ANIMAL TUMORS Production of Cmcer by Pure Hydrocarbons, Part III, G
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EXPERIMENTAL STUDIES; ANIMAL TUMORS Production of Cmcer by Pure Hydrocarbons, Part III, G. BARRY,J. W. COOK,G. A. K. HASLEWOOD,C. L. HEWITP,1. HIEGERand E. L. KENNAWAY.Proc. Roy. ha., Ser. B. 117: 318-351, 1935. The carcinogenic properties of 1 : 2 : 5 : Bdibensanthracene, 5 : Bcyclo-penteno- 1 : 2-benaanthracene and other closely related compounds have been discussed in a number of contributions (see Absts. in Am. J. Cancer 17: 181, 472, 1933, and original articles 16: 57, 1932; 17: 1, 1933; 20: 58, 1934). Here the authors report the results of a systematic examination for carcinogenic activity of tetracyclic and pentacyclic aromatic hydrocarbons, made by applying the substance, usually dissolved in bensene, to the interscapular region of mice twice weekly, for the production of carcinoma and papillomas, and by injecting it subcutaneously, in a fatty medium, usually lard, for the production of sarcomas in rats and mice. Only one of the six possible hydrocarbons, consisting of four condensed aromatic rin~,showed any considerable carcinogenic power. This compound, 3 : 4-benzphen- anthne, is the simplest hydrocarbon so far shown to have such power in a pronounced degree, and the only one yet made which is not derived from or related to 1 : 2-bensan- thracene. Of the fifteen possible hydrocarbons containing systems of five condensed bensene rings in the molecule, twelve have now been tested, and only two of these 1 : 2 : 6 : 6dibenzanthracene and 1 : 2-benspyrene, have shown pronounced activity. Testa on twenty simple derivatives of the former are now almost complete, and the re- sults justify Cook’s conclusion that substitution, especially in the meso position, tends to diminish the carcinogenic power. 1 : 2-benzpyrene is the only carcinogenic substance so far examined which has been shown to occur in coal tar, besides having been pre- pared synthetically from pyrene. The natural and synthetic materials gave similar results, and from the high incidence of tumors (47 epitheliomas and 11 papillomas in 100 mice) this appears to be a considerably more active agent than 1 :2 :6 :Mibensanthracene. The investigation of pure synthetic carcinogenic agents of known molecular structure haa eegumed an entirely new aspect with the recognition and proof of tho true molecular struotures of the group of natural products which comprise the sterola and bile acids, between which and the carcinogenic hydrocarbons there is a definite similarity in struc- ture. In particular the sterols and bile acids contain in their molecules condensed carbon-ring systems to which is attached a long side chain in such a position that a new six-membered ring can be formed so as to give the 1 : 2-bensanthrscene ring system without molecular rearrangement or group migration. The purely aromatic hydro- carbon, methylcholanthracene, obtained thus from the bile acid, dioxycholic acid, and recently synthesized by Fieser and Seligman (J. Am. Chem. Sac. 57: ,228, 1935), is a bensanthrscene with substituents in positions 5 and 6, a favorable type of molecular structure for the development of carcinogenic properties. Testa by the authors have shown that its activity is at least equal to that of 1 : 2-benspyrene. In one series of 20 mice it produced 17 epitheliomas and one papilloma within 180 days, and in a second series the 6rst tumor appeared after 31 days. When it was dissolved in lard and in- jected into the thighs of 15 r&s, connective-tissue tumors arose in every one of the 9 animals which lived for more than 70 days. That is, it produces connective-tissue tumors more rapidly than any other hydrocarbon so far tested. The tumors were spindle-celled, and some contained numerous giant cells. They rarely metastasised, despite their great sise, but gave vigorous autografts. Of four beterografts three were negative and the fourth failed after the third generation, as compared with a 1 : 2 : 5 : 6 dibenranthracene tumor which has now reached the 71st generation. The authors have now examined for carcinogenic activity 71 compounds not related in molecular structure to 1 : 2-bensanthracene, and 65 of these have given entirely 846 846 ABSTRACTS negative results on 20.26 tested mice. Of the 6 compounds which gave positive results (22 tumors in 380 mice) only 3 : 4-benephenanthrene has considerable activity. On the other hand, out of 69 compounds related to 1 : 2-benaanthracene 25 gave positive results (437 tumors in 1220 mice); the remaining 44 (no tumors in 619 mice) were for the most part derivatives in which the substituents were attached to the molecule in positions other than 5 and 6. There are seven photomicrographs, and a full bibliography is appended. F. CAVERS Reduction of Cancer in the Rabbit with 1 :2 :5 :bDibenzanthracene, A. LACASSAGNE. Essais de production de cancer chee le lapin au moyen du 1-2-58 dibeneanthracbne. Compt. rend. SOC.de biol. 114 : 660-662, 1933. Dibeneanthracene was dissolved in lard in dilutions of 1 to 4 mg. per C.C. and in- jections of 1 C.C. were made in rabbits every two weeks. The material was introduced into the breast, the knee joint, the marginal vein of the ear, and the testicle. Up to the time of the report the only tumor produced was one of the testicle. The tumor appeared in about six months. None of the autografts or subcutaneous grafts in 9 small rabbits, or the intracerebral grafts in 5 adult rabbits grew. About a year after the first inoculation the animal was killed and was found to have invasion of the pre- aortic lymph nodes and extensive metastases in the lung. The exact type of the growth is still uncertain. [Prof. Lacassagne informs the abstractor that further study of the tumor suggests that it might be derived from the remnants of adrenal cortex which normally occur in the rabbit’s testicle.] Lesions Induced in the Lungs by Intravenoue Injection of Tar, JAMESP. SIMONDSAND JOHN8. CURTIS. Arch. Path. 19: 287-302, 1935. Though a number of investigators have attempted to induce carcinoma of the lungs by the introduction of tar into these organs, the results have been sufficiently confusing to warrant repetition of the experiment. The authors therefore injected 31 rabbits (2,500 to 5,000 gm.)with 0.2 or 0.4 C.C. of liquid petrolatum containing 5 per cent of a tar known to be carcinogenic for mice. This mixture was slowly introduced into a vein of the ear, usually once a week unless the rabbit became sick or appeared undernourished; in such an event the injections were discontinued. The animals survived for from eight days to more than eighteen months after the first injection; all were allowed to die epontaneously. [There is no mention of controls injected with oil alone.] In 17 rabbits that lived for more than two weeks, there were varying degrees of epithelial proliferation combined with such pathologic processes as thrombosis, em- bolism, and chronic inflammation. In 12 of this group (and in one additional rabbit injected with anthracene) the epithelial hyperplasia was advanced. The authors are not convinced, however, that actual carcinoma had been induced, for although the proliferation was sufficiently massive and atypical to suggest strongly a malignant growth, there were no discoverable metastases, the lesion was multicentric, and it was constantly and intimately associated with granulation tissue .without definite relation to the amount of tar injected or the length of time that the animal survived. It is remarkable that such extensive and even atypical epithelial proliferation can take place without acquiring a definitely malignant character. The normal cell, at least in the rabbit lung, must possess a large measure of inertia that resists transfer across the ill-defined border separating inflammatory hyperplasia from the true neoplasms. WM.H. WOGLOM Scarlet Red as a Possible Carcinogenic Agent. An Experimental Study, CLARENCET. ECKERT,ZOLA K. COOPIW~AND M. G. SEELIO. Arch. Path. 19: 83-90, 1935. As the authors could find no record of long-continued surface and subepithelial applications of scarlet red, they applied a 2.6 per cent solution of the dye in olive oil to the skin of 161 young white mice three times weekly over a period of 312 days and during this time made 7 subcutaneous injections (0.50 to 0.75 C.C. each) of the same EXPERIMENTAL STUDIES ; ANIMAL TUMORS 847 preparation as nearly as possible under the painted area. They saw no such epithelial hyperactivity as waa described in rabbits by B. Fischer and many of his followers. WM. H. WOQLOM Experimental Papillomu of the Urinary Bladder. (1) The Production of Papilloma in the Rat Bladder with Pellets of Tar, Scarlet Red, and Par&, 8. WATANABE. Experimentelle Papillombildung in der Harnblaae. (1). Eraeugung von Papillom in der Rattenblase durch Einbringen von Teer-Scharlachrot-Paraffin-Kugeln, Acta Dermat. 23: 28-31, 1934. Pellets made of equal parts by weight of coal tar, scarlet red, and paraffin were placed in the urinary bladders of rats. There were ultimately available for histological examination 55 bladders from survivors killed after the lapse of various periods (14 to 396 days). In 9 of these, heterotopic and atypical growth of epithelium had taken place. Where the lesion was most advanced alveolar cell nests had penetrated as far down as the muscularis, and in a few instances this layer had been damaged by pres- sure. In brief, proliferation was definitely of the malignant type. [Such invasion is not, under the circumstances of the experiment, any proof of malignancy. See, for example, Bullock and Rohdenburg; J. Cancer Res. 3: 227, 1918.1 The remaining bladders were the seat of papillomas in various stages of growth, except for 4 which contained no outgrowths and 2 in which the wall of the viscus had undergone necrosis.