RECENTLY DISCOVERED CARCINOGENIC and ANTI-CANCER AGENTS JOHN R. SAMPEY Furman University, Greenville, South Carolina
T
HE first experimentally produced cancer in 1915 by the long-continued application of a coal-tar distiiate to the ear skin of rabbits (149) confirmed the suspicion that cancer among workmen engaged in coal-tar distillation was an occupational disease. The search for the carcinogenic agent or agents in coal tar has been extended until today scores of substances, many of them far removed chemically from coal tar, are known to produce malignant tumors in laboratory animals. Early in the prosecution of this research the discovery was made that certain agents would prevent the formation of experimental cancer, while others would retard the growth of tumors already present, or bring about their disappearance. A number of reviews of early work on carcinogenic and anti-cancer agents have appeared from time to time. The following bibliography is so arranged as to bring out the major lines the investigations are following a t present. I.
CARCINOGENIC AGENTS I N TARS
Brownlie (20) has recently presented a mass of data in support of the theory that poisonous organic products of high-boiling benzenoid hydrocarbons cause cancer. These products were obtained by the pyrolysis of coal, petroleum, shale, and wood. Kling (68) on the other hand, maintained that it was the lighter oils of coal tar, with boiling points of 75-200°C., which produce primary cancer in mice. Domagk (40) traced the history of carcinogenic agents and gave experimental results on the production of tumors with coal and gas tar. Andervont and Lorenz (3) produced tumors with tar and shale. Oberling and associates (106) showed that tar cancer can develop in mice, rats, and rabbits. Waterman (147) caused carcinoma of the stomach with tar, while Cholewa (28) found a solid carcinoma of the heart following tar painting of the ear. Dobrovolskaya-Zavadskaya and associates (37, 38, 39) produced sarcomas in various locations in mice by tars. Kinoshita (66) secured epithelioma by painting the skin with tobacco-tar. Roffo (113) showed that direct distillation in closed vessels of tobacco from Germany, Italy, Turkey, and other countries gave on spectrographic examination hydrocarbons with condensed benzene nuclei. 11.
CARCINOGENIC HYDROCARBONS
1. Benzopyrenes.-Four of the workers reporting tar cancers in the preceding section have investigated
the carcinogenic activity of benzopyrene-hydrocarbons. Kling (68) identified benzopyrene as the light oil in coal-tar producing cancer. Domagk (40) and Oberling (106, 107) used 1,2- and 3,4-benzopyrene to develop tumors. Waterman (147) found benzopyrene dissolved in fat-produced carcinoma of the stomach even more readily than tar. Moore (91), Dansi (35), Cornil (32), and Klinke (69,70,71)all used 1,2-benzopyrene to develop tumors. Larnbret (76), however, reported that rabbits resisted the action of 1,2-benzopyreue. The isomeric 3,4benzopyrene caused carcinogenesis in mice, according to Nakahara (95) and Haddow (56). LeRoy (77) on the other hand, reported no tumors in rabbits injected with colloidal solutions of 3,4-benzopyrene. Klar (67) cited the case of a man developing epithelioma three months after working with benzopyrene. Taschner (137) produced leucopenia in mice with benzopyrene. Rondoni (117) in a paper setting forth the theory of cancerigenis as an irreversibleprocess of nuclear injury described the formation of sarcoma by benzopyrene. Maisin (85, 87,88,89) has studied the inhibiting power of a number of reagents on the development of cancers from benzopyrene (see anti-cancer agents below). 2. Cho1anthrenes.-The carcinogenic activity of cholanthrenes has been investigated extensively. In 1936 Maisin (86), Dansi (35), and Domagk (40) reported tumors from methylcholanthrene. The following year this was conlirmed by Fieser (44), Nakahara (96). Taschner (137), and Valade (l42), and again in 1938 by Athias (9) and Andervont (4). Fieser (44, 48) also produced tumors with cholanthrene, 16, 20-dimethylcholanthrene and 20-methylcholanthrene. Shear (127, 129) found cholanthrene, 20-ethylcholanthrene, 20-methylcholauthrene, and 16,20-dimethylcholanthrene all carcinogenic. Bachmann ( l l ) , in his fourth communication on the production of cancer by pure hydrocarbons, stated that methylcholanthrene was more potent than cholanthrene, while Brnce and Kahn (21) announced that 20-ethylcholanthrene took twice as long to produce tumors in mice as did 20methylcholanthrene. Boyland (17) reported that methylcholanthrene was more effective in fatty solutions than in colloidal suspensions in inducing tumors in mice. LeRoy and associates (77), however, failed to discover any carcinogenic activity in rabbits injected with colloidal solutions of methylcholanthrene. 3. Benzanthracenes.-Benzanthracenes rival the cho-
lanthrenes as compounds of carcinogenic activity. IV. CHOLESTEROL, ERGOSTEROL, AND LECITHIN I N CARCINOGENESIS Fieser (47) has produced a number of derivatives of 1,2-benzanthracene with alkyl-substituents in the 10The structural relationship of the ergosterol and position, and also some simpler compounds which lack cholesterol molecules to the sex hormones finds a parallel the cyclopentane ring; both classes of componnds pos- relation in the action of these agents in carcinogenesis. sessed high carcinogenic potency. Some hydroxy- Polettini (110) in 1936 demonstrated that irradiated and methoxy-derivatives of these, however, were only ergosterol produced tumors in mice. The following weakly carcinogenic. This same investigator (44) ye& ~ c h m i d(124) reported similar results with pigeons, produced tumors with 5,lO-dimethyl-1,2-benzanthra- and Burrows and Mavneord 1221 ~, found tumors in mice cene and 10-methyl-1,2-benzanthracene; in earlier following injection of irradiated cholesterol in lard. work (45) Fieser showed that 3-hydroxy-1,2-henzan- Amano and Tomita ( 1 ) found that cholesterol stimuthracene and its methyl ether had weak carcinogenic lated Flexner-Jobling rat carcinoma and Fujinawa rat properties, and that 5,lO-dimethyl-1,Z-benzanthracenesarcoma, while lecithin stimulated the production of had cancer-producing characteristics (43). hepatoma in rats. Rondoni (117) described the proShear (129) confirmed the carcinogenic activity of duction of sarcoma by benzopyrene along with choles5,lO-dimethyl-1,2-benzanthracene;in the same publi- terol. Gutschmidt (54) pointed to the structural relacation he added 10-methyl-1,2-benzanthracene, 5 3 tion of benzopyrene to cholesterol and ergosterol. dimethyl- 1,2-benzanthracene, 9-methyl- 12-benzan- Waterman (147) used cholesterol oleate to produce thracene, 4,lO-ace-1,2-benzanthracene and its 11,2',3',- carcinoma of the stomach. Roffo (114) has developed 4'-tetrahydro derivative as tumor producing. In a theory that sunlight and ultra-violet light rays transearlier work Shear (127) found 8,9-dimethyl-1,2-ben- form cholesterol in the skin into carcinogenic substances zanthracene and l,9-methylene-1,2,5,6-dibenzanthra- with phenanthrene nuclei. cene also carcinogenic. Comil (32), Dobrovolskaya-Zavadskaya and asso- V. AMINO, AZO, AND NITRO COMPOUNDS AS CARCINOGENIC AGENTS ciates (38, 39), Hieger (61)and Yudina (150) reported 1,2,5,6-dibenzanthraceneas carcinogenic. Cook (30) There is considerable controversy in the recent literastated that the same reagent increased yeast prolifera- ture on the carcinogenic activity of amino, azo, and tion fifty per cent. Andemont and co-workers pro- nitro compounds. Aoji (6) in 1936 reported injections duced tumors with 1,2,5,6-dibenzanthraceneabsorbed of o-aminoazotolnene produced adenocarcinoma of the on charcoal ( 3 ) ,or dispersed in either lard solution or in liver of chickens. The following year Waters (148) dog and horse serum ( 2 ) . More recent work has dealt caused tumors in albino rats with the same reagent, with hereditary effects (4, 5 ) . LeRoy and co-workers and Shear (128) noted the development of tnmors in (77) included 1,2,5,6-dibenzanthracenein their intrave- mice from 2-amino-5-azotoluene. Nakahara (94),hownous administration of colloidal solutions of carcino- ever, was unable to produce malignant tumors in genic hydrocarbons, and found no tumors developed in chickens with o-aminoazotoluene. Zylberzac (151) has rabbits so treated. discussed the production of tumors with o-aminoazotoluene. Kinoshita (66) obtained tumors in mice 111. CARCINOGENIC ACTION OF SEX HORMONES following injections of azo and N-methylated azo comThe carcinogenicaction of sex hormones has fascinated pounds, like butter yellow. a number of investigators. Kinoshita (66) produced Maio (84) described two hundred forty-eight cases carcinoma in mice by injections of the follicular hor- of cancer due to amino and nitro compounds, including mone. Champy (25,26)developed tumors in the ova- aniline, alpha- and beta-naphthylamines, and benzidine. ries of rabbits, rats, and guinea pigs by follicular and Hueper (63, 64) reported tumors from aromatic amines testicular hormones. Prolonged treatment of mice with and beta-naphthylamine. Berenblnm and Bonser ( I d ) , estrogenic hormones caused sarcoma to develop accord- on the other hand, obtained negative results on injecting to Lacassagne (74). This same worker later (73) ing and feeding mice, rats, and rabbits benzidine, conlirmed this by noting the carcinogenic action on mice alpha- and beta-naphthylamines, aniline, 5-chloi-oof estrone, equilin, estradiol, and other estrogenic orthotoluidine hydrochloride, and extracts of workmen's bodies. Bonser (16) and associates developed mam- urine. Evans (42) recorded tumors developing in mary carcinomas in mice with estrone benzoate and eighty-three cases from six to twenty years' exposure prolactin. Nitta (104) found that injections of corpus to benzidine, alpha- and beta-naphthylamines, and luteum hormone accelerated the growth of rat car- other nitro and amino compounds, but he did not find cinoma. Estrone hastened the appearance of tumors any tumors in those exposed to aniline. Creech and in treatments with the carcinogenic hydrocarbon, Franks (34) synthesized compounds from proteins and 3,4-benzopyrene (52). Peny and Ginzton (109) noted carcinogenic hydrocarbons, and they reported the that tumors developed earlier and in greater numbers compounds showed an immunological specificity due in mice when theelin was mixed with 1,2,5,6-dibenzan- to the hydrocarbon group. thracene than when the hydrocarbon was used alone. VI. INORGANIC CARCINOGENIC REAGENTS Gutschmidt (54) has recently called attention to the Little investigation is in progress on the carcinogenic relation between benzopyrene and the sex hormones.
activity of inorganic reagents, aside from radioactive substances. In 1936 Roussy (118) produced sarcomas in rats and mice with thorotrast, a colloidal solution of Thoz. Selbie (125) in the same year reported similar results, and more recently (126) carried the study further. Boglioli (15) in his experimentally produced sarcomas injected a solution of twenty-five per cent. colloidal thorotrast, fifty per cent. carbohydrate, and twenty-five per cent water. Nordmann (105) observed cancer of workers in asbestos, and on examination found many needles of asbestos in the lungs of those afflicted with malignant growths.
extracts, by urea, vitamins, and so forth. On the other side, they cited an equally imposing list of compounds which shortened life or accelerated tumor growth; among these may be mentioned guanidine compounds, dextrin, dextrose, citric acid, oleic acid, anterior pituitary extract, and so forth. In order to emphasize the similarity in chemical nature of the carcinogenic and anti-cancer agents, the material on the latter is presented under headings similar to those employed above on the classification of carcinogenic compounds. I.
ANTI-CANCER HYDROCARBONS
In 1936 Morelli and Guastalla (92) reported that the active carcinogenic hydrocarbon 1,2-benzopyrene inGROWTHS hibited the growth of transplanted tumors in rats. The carcinogenic activity of several oils has been The following year Haddow and associates published investigated recently. Rowntree (119) and associates two articles on carcinogenic hydrocarbons; in the found ingestion of ether extracts of wheat-germ oil first (57) they found 1,2,5,6-dibenzanthracene,5,6made sarcomas in rats. Dorrance and Ciccone (41) cyclopentane - 1,2 - benzanthracene, 3,4 - benzophenone reported similar results. Chevrel-Bodin and Cormier chrysene, and certain benzanthracene compounds, and (27) produced tumors by daily injections of campho- 9,lO-dihydroxy-1,2,5,6-dibenzanthracene inhibited the rated vegetable oil. Harmant and Watrin (59) de- growth of Jensen and Walker tumors; in the second scribed tumors developed in a woman from oil of cam- publication (58) they list 3,4benzopyrene, 1,2,5,6-diphor and eucalyptus. benzanthracene, and 1,2,5,6-dibenzacridineas reducing A few tissue extracts have been employed as carcino- the rate of growth of rats. Gottlieb (53) and associates genic agents. Sproul and co-workers (130) produced showed that grafted carcinoma on mice grew more tumors with extracts from Rous chicken sarcoma when slowly if the mice were first treated with dibenzanmixed with ascorbic acid, or a saline extract of muscle, thracene and methylcholanthrene. Pybus and Miller casein, gelatin, or acacia. Liombart (78) employed (112) found 1,2,5,6-dibenzanthracenehad an inhibitory glycerol extracts of Rous sarcoma in chicks to develop effect on the growth of mammary tumors, but that prohepatic lesions. This investigator did not secure any tective action was only temporary. McJunkin and carcinogenic action from extracts of human carcinoma, Wolavka (82) injected aqueous emulsions of 1,2,5,6but Schabad (121) caused tumors in mice by benzene dibenzanthracene into a rat sarcoma with the result extracts of human liver of a man who died with cancer. that the sarcoma was made to disappear. Tchakhotine (138) used sodium salts of iodo- and 11. ANTI-CANCERIGENIC ACTION O F HORMONES bromo-acetic acids to produce misshapen forms in cancerization of embryonal sea urchin eggs. The anti-cancerigenic action of hormones has not Schiller (122) secured rat sarcoma by injection of the been limited to those of the sex glands only, but recent dye Light Green F.S., which is the calcium or sodium publications include those from the pancreas and the salt of diethyl-dibenzyl-diaminotr-pheny-carbinol tri- pituitary. Nitta (102, 103, 104) has investigated the sulfonic acid. Nishiyama (100,101)produced sarcoma effect of both male and female sex hormones on malignant tumors. In addition to his findings on respiration in rats by repeated injections of glucose solutions. Cook (29) prepared a number of glucosides related to and glucolysis as influenced by sex hormones, he recarcinogenic hydrocarbons but found none of them ported that the follicle hormone of the anterior pituitary carcinogenic. Strong (135) and Boyland,(18) produced inhibited the growth of rat sarcoma, while injections of the corpus luteum hormone accelerated the growth of malignant change with several dibenzocarbazides. rat carcinoma. Flaks and Ber (50) decreased slightly ANTI-CANCER AGENTS the incidence of cancer in mice treated with methylOn the theory that "X-rays cause cancer and X- cholanthrene by repeated injections of testosterone rays cure cancer" there is a rapidly growing literature propionate. Cornell (31) secured marked tumor redealing with chemical agents which retard the growth gression and relief in fifty-five out of sixty human cases of cancers, and in some cases lead to the disappearance of carcinoma by extracts of beef gonads. He found of the malignant growths. ovarian extracts were effective only in men, and tesLustig and Wachtel (80) have amassed the largest ticular extracts only in women. Savignomi (120) relist of agents which retard and accelerate cancer growth ported pregnancy urine contained a hormone which both in nitro and in vino. Dealing only with experi- inhibited the growth of tumors. ments of the latter kind, their data show that life was Lambret and Driessens (75) have demonstrated that prolonged and tumor growth was retarded by a num- injections of insulin into rats with Jensen sarcoma ber of amino acids and amino bodies, by tissue and organ caused disappearance of the tumors. VII.
MISCELLANEOUS REAGENTS PRODUCING MALIGNANT
Spontaneous mammary cancer in mice may be prevented according to Cramer and Homing (33) by the thyrotropic hormone of the pituitary gland. In a series of five articles Narimatsu (97) studied the effect of the posterior pituitary hormone on growth of malignant tumors. 111.
ACIDS, ALDEHYDES, A N D
AMINO BODIES I N CANCER
tion, which was found to be lowest in solutions of the peroxide. The influence of amino bodies, aside from amino acids, has received less attention. Ludford (79) arrested the growth of malignant cells by solutions of auramine, ethyl urethane, and colchicine. INORGANIC
IV.
CHEMOTHERAPY
Amino acids have been used both to accelerate and to retard growth of malignant tumors, but there is little agreement a t present as to the r61e of individual amino acids. Tokuyama and associates (139, 140, 141) reported that argiuine stimulated but lysine retarded the growth of tumors. Voegtlin (146) had found previously that lysine was essential to the growth of mammary carcinoma. In a more recent communication (145) this investigator listed cystine and methionone as inhibiting growth of such carcinoma, while cystine and glutathione stimulated the growth after an initial period of inhibition. Suzuki and Maiyao (136) classified histidine, tyrosine, leuciue, and tryptophane among the growthretarding amino acids, while arginine and glutamic acid favored the growth of rat carcinoma. Roffo (115) and Figari and Sivori (48) reported amino acids led to regression of tumors. Aromatic and fatty acids have been useful in the chemotherapy of cancer. Guy (55) used benzoic acid with good results in the treatment of cancer of the nose. Helmer and Clowes (60) reported that straight chain unsaturated fatty acids with eighteen or more carbons showed more inhibiting power than saturated fatty acids in chicken tumor development. According to Freund and Pearson (51) substances which dissolved carcinoma and sarcoma cells were obtained from fatty acids resulting from culture of intestinal bacteria on fatty nutrient media. Arloing and co-workers ( 7 ) reported metallo ascorbates possessed anti-tumoral activity, and in a second paper (8) they described the use of titanium and copper complexes of ascorbic acid in the treatment of cancer. Mayneord and Parsons (90) irradiated mice before and during injections of sodium-1,2,5,6-dibenzanthracene-9,10-endo-a1pha betasuccinate and found such treatment accelerated tumor formation. Several papers bave appeared on the influence of aldehydes on cancer. Strong (131) noted the liquefaction and retrogressive changes in tumors of mice following the use of heptyl aldehyde. Shortly afterward he followed this work with a study of heptyl aldehyde on spontaneous carcinomas of mammary glands of dogs, and obtained similar liquefaction of the tumors, followed by the gradual disappearance of the same (132). Maisin and associates (85) reported in 1936 that incidence of cancer in mice treated with benzopyrene was decreased by injection of peroxide of diformaldehyde or performic acid. Later (88) these workers found that a concentration of '/looo of diformaldehyde peroxide hastened the development of benzopyrene cancers, while concentrations of '/106 to 1/1018 had inhibitory ac-
REAGENTS POSSESSING PROPERTIES
ANTI-CANCER
The number of inorganic reagents investigated recently for anti-cancer effects is limited. Nemec (99) claimed remarkable beneficial results from injection of barium nitrate in cases of pulmonary and other types of carcinoma. Schmidt (123)found the following complex lead compounds effective in the treatment of mice carcinoma: sodium-diphenyl-lead-pyrocatechol disnlfonate, sodium-calcium-dipbenyl-lead-pyrocatecholdisnlfonate, and sodium-diamino-diphenyl-lead-pyrocatechol-disulfonate. Sodium bicarbonate retarded the growth of rabbit sarcoma according to Kageyama (65). Konsulov (72) arrested the gmwth of cancer in rats with sea water. Barbour and Allen (12) found the survival time of mice with tumors was shortened by deuterium oxide, but Fischer (49) claimed the growth of carcinoma cells of mice was completely stopped at concentrations of fifty per cent. heavy water. V.
EXTRACTS OF ANIMAL TISSUES AND ORGANS EPPECTNE I N CANCER TREATMENT
Extracts of various animal tissues and organs bave proved effective as anti-cancer agents. Dittmar (36) reported that cell-free extracts from tumors inhibited growth of tumors in mice. MacFadyen and Strum (81) found tumor growth was inhibited by water extracts of the ether-insoluble fraction of the rabbit, mouse, and cow mammary gland, but that the ethersoluble fraction of the same stimulated the growth. The hydrolyzate of striated muscle caused the disappearance of malignant tumors in rats in the experiments of Roffo (116). British patent (108) number 454,440 covered the water-soluble extracts of a number of animal organs which inhibited tumor growth. Maisin and fellow workers (88) greatly decreased the incidence of benzopyrene cancer in mice by feeding large amounts of yeast. McLeod and Ravenel (83) used extract of yeast to bring about shrinkage of tumors in one hundred fifty patients. Atzler (10)used extracts of fish and crustacea as remedies for tumors. Negro (98) employed cobra venum in the treatment of cancer of stomach. VI.
MISCELLANEOUS AGENTS RETARDING TUMOR GROWTH
A number of sulfur compounds have been used to retard tumor growth. Boyland (19) experimented with twenty-five substances related to sulfanilamide or diphenyl-sulfide; about fifty per cent. of the compounds inhibited tumor growth in mice; the most effective were 9,p'-diamino-diphenyl-sulfoxide and sodium-sulfanilylsulfanilate. Muller (93) claimed that hydrogen
acceptors, such as unsaturated sulfides, allylthiourea, or any substance which reduced methylene blue inhibited tumor growth. Ludford (79) reported arrested development of malignant cells by methyl-sulfonal and sodium-cacodylate. Vannfalt (143, 144) found that mice which drank a fifty per cent. glucose solution showed longer survival time after tar cancer. Insulin, however, decreased the survival time in the work of this same experimenter. Kageyama (65) confirmed the retarding action of an acid diet on sarcoma by showing that sucrose acted like glucose. In 1936 Homer (62) reported that vitamin C did not favor growth of mouse sarcoma. The following year experiments of Cameron and Meltzer (23) showed that diets rich in vitamins delayed growth of tar tumors, but that the final proportion of mice which developed growths was the same as normal.
Strong (133) originally reported that the survival time of animals harboring tumors was increased by natural oil of wintergreen. Two years later (134) he revised this statement by showing that i t was the low-boiling fraction (six per cent. fraction) of the natural oil which was more effective; neither the highboiling fraction (eight per cent. fraction) nor synthetic methylsalicylate was effective. Barna (13) stated that cancer cells died in a much shorter time under the effects of acetone than did healthy cells. The author wishes to express his indebtedness to Dr. E. Emmet Reid, Professor Emeritus of the Johns Hopkins University, and to Dr. Charles F. Geschickter, Department of Surgical Pathology, the Johns Hopkins Hospital, under whose joint direction this study was made. Acknowledgment is due also to the Bloodgood Cancer Fund for financial assistance.
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