazine sulfate produces any teratogenic effects, other hydrazine derivatives have been shown to be teratogens in several animal species.^24,27 Therefore, pregnant women and women of child-bearing age who are having unprotected sex should avoid using hydrazine sulfate.

[ Contents ]

Several researchers have noted that hydrazine sulfate inhibits the enzyme PEP-CK^7,28,29 and that it may interfere with gluconeogenesis.^7,30,31 Some animal studies have reported that these effects are potentiated when hydrazine sulfate is used in conjunction with other agents known to affect carbohydrate, lipid or protein metabolism positively.^32–34

Hydrazine sulfate has been reported to have a cytotoxic effect on human glioblastoma cell lines.³⁵ This finding has led some to suggest that the agent may be of value in the management of glioblastomas.³⁶ A few animal studies have shown that hydrazine sulfate can stabilize or inhibit tumour growth. Most of these studies were by Gold,^8,9 but some other researchers have reported similar results.³³

Gold's findings from animal studies suggesting that hydrazine sulfate enhances the effects of conventional chemotherapeutic agents^15,37 serve as the basis for his recommendation that it be used in conjunction with any appropriate conventional therapy for cancer.

With respect to clinical evidence, the scientific literature has fairly consistently reported that hydrazine sulfate is metabolically active and that it may normalize the carbohydrate metabolism of cancer patients with cachexia.^14,16,38,39 However, the mechanisms of cachexia are now considered to be complex and to involve much more than anaerobic glucose metabolism. The prevailing theory is that cachexia results from a combination of metabolic abnormalities, including abnormal lipolysis caused by a combination of reduced energy intake and the effects of substances released by tumour tissue.^40–42

In terms of a direct effect of hydrazine sulfate on tumour growth, the clinical evidence has been much less consistent. A noticeable discrepancy was found between the results of clinical studies performed in the US and those conducted in Russia. Most of the US studies showed minimal, if any, beneficial effects,^38,43–47 whereas those conducted in Russia typically reported significant improvements in well-being, tumour stabilization and survival.^16,36,48,49 The exceptions to this generalization are the studies carried out by Gold^11,12,50 and by Chlebowski and colleagues^14,16,39 in the US that showed positive results. The Russian studies were mostly case series, and some included patients with many different types of cancer.^49,51 Although reports of case series are of more value than anecdotal reports, it is difficult to evaluate the effects of hydrazine sulfate reliably in the absence of a control group and in a study population whose conditions and prognoses differ widely. Also, because most of the outcomes are subjective, the possibility of placebo effects must be considered.

The most recent US studies were randomized controlled trials that showed no benefit from the use of hydrazine sulfate in patients with advanced lung and colorectal cancer.^45–47 However, Gold and other supporters of hydrazine sulfate were unconvinced by these findings. They argued that the treatment protocol used in these studies did not comply fully with the recommendation that patients receiving hydrazine sulfate strictly avoid the use of agents such as barbiturates, alcohol and benzodiazepines. (Gold believes that these substances interfere with hydrazine sulfate's effectiveness.^52–56) The expressed concerns of both Gold and the public⁵⁷ subsequently led to a review of the study by the US Government Accounting Office in 1997. This review found that the protocol used by the investigators was appropriate given the information available to them, but it did not formulate or express an opinion on the effectiveness or otherwise of hydrazine sulfate.⁵⁸ The potential benefits of hydrazine sulfate as an adjunctive therapy in the management of cancer remain controversial.

[ Contents ]

There is good evidence that hydrazine sulfate inhibits gluconeogenesis. Therefore, it may play a role in reducing the severity of cachexia and in improving the quality of life of cancer patients. The value of hydrazine sulfate as an antitumour agent — specifically its capacity to stabilize tumour size, cause tumour regression and improve survival — remains uncertain.

Further clinical research is needed to confirm and quantify the benefits of hydrazine sulfate in reducing the severity of cachexia and in improving quality of life, alone or in combination with conventional chemotherapeutic agents. In addition, further animal and clinical studies to assess the antitumour effects of hydrazine sulfate, either alone or in combination with conventional chemotherapeutic agents, should be considered. The design of these studies is challenging, and in order to ensure that their results are of the greatest possible value in confirming or refuting claims of hydrazine sulfate's effectiveness, the studies should ideally be done in collaboration with Gold, the main proponent of hydrazine sulfate in Canada and the US.

This article reports some of the work carried out by the Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative (CBCRI). The CBCRI is the main funder of breast cancer research in Canada and was established in 1993 as a consortium of the Canadian Cancer Society (CCS), the National Cancer Institute of Canada (NCIC) — which also serves as the administrative home of the CBCRI — and the federal government (through the participation of the Medical Research Council of Canada and the National Health Research and Development Programme). In addition to the author, a number of other CBCRI staff worked on the project, including Dr. Carmen Tamayo (research associate), Ms. Rebecca McDonald and Ms. Jess Merber. Others contributed to the reviews of specific agents. The task force was chaired by Ms. Donna Cappon. Dr. Kaegi was the Director of Medical Affairs and Cancer Control for the CCS and the NCIC and staff partner with the task force.

[ Contents ]

1. Warburg O. On the origin of cancer cells. Science 1956;123:309-14.
2. Macbeth RAL, Bekesi JG. Oxygen consumption and anaerobic glycolysis of human malignant and normal tissue. Cancer Res 1962;22:244-8.
3. Gold J. Metabolic profiles in human solid tumors: I. A new technic for the utilization of human solid tumors in cancer research and its application to the anaerobic glycolysis of isologous benign and malignant colon tissues. Cancer Res 1966;26:695-705.
4. Gold J. Proposed treatment of cancer by inhibition of gluconeogenesis. Oncology 1968;22:185-207.
5. Ray PD, Foster DO, Lardy HA. Paths of carbon in gluconeogenesis and lipogenesis: IV. Inhibition by L-tryptophan of hepatic gluconeogenesis at the level of phosphoenolpyruvate formation. J Biol Chem 1966;241(17):3904-8.
6. Gold J. Inhibition of Walker 256 intramuscular carcinoma in rats by administration of L-tryptophan. Oncology 1970;24(4):291-303.
7. Ray PD, Hanson RL, Lardy HA. Inhibition by hydrazine of gluconeogenesis in the rat. J Biol Chem 1970;245(4):690-6.
8. Gold J. Inhibition of gluconeogenesis at the phosphoenolpyruvate carboxykinase and pyruvate carboxylase reactions, as a means of cancer chemotherapy. Oncology 1974;29:74-89.
9. Gold J. Inhibition of Walker 256 intramuscular carcinoma in rats by administration of L-tryptophan and hydrazine sulfate [abstract 116]. Proc Am Assoc Cancer Res 1970;11:30.
10. Gold J. Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology 1971;25:66-71.
11. Gold J. Use of hydrazine sulfate in terminal and preterminal cancer patients: results of investigational new drug (IND) study in 84 evaluable patients. Oncology 1975;32:1-10.
12. Gold J. Anabolic profiles in late-stage cancer patients responsive to hydrazine sulfate. Nutr Cancer 1981;3(1):13-9.
13. Ontario Breast Cancer Information Exchange Project. A guide to unconventional cancer therapies. Aurora (ON): R&R Bookbar; 1994. p. 278-80.
14. Chlebowski RT, Bulcavage L, Grosvenor M, Oktay E, Block JB, Chlebowski JS, et al. Hydrazine sulfate influence in nutritional status and survival in non-small-cell lung cancer. J Clin Oncol 1990;8(1):9-15.
15. Gold J. Enhancement by hydrazine sulfate of antitumor effectiveness of cytoxan, mitomycin C, methotrexate and bleomycin, in Walker 256 carcinosarcoma in rats. Oncology 1975;31:44-53.
16. Chlebowski RT, Heber D, Richardson B, Block JB. Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. J Cancer Res 1984;44:857-61.
17. Tweedie DJ, Erikson JM, Prough RA. Metabolism of hydrazine anti-cancer agents. Pharmacol Ther 1987;34:111-27.
18. Noda A, Sendo T, Ohno K, Noda H, Goto S. Metabolism and cytotoxicity of hydrazine in isolated rat hepatocytes. Chem Pharma Bull (Tokyo) 1987;35(6):2538-44.
19. Gold J. Incompatibility of hydrazine sulfate and pentobarbital in the treatment of tumor bearing animals [abstract 999]. Proc Am Assoc Cancer Res 1977;18:250.
20. 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 1993;1A:111-7.
21. Zimmerman HJ, Ishak KG. The hepatic injury of monoamine oxidase inhibitors. J Clin Psychopharmacol 1987;7(4):211-3.
22. Berkow R, editor. The Merck manual of diagnosis and therapy. 16th ed. Toronto: WB Saunders Publishers; 1992.
23. Toth B. Hydrazine, methylhydrazine and methylhydrazine sulfate carcinogenesis in Swiss mice: failure of ammonium hydroxide to interfere in the development of tumors. Int J Cancer 1972;9:109-18.
24. Menon MM, Bhide SV. Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 1983;105:258-61.
25. Baló J. Role of hydrazine in carcinogenesis. Adv Cancer Res 1979;30:151-64.
26. Bosan WS, Shrank RC, MacEwan JD, Gaworski CL, Newberne PM. Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine. Carcinogenesis 1987;8:439-44.
27. Toth B. Teratogenic hydrazines: a review. In Vivo 1993;7(1):101-10.
28. Silverstein R, Christoffersen CA, Morrison DC. Modulation of endotoxin lethality in mice by hydrazine sulfate. Infect Immun 1989;57(7):2072-8.
29. Chlebowski RT, Heber D. Metabolic abnormalities in cancer patients: carbohydrate metabolism. Surg Clin North Am 1986;66(5):957-68.
30. Filov VA, Burova TM. [Gluconeogenesis during therapy of experimental tumors with hydrazine sulfate] (Russian). Biull Eksp Biol Med 1984;97(1):73-4.
31. Grubbs B, Rogers W, Cameron I. Total parenteral nutrition and inhibition of gluconeogenesis on tumor-host responses. Oncology 1979;36:216-23.
32. Gold J. Potentiation by clofibrate of in vivo tumor inhibition by hydrazine sulfate and cytotoxic agents, in Walker 256 intramuscular carcinoma. Cancer Biochem Biophys 1978;3(1):41-5.
33. Nelson JAS, Falk RE. The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res 1993;13:2287-92.
34. Ottery FD. Supportive nutrition to prevent cachexia and improve quality of life. Semin Oncol 1995;22(2 Suppl 3):98-111.
35. Chlebowski RT, Dietrich M, Tsunokai R, Block JB. Hydrazine sulfate: clinical pharmacokinetics and influence on in vitro growth of human glioblastoma cell lines [abstract 1002]. Proc Am Assoc Cancer Res 1985;26:254.
36. Filov VA, Gershanovich ML, Ivin BA, Danova LA, Gurchin FA, Naryshkin AG, et al. [Therapy of primary brain tumors with Sehydrin] (Russian). Vopr Onkol 1994;40(7-12):332-6.
37. 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 1973;27:69-80.
38. Ochoa M Jr, Wittes RE, Krakoff IH. Trial of hydrazine sulfate (NSC-150014) in patients with cancer. Cancer Chemother Rep 1975;59(6):1151-4.
39. Tayek JA, Heber D, Chlebowski RT. Effect of hydrazine sulfate on whole-body protein breakdown measured by ¹⁴C-lysine metabolism in lung cancer patients. Lancet 1987;2:241-3.
40. Bruera E. Current management of anorexia and cachexia in patients with advanced cancer. Oncology 1992;49(Suppl 2):35-42.
41. Parnes HL, Aisner J. Protein calorie malnutrition and cancer therapy. Drug Saf 1992;7(6):404-16.
42. Pisters PWT, Pearlstone DB. Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions. Crit Rev Clin Lab Sci 1993;30(3):223-72.
43. Strum SB, Bierman HR, Thompson R. Hydrazine sulfate in patients with neoplasia [abstract 1090]. Proc Am Assoc Cancer Res 1975;16:243.
44. Lerner HJ, Regelson W. Clinical trial of hydrazine sulfate in solid tumors. Cancer Treat Rep 1976;60(7):959-60.
45. Kosty MP, Fleishman SB, Herndon JE, Coughlin K, Kornblith AB, Scalzo A, 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 1994;12(6):1113-20.
46. Loprinzi CL, Kuross SA, O'Fallon JR, Gesme DH, Gerstner JB, Rospond RM, et al. Randomized placebo-controlled evaluation of hydrazine sulfate in patients with advanced colorectal cancer. J Clin Oncol 1994;12(6):1121-5.
47. Loprinzi CL, Goldberg RM, Su JQ, Mailliard JA, Kuross SA, Maksymiuk AW, et al. Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol 1994;12(6):1126-9.
48. Gershanovich ML, Danova LA, Kondratyev VB, Malyugina LL, Stukov AN, Seitz JF, et al. Clinical data on the antitumor activity of hydrazine sulfate. Cancer Treat Rep 1976;60(7):933-5.
49. Gershanovich ML, Danova LA, Ivin BA, Filov VA. Results of clinical study of antitumor action of hydrazine sulfate. Nutr Cancer 1981;3(1):7-12.
50. Gold J. Hydrazine sulfate: a current perspective [review]. Nutr Cancer 1987;9(2-3):59-66.
51. Filov VA, Danova LA, Gershanovich ML, Ivin BA, Dementyeva NP, Beyvis PV, et al. Results of clinical evaluation of hydrazine sulfate. Vopr Onkol 1990;36(6):721-6.
52. Gold J. Hydrazine sulfate in the treatment of cancer. Cancer Treat Rep 1976;60(7):964-5.
53. Piantadosi S. Hazards of small clinical trials. J Clin Oncol 1990;8(1):1-3.
54. Gold J. Hydrazine sulfate in nonsmall-cell lung cancer. J Clin Oncol 1990;8:1117-8.
55. Herbert V. Three stakes in hydrazine sulfate's heart, but questionable cancer remedies, like vampires, always rise again. J Clin Oncol 1994;12(6):1107-8.
56. Kosty MP, Herndon JE, Green MR, McIntyre OR. Placebo-controlled randomized study of hydrazine sulfate in lung cancer. J Clin Oncol 1995;13(6):1529-30.
57. Kamen J. The cancer empire strikes back. Penthouse 1994;Nov:104-5.
58. Steinhardt B, director, Health Services Quality and Public Issues, US General Accounting Office, Washington. Letter to Leonard Weiss, PhD, Minority Staff Director, Senate Committee on Governmental Affairs; 1998 Jan 8. [Letter in public domain; on file with the Canadian Breast Cancer Research Initiative.]

General reference books and journals

1. Alternative medicine: expanding medical horizons: a report to the National Institute of Health on Alternative Medical Systems and Practices in the United States. Washington: National Institutes of Health; 1994. Publ no NIH 94-066.
2. Lerner M. Choices in healing: integrating the best of conventional and complementary approaches to cancer. Cambridge (MA): MIT Press; 1994.
3. Ontario Breast Cancer Information Exchange Project. A guide to unconventional cancer therapies. Aurora (ON): R&R Bookbar; 1994.
4. Fugh-Berman A. Alternative medicine, what works. Baltimore: Williams & Wilkins; Press; 1997.
5. Peer-reviewed journals dealing with unconventional therapies:
   Alternative Therapies in Health and Medicine
   The Journal of Alternative and Complementary Medicine

Send a letter to the editor Envoyez une lettre à la rédaction