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
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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]
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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]
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Toth B: Lung tumor induction and inhibition of breast adenocarcinomas by hydrazine sulfate in mice. J Natl Cancer Inst 42 (3): 469-75, 1969.
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Menon MM, Bhide SV: Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J Cancer Res Clin Oncol 105 (3): 258-61, 1983.
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Biancifiori C, Giornelli-Santilli FE, Milia U, et al.: Pulmonary tumours in rats induced by oral hydrazine sulphate. Nature 212 (60): 414-5, 1966.
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Toth B: Tumorigenesis studies with 1,2-dimethylhydrazine dihydrochloride, hydrazine sulfate, and isonicotinic acid in golden hamsters. Cancer Res 32 (4): 804-7, 1972.
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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.
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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.
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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.
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Toth B: Synthetic and naturally occurring hydrazines as possible cancer causative agents. Cancer Res 35 (12): 3693-7, 1975.
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National Toxicology Program.: Hydrazine and hydrazine sulfate. Rep Carcinog 10: 138-9, 2002.
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Gold J: Inhibition of Walker 256 intramuscular carcinoma in rats by administration of hydrazine sulfate. Oncology 25 (1): 66-71, 1971.
[PUBMED Abstract]
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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]
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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.
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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.
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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.
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Nelson JA, Falk RE: The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res 13 (6A): 2287-92, 1993 Nov-Dec.
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Kamradt JM, Pienta KJ: The effect of hydrazine sulfate on prostate cancer growth. Oncol Rep 5 (4): 919-21, 1998 Jul-Aug.
[PUBMED Abstract]
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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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