Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
[CANCER RESEARCH 35, 3693-3697 December 1975] Synthetic and Naturally Occurring Hydrazines as Possible Cancer Causative Agents Bela Toth' The Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105 SYNTHETIC SUMMARY The various synthetic substituted hydrazines, which cause tumors in animals, are briefly enumerated. To date, 19 of them have proved to be tumorigenic in animals. A number of these chemicals are found today in the environment, in industry, in agriculture, and in medicine, and the human population is exposed to a certain degree to some of them. Hydrazine also occurs in nature in tobacco and tobacco smoke. The three other naturally occurring hydrazine compounds are N-methyl-N-formylhydrazine, which oc curs in the wild edible mushroom, Gyromitra esculenta, and @-N-[―y-L(+)-glutamylJ-4-hydroxymethylphenyl hydrazine and 4-hydroxymethylphenylhydrazine, whkh are found in the commonly eaten cultivated mushroom, Agaricus bisporus. Tumorigenesis studies with the natu rally occurring hydrazines are in progress. Interest in chemical carcinogenesis in the past few decades has focused on the possible roles of synthetic chemicals that may cause cancer in man. This appeared justifiable on the. grounds of recent estimates that approxi mately 200,000 new chemicals enter our environment each year. If only 1% of these chemicals enter at reasonably high levels, this means that man may be exposed to around 2,000 new chemicals annually. To date, around 6,000 chemicals have been studied for carcinogenic activities; of these, approximately 1,000 compounds have thus far been found to be tumorigenic in animals. According to some experts, the exogenous hazardous agents are to a large extent responsible for the cancer incidence in the human popula tion. The aim of this report is to draw attention and naturally occurring derivatives to both the of hydrazine. The synthetic hydrazines in recent years were shown to produce tumors in animals, and therefore they may play a role in the etiology of human cancer. With the exception of hydrazine itself, the other naturally occurring derivatives of this compound, tumor-inducing however, have thus far not been studied for abilities. aRecipient of USPHS Research Career Development K04-42,552 from the National Cancer Institute. Received June 5, 1975; accepted August 26, 1975. DECEMBER Studies on the carcinogenic potentialities of synthetic substituted hydrazines began in 1962, when it was shown that the base compound hydrazine sulfate induced lung neoplasms in mice (1). Subsequently, a series of hydrazine derivatives were investigated in various laboratories for tumor-inducing capabilities. These studies clearly demon strated that these chemicals are indeed powerful tumori genic substances in mice, hamsters, and rats, due to their tumor-inducing abilities in the intestines, brain, lungs, blood vessels, liver, breasts, kidneys, etc. Now, we know of 19 hydrazine Award derivatives that have been shown to be tumor inducers. These include, in addition to hydrazine (1, 32), methyl- (35, 40), 1,2-dimethyl- (6, 27, 36, 46, 52), 1,1dimethyl- (28, 37), benzoyl- (2, 34), phenyl- (2), 2-hydrox yethyl- (I I), 1,2-diethyl- (5), l-acetyl-2-isonicotinoyl(39) hydrazines; INTRODUCTION synthetic HYDRAZINES N-isopropyl-a- (2-methythydrazino)-p-tolua mide (13, 14); and l-isonicotinoyl-2-isopropyl(2), or thometoxybenzoyl(2), paramethoxybenzoyl(2), 1-meth yl-2-butyl- (4), l-methyl-2-benzyl(4), ethyl- (42, 44), n-butyl- (44), 1-carbamyl-2-phenyl(4 1), carbamyl- (43), and n-amyl- (33, 38) hydrazines. Their names, chemical structures, treatments, and action sites are summarized in Table 1. These studies received particular attention because syn thetic hydrazines are present in the environment and are used in industry, agriculture, and medicine. They include hydrazine, monomethylhydrazine, and 1, l-dimethylhydra zinc, which are components of rocket fuels (26); carbamyl hydrazine, an industrial and laboratory reagent (26); 2hydroxyethylhydrazine, a ripener for pineapple and other plants (10); phenylhydrazine, used in treatment of polycy themia vera (26); 1-isonicotinoyl-2-isopropylhydrazine, an antidepressant and antituberculotic drug (3 1, 53); and N-isopropyl-a-(2-methylhydrazino)-p-toluamide, an an tineoplastic agent (25). To what extent humans are exposed to the industrial hydrazines is presently not known. We do not even have data concerning whether or not the pineapple fruit contains the ripening agent. The amounts of these various hydrazines used as therapeutic drugs are known and they are not administered, however, on massive scales. The fact should be also emphasized that all hydrazine derivatives studied in laboratory altogether) to be tumor-producing animals were found (19 substances. It is esti 1975 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research. 3693 B. Toth Table I Tumorigenic hydrazine compounds Compound Species Organ Treatment References c0N14-*4C0c143 MiceLungsp.o.39MiceLungs, 1-k,TyL-2-,,olucoyn.oyu,vz*,z,.i CH,—CH,—CH,---CH,—CH,—NH—NH, N-Amylhydrazine HCI K@N@*2 vesselsp.o.33P.O.2,34p.o.44P.O.43p.o.41s.c.5p.o.28,37Mice blood Mice Lungs, lymphoreticular tissue NH,—NH—CH2—CH,—CH2—CH,. N Butylhydrazine HC1 Mice Lungs NH,—NH---CO—NH2. HCI Carbamylhydrazine . HCI M ice Lungs, blood vessels Mice Lungs Rats Lymphoreticular kIIZOYUIYDIAZIII CH,—CH,—NH—NH—CH2—CH1 1,2-Diethylhydrazine• and nerve tissues,liver,ethmotur binal (CH1), N—NH, 1.1-Dimethyihydrazine CH,—NH—NH—CH, 1,2-Dimethyihydrazine . 2HC1 Mice Lungs. blood vessels, kidney, liver Colon, lungs, blood vessels 27,36Ratss.c., Hamsterss.c., Liver, stomach, intestine, p.o. i.m.,p.o.46, 52 bloodvessels Intestine p.o.6Micep.o.42Mice NH,—NH—CH,—CH,. Ethylhydrazine . HCI NH,—NH,. H,SO4 Hydrazine sulfate Lungs, blood vessels liver RatsLungs, Liver, lungsp.o. 32MiceLiverp.o.11MiceLungsp.o.2Mice p.o.1 NH,—NH—CH,—CH,OH 2-Hydroxyethythydrazine 1I$ONICOTIIOYI.2IIOPIOPYU4YDMZI@( QCr*-IC-012 @J co@NI1 N-Isopio@vi-d-(2-ICTwyi.syDI*zIuo)P-TO@uMIX CCI lymphoreticular tissue, kidney 14MiceLungsp.o.2MiceLungsp.o.2Mice RatsLungs, Breast, lungs, blood i.p. p.o., i.p.13 vesselsp.o., 2043 O-@ThOXYIINZOYUIYDIAZINI 0I@0 P—@THOXYWIZOYLHYDIAZINt CH,—NH—NH, Methylhydrazine 3694 HamstersLungsKupffer cells, cecump.o. p.o.35 40 CANCER RESEARCH VOL. 35 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research. Hydrazines and Cancer Table I—Continued CompoundSpeciesOrganTreatmentReferencesCH3-NN-mC-CH2 @ p.o.4CH,—NH—NH—CH,—CH,—CH,—CH,.2HCI and peripheral ncr vous systems, bulbus ol 14@T)ffL2UNZYUIYDIAZINtRatsCentral factoriuss.c., p.o.4KI@:I:@@l—Methyl—2—butylhydrazine @ intestine, olfactoriuss.c., 2 HCIRatsLarge bulbus .‘ic' PHENYLHYI*AZINE CCIMiceLungsp.o.2 mated that well over 100 synthetic substituted hydrazines are used today in the environment (26). NATURALLY OCCURRING HYDRAZINES Hydrazine in Tobacco Hydrazine (Chart 1F) has been found in both tobacco and tobacco smoke (23). At first the presence of hydrazine was attributed to maleic hydrazide, a widely used plant growth retardant, which is sprayed on tobacco plants. Actually, the technical graded maleic hydrazide contains free hydrazine. zinc derivatives of as yet undetermined structures. In addition, the occurrence of 4-hydroxymethylbenzene diazo nium ion (19), phenol, “y-L-glutamyl-4-hydroxybenzene, and possibly -y-L-glutamyl-3,4-benzoquinone (48-5 1) in the mushroom was reported. Also, a substance closely similar in structure to agaritine N-('y-L-glutyamyl)-p-hydroxyani line has been isolated (12) from the European “champig non―Agaricus hortensis (apparently it is the same as A. bisporus). The estimated United States A . bisporus consumption (production plus imports) totaled approximately pounds from July 1972 to June 1973 (47). The presence More recently, however, hydrazine has been identified in was discovered tobacco grown under well-defined conditions, to which maleic hydrazide has not been added. The actual amount of hydrazine in each cigarette was shown to be 30 ng (24). This of hydrazines in the cultivated 300 million mushroom in studies directed toward investigation of metabolism of nonprotein amino acids. In 1962 and in subsequent years when the tumor induction capabilities of hydrazine and its derivatives became known, it was appar means actually that hydrazine occurs naturally in the ently unnoticed by the investigators working with the tobacco plants. Hydrazines in Mushrooms Agaricus bisporus. Levenberg (17, 18) reported in 1960 the isolation of agaritine from A . bisporus, the most commonly eaten commercial mushroom in the United States. This compound occurs predominantly in the fruiting mushrooms. Gyromitra esculenta. List and Luft's (21, 22) analytical investigations showed that the extracts of one of the wild and edible mushrooms, Gyromitra escu!enta, contained gyromitrin, an acetaldehyde formylmethylhydrazone, Nmethyl-N-formyl hydrazine, and methylhydrazine. Subse quently, they postulated that the 2 latter chemicals were produced from gyromitrin by hydrolysis during maceration and cooking (Chart lC to E). When the mushrooms are and its concentration diminishes with age. Subsequently, Daniels et a!. (3) and Kelly et a!. cooked in an open kettle, methylhydrazine is lost by steam body of young mushrooms (15) isolated agaritine from mushroom sporophores that distillation and no toxicity is observed. When prepared in a dish, the compounds are not lost, and in this condition mild hydrazine poisoning may be discerned (16). yielded 0.04% based on fresh tissue weight and confirmed its closed structure as phenylhydrazine @-N-[―y-L(+ )-glutamyl]-4-hydroxymethyl by degradation and synthesis (Chart IA). More recently in this laboratory, agaritine was also charac terized and isolated in the mushroom. Preliminary toxicity studies with agaritine were performed in mice and published recently (38, 45). Gigliotti and Levenberg (8, 9) also found an enzyme in the mushroom, ‘y-glutamyltransferase,that catalyzes the breakdown of agaritine to L-glutamate and 4-hydroxymethylphenylhydrazine (Chart 1B). Agaritine was found in comparable quantities in 10 other species belonging to the genus Agaricus. Only 5 other species belonging to the sylvaticus subgroup were devoid of the compound (20). Furthermore, 3 other members of the Agaricaceae are believed to contain other aromatic hydra DECEMBER Furthermore, it was demonstrated recently that this mush room contains up to 0.3% gyromitrin and 0.05% N-methyl N-formylhydrazine (30). Also, an extensive literature survey was compiled dating from 1782, which documents the various human mushroom poisoning cases attributed to G. esculenta (7). In Germany alone in 1930, the estimated imported quantity of this mushroom was 350,000 kg (7). It also grows in the United States and Canada, mainly in sandy soil under pine trees (29). Quantitative data on its consumption by the human population in North America is not available. Only 2 hydrazines, found or postulated hydrazine and monomethylhydrazine, to exist in the tobacco and mushrooms 1975 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research. 3695 B. Toth CH2OH ‘4 NH-NH-C-CH@-CH2-CH--COO AGARITINE, @8- N—(y-L (+1- GLUTAMYL)-4- NYDRCXYMETHYLPHENYLHYDRAZINE I CH@OH 0 @ NH@+ II a I + H@C-CH2@CH2-CH-COO @@NH2 L-ILUTAMIC ACID 4- KYONOXYMETHYLPHENYLHYDNAZ*I( CH3 C. CHçCHN41@CHO GY@0MIT@N,AOETALDENYOEMETHYLFO@MYLHYDNAZONE @H3 0 H2N-N-CHO+CH@—CHO N—METHYL—N--FOAVYL HYDRAZINE E H2N—NH--CH3 +H—C02 H METHYLHYDNAZINE HEN- NH2 HYDRAZINE Chart proved carcinogenic compounds, as in animals I . Chemical structures of naturally ( I , 35, 40). The other 4 identified and characterized in mushrooms @-N-[―y-L(+)-glutamyl]-4-hydroxymethylphenylhy drazine, 4-hydroxymethylphenylhydrazine, acetaldehyde formylmethylhydrazone, and N-methyl-N-formylhydra zinc, have not been studied by others thus far for cancer inducing capabilities. REFERENCES I. Biancifiori, C., and Ribacchi, R. Pulmonary Tumours in Mice Induced by Oral Isoniazid and Its Metabolites. Nature, 194: 488-489, 1962. 2. Clayson, D. B., Biancifiori, C., Milia, U., and Giornelli-Santilli, F. E. The Induction of Pulmonary Tumours in Balb/Cb/Se Mice by Derivatives of Hydrazine. In: L. Seven (ed), Lung Tumors in Animals, Proceedings of the Quadrennial Conference on Cancer, University of Perugia Department of Cancer Research, Perugia, Italy,1966,pp.869-880. 3. Daniels, E. G., Kelly, R. B., and Hinman, J. W. Agaritine: An Improved Isolation Procedure and Confirmation of Structure by Synthesis. J. Am. Chem. Soc., 83: 3333-3334, 1961. 4. Druckrey, H. Production ofColonic Carcinomas by 1,2-Dialkylhydra zines and Azoxyalkanes, In: W. J. Burdette (ed), Carcinomas of the 3696 occurring hydrazines and a hydrazone. Colon and Antecedent Epithelium, pp. 267-269. Springfield, III.: Charles C Thomas, Publisher, 1970. 5. Druckrey, H., Preussman, R., Matzkies, F., and Ivankovic, S. Carcinogene Wirkung von l.2-Diilthylhydrazin an Ratten. Naturwis senschaften, 53: 557-558, 1966. 6. Druckrey, H., Preussman, R., Matzkies, F., and Ivankovic, S. Selective Erzeugung von Darmkrebs bei Ratten durch 1,2-Dimethyl hydrazin. Naturwissenschaften, 54: 285-286, 1967. 7. Franke, S., Freimuth, U., and List, P. H. Uber die Giftigkeit der Friihjährslorchel Gyromitra (Helvella) esculenta Fr. Arch. Toxikol. 22:293-332,1967. 8. Gigliotti, H., and Levenberg, B. Enzymatic Transfer of the -y-Gluta myl Group between Naturally Occurring Aniline and Phenylhydrazine Derivatives in the Genus Agaricus. Biochim. Biophys. Acta, 81: 618-620. 1964. 9. Gigliotti, H., and Levenberg, B. Studies on the y-Glutamyltransferase of Agaricus bisporus. J. Biol. Chem., 239: 2274-2284, 1964. 10. Gowing, D. P., and Leeper, R. W. Induction of Flowering in Pineapple by Beta-hydroxyethylhydrazine. Science, 122: 1267, 1955. 11. Innes, J. R. M., Ulland, B. M., Valerio, M. G., Petrucelli, L., Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk, H. L., Gail, J. J., Klein, M., Mitchell, I., and Peters, J. Bioassay of Pesticides and Industrial Chemicals for Tumorigenicity in Mice. J. Natl.Cancerlnst.,42: 1101-1114, 1969. 12. Jadot, J., Casimir, J., and Renard, M. Separation et Caracterisation CANCER RESEARCH VOL. 35 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research. Hydrazines du i(+)-'y-(p-hydroxy) Anilide de l'acide Glutamique a Partir de Agaricus Hortensis. Biochim. Biophys. Acta, 43: 322-328, 1960. 13. Kelly, M. 0., O'Gara, R., Gadekar, K., Yancey, S. T., and Oliverio, V. T. Carcinogenic Activity of a New Antitumor Agent, n-Isopropyl a-(2-methylhydrazino)-p-toluamide Hydrochloride (NSC-772 I 3). Cancer Chemotherapy Rep., 39: 77-80, 1964. 14. Kelly, M. G., O'Gara, R., Yancey, S. T., and Botkin, C. Induction of Tumors in Rats with Procarbazine Hydrochloride. J. Natl. Cancer Inst., 40:l027-105l, 1968. 15. Kelly, R. B., Daniels, E. G., and Hinman, J. W. Agaritine: Isolation, Degradation, and Synthesis. J. Org. Chem., 27: 3229-3231, 1962. 16. Klosterman. H. J. Vitamin B6 Antagonists of Natural Origin. J. Agr. Food Chem., 22: 13-16, 1974. 17. Levenberg, B. Isolation and Enzymatic Reactions of Agaritine, a New Amino Acid Derivative from Agaricaceae. Federation Proc., 19: 6, 1960. 18. Levenberg, B. Structure and Enzymatic Cleavage of Agaritine, a New Phenylhydrazide of L-Glutamic Acid Isolated from Agaricaceae. J. Am. Chem. Soc., 83: 503-504, 1960. 19. Levenberg, B. An Aromatic Diazonium Compound in the Mushroom Agaricus bisporus. Biochim. Biophys. Acta, 63: 212-214, 1962. 20. Levenberg, B. Isolation and Structure of Agaritine, a ‘y-Glutamyl-sub stituted Arylhydrazine Derivative from Agaricaceae. J. Biol. Chem., 239: 2267-2273, 1964. 21. List, P. H., and Luft, P. Gyromitrin, das Gift der Frtlhjahrslorchel. Arch.Pharm.,301:294-305, 1968. 22. List, P. H., and Luft, P. Nachweis and Gehaltsbestimmung von Gyromitrin in Frischen Lorcheln. Arch. Pharm., 302: 143-146, 1969. 23. Liu, Y. Y., and Hoffmann, D. Quantitative Chromatographic Deter mination of Maleic Hydrazide in Cigarette Smoke. Anal. Chem., 45. 2270-2273,1973. 24. Liu, Y. Y., Schmeltz, I., and Hoffmann, D. Chemical Studies on Tobacco Smoke. Quantitative Analysis of Hydrazine in Tobacco and Cigarette Smoke. Anal. Chem., 46: 885-889, 1974. 25. Mathê, G., Schweisguth, 0., Schneider, M., Amid, J. L., Berumen, L., Brule, G., Cattan, A., and Schwarzenberg, L. Methylhydrazine in Treatment of Hodgkin's Disease. Lancet, 2: 1077- 1080, 1963. 26. The Merck Index, Ed. 8. Rahway. N. J.: Merck & Co., Inc., 1968. 27. Osswald, H., and Kruger, F. W. Die cancerogene Wirkung von 1,2-Dimethylhydrazin beim Goldhamster. Arzneimittel-forsch., 19: 1891—1892, 1969. 28. Roe, F. J., Grant, G. A., and Millican, D. M. Carcinogenicity of Hydrazine and l,l-Dimethylhydrazine for Mouse Lung. Nature, 216: 375—376, 1967. 29. Savonius, M. Mushrooms and Fungi. London: Octopus Books, Ltd., 35. Toth, B. Hydrazine, Methylhydrazine and Methylhydrazine Sulfate Carcinogenesis in Swiss Mice. Failure of Ammonium Hydroxide to Interfere in the Development of Tumors. Intern. J. Cancer, 9: 109—118, 1972. 36. Toth, B. Tumorigenesis Studies with 1,2-Dimethylhydrazine Dihydro chloride, Hydrazine Sulfate and Isonicotinic Acid in Golden Ham sters. Cancer Res., 32: 804-807, 1972. 37. Toth, B. l,l-Dimethylhydrazine (Unsymmetrical) Carcinogenesis in mice. Light Microscopic and Ultrastructural Studies on Neoplastic Blood Vessels. J. Natl. Cancer Inst., 50: 181-194, 1973. 38. Toth, B., Nagel, D., Shimizu, H., Sornson, H., Issenberg, P., and Erickson, J. Tumorigenicity of n Propyl-, n Amyl- and Allyl-hydra zines. Toxicity of Agaritine. Proc. Am. Assoc. Cancer Res., 16: 61, 1975. 39. Toth, B., and Shimizu, H. Lung Carcinogenesis with l-Acetyl-2isonicotinoylhydrazine, the Major Metabolite of Isoniazid. European J. Cancer, 9: 285-289, 1973. 40. Toth, B., and Shimizu, H. Methylhydrazine Tumorigenesis in Syrian Golden Hamsters and the Morphology of Malignant Histiocytomas. CancerRes., 33:2744-2753, 1973. 41. Toth, B., and Shimizu, H. I-Carbamyl-2-phenylhydrazine Tumorigen esisin SwissMice.Morphologyof LungAdenomas.J. NatI.Cancer Inst.,52:241-251, 1974. 42. Toth, B., and Shimizu, H. Ethylhydrazine Hydrochloride as Tumor Inducer in Mice. Intern. J. Cancer, 13: 500-505, 1974. 43. Toth, B., Shimizu, H., and Erickson, J. Carbamylhydrazine Hydro chloride as a Lung and Blood Vessel Tumor Inducer in Swiss Mice. European J. Cancer, ii: 17—22,1975. 44. Toth, B., Shimizu, H., and Nagel, D. Tumor Induction Studies with Ethyl-, n-Butyl- and l-Carbamyl-2-phenyl-hydrazines. Proc. Am. Assoc. Cancer Res., 15: 23, 1974. 45. Toth, B., Shimizu. H., Sornson. H., Issenberg, P.. and Erickson, J. Sex Dependent Toxicity of Four Chemicals. Res. Commun. Chem. Pathol. Pharmacol., 10: 577-580, 1975. 46. Toth, B., and Wilson, R. B. Blood Vessel Tumorigenesis by 1,2-Dime thylhydrazine Dihydrochloride (Symmetrical). Gross, Light and Elec tron Microscopic Descriptions. I. Am. J. Pathol.. 64: 585-600, l971. 47. United States Department of Agriculture, Statistical Reporting Serv ice,CropReportingBoard:Mushrooms,pp. 1-4, 1973. 48. Vogel, F. S., McGarry, S. J., Kemper, L. A. K., and Graham, D. G. Bacteriocidal Properties of a Class of Quinoid Compounds Related to Sporulation in the Mushroom, Agaricus bisporus. Am. J. Pathol., 76: 165—174,1974. 49. Weaver, R. F., Byrne, W. 1., and Vogel, F. S. Formation of the Dormant Spore in the Common Meadow Mushroom: Appearance of Respiratory Inhibitors. Federation Proc., 27: 248, 1968. So. Weaver, R. F., Rajagopalon. K. V., Handler, P., and Byrne, W. L. 1973. 30. Schmidlin-MêszAros, and Cancer J. Gyromitrin in Trockenlorcheln (Gyromitra esculentasicc.). Mitt. Gebiete Lebensm.Hyg.. 65: 453—465, 1975. Isolation Synthesis from the Mushroom Agaricus bisporus and Chemical of ‘y-L-glutaminyl-4-hydroxybenzene. J. Biol. Chem., 246: I. J., Robitzek, E. H., and Ornstein, G. G. Toxicity of 2010-2014, 1971. Hydrazine Derivatives of Isonicotinic Acid in the Chemotherapy of 51. Weaver, R. F., Rajagopalon, K. V., Handler, P., and Rosenthal, D. Human Tuberculosis. Quart. Bull. Sea View Hosp., 13: 17-26, 1952. ‘y-i-Glutaminyl 3,4-Benzoquinone: Structural Studies and Enzymatic 31. Selikoff, 32. Seven, L., and Biancifiori, C. Hepatic Carcinogenesis in CBA/Cb/Se Mice and Cb/Se Rats by Isonicotinic Acid Hydrazide and Hydrazine Sulfate. J. NatI. Cancer Inst., 41: 331-349, 1968. Synthesis. J. Biol. Chem., 246: 2015-2020, 1971. 52. Wiebecke, B., Löhrs, U., Gimmy, J., and Eder, M. Erzeugung von Darmtumoren bei Mäusen durch l,2-Dimethylhydrazin. Z. Ges. H., Nagel, D., and Toth, B. Tumor Induction Study with n Exptl. Med., 149: 277-278, 1969. Amylhydrazine Hydrochloride in Swiss Mice. Brit. J. Cancer, 31: 53. Zeller, E. A., Barsky, J., Fouts, J. R., Kirchheimer, W. F., and Van 492-496, 1975. Orden, L. S. Influence of Isonicotinic Acid Hydrazide (INH) and 33. Shimizu, 34. Toth, B. Bcnzoylhydrazine Carcinogenesis phoreticular Tissues of Swiss Mice. European 1972. in Lungs and Lym J. Cancer. 8: 341-346, l-Isonicotinoyl-2-isopropyl Hydrazine (IIH) on Bacterial malian Enzymes. Experientia, 8: 349-350, 1952. and Mam DECEMBER 1975 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research. 3697 Synthetic and Naturally Occurring Hydrazines as Possible Cancer Causative Agents Bela Toth Cancer Res 1975;35:3693-3697. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/35/12/3693 Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.