Low Incidence Of Spontaneous Tumors Research Articles

Regulatory Experience Assessing the Carcinogenic Potential of a Monoclonal Antibody Inhibiting PCSK9, Bococizumab, Including a 2-Year Carcinogenicity Study in Rats.

Bococizumab is an anti-PCSK9 monoclonal antibody that was intended for the treatment of hypercholesterolemia. After reviewing the 6-month rat toxicity study data, in which there was a low spontaneous tumor incidence, unrelated to bococizumab administration, the U.S. FDA granted a carcinogenicity waiver request based on a weight-of-evidence assessment of low carcinogenic risk. Subsequently, after reviewing 6-month rat toxicity study data from another anti-PCSK9 antibody, RN317, with a similar low tumor incidence (unrelated to RN317), the U.S. FDA rescinded the bococizumab carcinogenicity study waiver and requested a full 2-year rat carcinogenicity study be conducted. The resulting 2-year carcinogenicity study demonstrated no bococizumab-related increase in tumors, confirming the weight-of-evidence evaluation and alleviating concerns regarding the carcinogenic potential. Here we report the scientific and regulatory background that led to the request for a rat carcinogenicity study, the feedback on the design of the carcinogenicity study, and the results from this study which affirmed the original weight-of-evidence assessment of low carcinogenic risk.

Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague?Dawley rats

The plasticizer di-(2-ethylhexyl)-phthalate (DEHP) is the most important phthalate with respect to its production, use and occurrence in the environment. In standard carcinogenicity experiments with F344 rats and B6C3F1 mice, DEHP has been shown to induce hepatocellular tumors. Moreover, DEHP is strongly suspected to be a developmental and reproductive toxicant. The present study aimed at determining the long-term toxic effects of lifetime exposure to low concentrations of DEHP in Sprague-Dawley rat strain. Seven hundred and thirty male rats, stratified into four groups, received DEHP with the diet, resulting in dosages of 300, 95, 30 and 0 mg/kg per day for up to 159 weeks and were only sacrificed when moribund. All organs of the dead and sacrificed animals were histopathologically examined. Significantly increased tumor incidences after exposure to 300 mg/kg per day DEHP (P = 0.04 for testes and 0.05 for liver) and a significant dose-related trend (P(Trend) = 0.02 for testes and 0.03 for liver) were detected in both organs liver and testes. Time to tumor analysis revealed that DEHP-induced testicular tumors developed earlier in lifetime than hepatocellular neoplasias, and their multiplicity increased with time. In addition, animals exposed to the highest DEHP dose showed a significantly increased rate of testicular tubular atrophy (P < 0.01). In conclusion, this study shows for the first time that the rat testes are a target organ of DEHP carcinogenicity in Sprague-Dawley rats upon lifetime exposure. This new finding indicates the importance of evaluating the effects of lifetime exposure in assessing the potential human health risks of DEHP. In addition, the carcinogenicity should be evaluated in rat strains with low spontaneous tumor incidence in the organs known as target of DEHP toxicity.

Life span and spontaneous tumors incidence of the Wistar Mishima (WM/MsNrs) rat.

The life spans and spontaneous tumors in a total of 1960 Wistar Mishima (WM/MsNrs) rats, inbred strain, from the 80-130th generations were examined. The average life span (mean +/- SD) was 731 +/- 173 days (n = 1053) in the males and 813 +/- 214 days (n = 907) in the females (p < 0.0001). The average life span of tumor-afflicted females was significantly longer than that of the non-tumor group (p < 0.0001), while no such difference was observed in males. Tumors were observed in 33 males (3.1%) and 246 females (27.1%). In the males, tumors were often observed under the skin (2.2%). Frequencies of tumors in lung and liver, bones and intestine were less than 0.5%. In the females, incidence of mammary tumor was 20.1%, and various organs such as ovaries, uterus, bones, lung, and liver had tumor incidence frequencies of less than 3.5%. It was concluded that WM/MsNrs rats might be suitable for life span and age-related studies because of their characteristics of length of longevity and the low incidence of spontaneous tumors in both sexes.

On the occurrence of Leydig cell tumors in the F344 rat

Dunning began inbreeding, what is now the Fischer F344 rat, in 1931. Because of her publications showing a low incidence of spontaneous tumors to 35 months of age, we selected the F344 rat for most of the studies in the National Cancer Institute (NCI) Bioassay Program, beginning in 1964. We were surprised by the finding that untreated male F344 rats displayed a high incidence of Leydig cell tumors of the testes beginning at about 17 months of age. The key difference between the results of Dunning and the NCI Bioassay Program was that her animals were retired breeders, whereas the NCI studies utilized virgin rats. The question of breeding was, therefore, examined as a possible protective factor. Groups of male F344 CDF/Crl rats were kept as virgin animals, or permitted access to bilaterally tube ligated female F344/Crl rats that were replaced twice over a 52-week period. At that time, all males from both groups were housed three per cage to 85 weeks when they were killed in a CO 2 atmosphere and necropsied. Sections were prepared from the fixed tissues, stained and studied by histopathology. The results were evaluated by appropriate statistical methods. Virgin and sexually active F344 rats displayed monolateral or bilateral Leydig cell tumors. There was no statistical difference between the two groups. Despite the early difference between breeding and virgin F344 rats, a control experiment failed to disclose an effect of sexual activity on the occurrence of Leydig cell cancers. This disease displays some difference in incidence in various parts of the world, with the higher socioeconomic groups having a greater incidence. Etiological factors on the occurrence of this disease in animals and in humans remain to be discovered.

Fumonisin B1 Promotes Aflatoxin B1 and N-Methyl-N′-nitro-nitrosoguanidine-Initiated Liver Tumors in Rainbow Trout

Laboratory studies have described the carcinogenicity of fumonisin B1 (FB1) in rodents and epidemiological evidence suggests an association between FB1 (a mycotoxin produced by Fusarium moniliforme) and cancer in humans. This study was designed to reveal in rainbow trout, a species with very low spontaneous tumor incidence, if FB1 was (i) a complete carcinogen, in the absence of an initiator; (ii) a promoter of liver tumors in fish initiated as fry with aflatoxin B1 (AFB1); and (iii) a promoter of liver, kidney, stomach, or swim bladder tumors in fish initiated as fry with N-methyl-N′-nitro-nitrosoguanidine (MNNG). FB1 was not a complete carcinogen in trout. No tumors were observed in any tissue of fish fed diets containing 0, 3.2, 23, or 104 ppm FB1 for a total of 34 weeks (4 weeks FB1 exposure, 2 weeks outgrowth on control diet, followed by 30 weeks FB1 diet) in the absence of a known initiator. FB1 promoted AFB1 initiated liver tumors in fish fed ≥23 ppm FB1 for 42 weeks. A 1-week pretreatment of FB1 did not alter the amount of liver [3H]AFB1 DNA adducts, which suggests that short-term exposure to FB1 will not alter phase I or phase II metabolism of AFB1. In MNNG-initiated fish, liver tumors were promoted in the 104 ppm FB1 treatment (42 weeks), but FB1 did not promote tumors in any other tissue. Tumor incidence decreased in kidney and stomach in the 104 ppm FB1 treatment of MNNG-initiated trout. The FB1 promotional activity in AFB1-initiated fish was correlated with disruption of sphingolipid metabolism, suggesting that alterations in associated sphingolipid signaling pathways are potentially responsible for the promotional activity of FB1 in AFB1-initiated fish.

Radon-induced lung cancer in smokers and non-smokers: risk implications using a two-mutation carcinogenesis model.

Three sets of data (population statistics in non-smokers, data from an investigation of the smoking habits of British doctors and a study of Colorado uranium miners) were used to analyse lung cancer in humans as a function of exposure to radon and smoking. One of the aims was to derive implications for radon risk estimates. The data were analysed using a two-mutation radiation carcinogenesis model and a stepwise determination of the model parameters. The basic model parameters for lung cancer were derived from the age dependence fit of the spontaneous lung cancer incidence in non-smokers. The effect of smoking was described by two additional parameters and, subsequently, the effect of radon by three other parameters; these five parameters define the dependence of the two mutation steps on smoking and exposure to radon. Using this approach, a consistent fit and comprehensive description of the three sets of data have been achieved, and the parameters could, at least partly, be related to cellular radiobiological data. The model results explain the different effect of radon on non-smokers and smokers as seen in epidemiological data. Although the analysis was only applied to a limited number of populations, lung cancer incidence as a result of radon exposure is estimated to be about ten times higher for people exposed at the age of about 15 than at about 50, although this effect is masked (especially for smokers) by the high lung cancer incidence from smoking. Using the model to calculate the lung cancer risks from lifetime exposure to radon, as is the case for indoor radon, higher risks were estimated than previously derived from epidemiological studies of the miners' data. The excess absolute risk per unit exposure of radon is about 1.7 times higher for smokers of 30 cigarettes per day than for non-smokers, even though, as a result of the low spontaneous tumour incidence in the non-smokers, the excess relative risk per unit exposure for the smokers is about 20 times lower than for the non-smokers. This prediction could have serious consequences for the transfer of risk estimates between populations. Although the solution of the model presented here is not unique but dependent on the model assumptions, the predictions and risk implications are sufficiently supported to justify a thorough investigation of the applicability of the model to other radon data sets.

Evaluation of the Emu-pim-1 transgenic mouse model for short-term carcinogenicity testing.

The value of the chronic rodent carcinogenicity assay in adequately predicting cancer risk in humans has become a matter of debate over the past few years. Therefore, more rapid and accurate alternative tests are urgently needed. Transgenic mouse models, those harboring genetic changes that are relevant to the multistage cancer process, may provide such alternative tests. Transgenic Emu-pim-1 mice, developed by Berns and coworkers in 1989, contain the pimn-1 oncogene, which is expressed at elevated levels in their lymphoid compartments. As a result, these mice are predisposed to the development of T-cell lymphomas. Because of the low incidence of spontaneous tumors and the increased sensitivity to N-ethyl-N-nitrosourea-induced carcinogenesis, Emu-pim-1 mice were suggested to be one of the first potential and attractive candidates to be used in short-term carcinogenicity testing. In the present article, the results from 2 recent short-term assays (with mitomycin C and x-rays) are briefly presented, together with a review of all 11 performed bioassays and their corresponding histopathologic and molecular data. The overall results allow the first evaluation of the Emu-pim-1 mouse model with regard to its usefulness in short-term carcinogenicity testing. It has been shown that the model is primarily suitable as a sensitive short-term assay for genotoxic carcinogens that not only induce (at least) gene mutations and/or large deletions and rearrangements but that also sufficiently target the lymphoid system. However, the Emu-pim-1 mice lack sufficient sensitivity to justify their routine use in short-term carcinogenicity testing in general.

Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA.

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild-type mice, appear to be efficiently identified.

Conditional expression and oncogenicity of c-myc linked to a CD2 gene dominant control region.

Over-expression of the c-myc gene is widely implicated in the genesis of lymphoid neoplasia, including tumours of the T-cell lineage. To study the effects of deregulated c-myc expression on T-cell development and oncogenesis, we sought to generate a transgenic mouse model in which c-myc expression was targeted specifically to the T-cell lineage. A plasmid construct containing a dominant control region (DCR) from the human CD2 locus linked 5' to the human c-myc gene was used to generate 2 lines of transgenic mice. Both strains developed thymic lymphoma at low frequency, but thymic development and peripheral T-cell numbers were otherwise apparently normal. Low tumour penetrance was consistent with the observed lack of stable CD2-myc transgene mRNA in tissues of healthy transgenic mice. In contrast, transgene RNA was detected in all malignant tumours as well as in early lymphomatous lesions. RNase protection analyses confirmed these findings and showed that the PI human c-myc promoter was active in all neoplastic tissues but not in the thymus or other tissues of healthy transgenic mice. Despite the low spontaneous tumour incidence, the presence of the transgene markedly and uniformly accelerated the onset of tumours after neonatal infection with Moloney murine leukaemia virus. All tumours were rearranged for T-cell receptor beta-chain genes and were of T-cell origin from their surface phenotype (Thy-1+, CD3+, CD4+/-, CD8+, sIg-). Virus-accelerated tumours contained clonal integrations of Moloney murine leukaemia virus, suggesting that proviral insertional mutagenesis may have played a role in tumour development. Analysis of several candidate myc-cooperating genes failed to reveal any rearrangements apart from a low frequency involving proviral insertion at the pim-1 locus. The CD2-myc mouse should therefore be a valuable system in screening for novel myc-collaborating genes involved in T-cell lymphoma.

Base-Line Data in a Carcinogen-Susceptible First-Generation Hybrid Strain of Syrian Golden Hamsters: F1D Alexander

Base-line data in over 600 control animals of both sexes of the first-generation hybrid BIO F1D Alexander strain of Syrian golden hamsters are presented. They involve mortality, body weights, spontaneous tumor incidence, and incidence of nonneoplastic lesions. The results confirmed previously published data on smaller numbers of animals of this hamster strain. Spontaneous tumors with an incidence of more than 2% were limited to lymphomas (less than or equal to 6%), adrenocortical carcinomas (less than 8%), adrenal adenomas (9-14% in males; 3.5% in females), islet cell adenomas (less than 6%), and follicular adenomas of the thyroid gland (3.5% in females only). This low incidence of spontaneous tumors and the high survival rate (compared to those of hamsters from other sources), together with the previously established high susceptibility to tumor induction by carcinogen administration, render the F1D Alexander hamster an excellent animal model for lifetime carcinogenesis bioassays.

Sublethal fractionated total-body irradiation and donor bone marrow infusion for induction of allograft tolerance.

Tolerance to skin allografts across the strong histocompatibility barrier H-2b to H-2d was achieved with sublethal fractionated total-body irradiation, FTBI, delivered to H-2d mice in 3 doses of 250 rads within 24 hr, followed by transfusion of 3 X 10(7) H-2b donor bone marrow (BM) cells. H-2b skin allografts were applied within 48 hr after the initial radiation. 70% of the mice became long-term (greater than 180-day) survivors with fur-bearing grafts. Marked interexperiment variability in survival rates suggested that infection was the major cause of death in this model and lower weight gain and survival rates for allogenic BM vs. media-treated controls suggested that graft-versus-host disease (GVHD) was also a factor. The observation, however, that long-term survivors (70% of all mice) gained weight and appeared healthy suggested that the GVHD might be self-limiting. Chimeric analysis revealed that approximately 25% of spleen cells were of donor origin, both at short-term (6 weeks) and long-term (greater than 1 year) intervals after tolerance induction. In spite of hematopoietic chimerism, a low incidence of spontaneous tumors, less than 1%, occurred in the long-term survivors.

Characterization of a microsomal fraction from rat small intestine for metabolic activation of some promutagens.

Rat small intestine possesses cytochrome P-450 mixed function oxidase activity and is thus potentially capable of activating procarcinogens during absorption. The low spontaneous tumour incidence at this site may be due partially to the detoxification activity of the intestinal mucosa. To study the contribution of the intestine to the metabolism of foreign chemicals, microsomes have been obtained from rat small intestine by a procedure facilitating recovery of preparations with consistently high enzyme activities and abilities to activate some selected promutagens in the Salmonella mutagenicity assay. Intestinal microsomes from animals with and without pretreatment with inducers have been used for investigations of biochemical properties and ability to activate several mutagens in the Salmonella plate incorporation assay. The effects of microsomal protein concentration and inhibitors were also studied. The results are compared with data obtained using liver microsomes from the same animals. Despite the induction of lower numbers of revertants, intestinal microsomes were at least as efficient as liver preparations for the activation of all the promutagens used when the data were corrected for cytochrome P-450 contents. Differences in dose-response curves for certain mutagens using liver and intestinal microsomes are discussed in relation to variation in metabolism of promutagens. Activation was linearly dependent on microsomal protein concentration, for both liver and small intestinal microsomes. The intestine was generally less susceptible to the effects of cytochrome P-450 and P-448 inducers, although sensitivity to orally administered phenobarbitone was increased by extending treatment times. SKF525A and beta-naphthoflavone inhibited microsomes from both sources, equal inhibition being observed for each type following incorporation of the inhibitor, although they differed in their ability to activate 2-acetylaminofluorene in the presence of the deacylase inhibitor, NaF. The data are discussed in relation to the possible role of the small intestine in metabolic activation in vivo and the utility of microsomes therefrom for the in vitro detection of putative dietary carcinogens.

Promotion of lung tumors in mice.

Several elements of two-stage carcinogenesis apply to the development of lung tumors in Strain A or Swiss-Webster mice. At least three agents which have been identified as promoters in skin, urinary bladder and liver will also enhance tumor formation in lung; phorbol, saccharin and butylated hydroxytoluene (BHT). The antioxidant BHT acts in many respects like a typical promoting agent: it is effective if animals are treated after exposure to an initiating agent, but not if they are treated beforehand. Administration of BHT can be delayed up to 5 months after urethan treatment and still enhance tumor formation. BHT enhances lung tumor formation regardless of its route of administration (IP injection, gavage, or ingestion in the diet). The lowest dose of BHT required to produce an effect has not yet been determined. In at least one mouse strain, BHT also enhances tumor formation in animals initiated with 3-methylcholanthrene or dimethylnitrosamine. On the other hand, no evidence is available yet to show that BHT would enhance tumor development in animals treated with subcarcinogenic doses of an initiating compound. Nor has it been possible to produce more tumors with BHT in mouse strains which have a low spontaneous tumor incidence and respond poorly to urethan. The question has not been resolved whether BHT accelerates growth of preformed tumors only or whether it induces the formation of more tumors. Nevertheless, the data collected on the effects of BHT on mouse lung tumor development have broadened the concept of two-stage carcinogenesis and complement the evidence for initiation- promotion available for other epithelial tissues such as liver, colon, stomach, trachea, urinary bladder and mammary gland.

Promotion of Lung Tumors in Mice

Several elements of two-stage carcinogenesis apply to the development of lung tumors in Strain A or Swiss-Webster mice. At least three agents which have been identified as promoters in skin, urinary bladder and liver will also enhance tumor formation in lung; phorbol, saccharin and butylated hydroxytoluene (BHT). The antioxidant BHT acts in many respects like a typical promoting agent: it is effective if animals are treated after exposure to an initiating agent, but not if they are treated beforehand. Administration of BHT can be delayed up to 5 months after urethan treatment and still enhance tumor formation. BHT enhances lung tumor formation regardless of its route of administration (IP injection, gavage, or ingestion in the diet). The lowest dose of BHT required to produce an effect has not yet been determined. In at least one mouse strain, BHT also enhances tumor formation in animals initiated with 3-methylcholanthrene or dimethylnitrosamine. On the other hand, no evidence is available yet to show that BHT would enhance tumor development in animals treated with subcarcinogenic doses of an initiating compound. Nor has it been possible to produce more tumors with BHT in mouse strains which have a low spontaneous tumor incidence and respond poorly to urethan. The question has not been resolved whether BHT accelerates growth of preformed tumors only or whether it induces the formation of more tumors. Nevertheless, the data collected on the effects of BHT on mouse lung tumor development have broadened the concept of two-stage carcinogenesis and complement the evidence for initiation- promotion available for other epithelial tissues such as liver, colon, stomach, trachea, urinary bladder and mammary gland.

Immunological surveillance against neoplasia: An immunological quandary

Immunological endéavor in recent years calls for a reappraisal of the concept of immunosurveillance against neoplasia. This concept proposes an immunological policing system capable of aborting tumor growth by the recognition of “nonself” tumor associated antigens on neoplastic cells. The model is supported by evidence of tumor induction in the immunosuppressed host and the demonstration of an immune response to tumors in animals. The occurrence of tumor, regarded as a failure of immunosurveillance, is attributed to selection of neoplastic cells for immunological or other reasons or abnormal humoral or cellular antitumor immune responses. However protagonists of the postulate are faced with mounting evidence that fails to support the surveillance hypothesis. These observations include, inter alia, the monoclonality of certain tumors, the low incidence of spontaneous tumors in genetically immunodeficient mice and immunological privileged sites, and new ideas about the pathogenesis of lymphoproliferative neoplasms. However, contradictory arguments are not sufficiently substantiated to prosecute the case against surveillance conclusively. In citing highlights of the evolving quandary, both the pros and cons of immunological surveillance are presented here.

Incidence of spontaneous ileocecal immunocytomas in hybrids of LOU/C rats and rat strains with low spontaneous tumor incidence.

Monoclonal immunoglobulin-secreting tumors (immunocytomas or plasmacytomas) appear in many species, but they occur at a low incidence and usually originate in lymphoid tissues. However, in the rat, the incidence of malignant spontaneous immunocytomas (or plasmacytomas) was high and the tumors consistently arose in the ileocecal lymph nodes. In inbred LOU/C/Wsl rats, these immunocytomas developed in twice as many males (31%) as females (16%). The susceptibility of the rats to immunocytoma was under genetic control; e.g., LOU/C/Wsl rats had a dominant locus (or loci) of susceptibility that could induce immunocytoma in inbred AUG/Wsl or inbred A X C9935/Wsl rats. However, inbred Okamoto/Wsl rats had at least one dominant locus of resistance that did not exist in LOU/C/Wsl, LOU/M/Wsl, AUG/Wsl, or A X C9935/Wsl rats.

The use of rodents for studies of toxicity in contraceptive research.

ABSTRACT After nearly two decades of clinical use of oral contraceptives, clinical studies have shown a few rare adverse reactions, including jaundice, venous thrombosis and pulmonary embolism, ischaemic cerebrovascular effects, hypertension, amenorrhoea, breakthrough bleeding, anxiety, depression, weight gain, and changes in libido. Preclinical studies in rodents dosed with oral contraceptives did not and would not be expected to reveal side effects of such low incidence. A carcinogenic effect can be produced in certain strains of mice and rats when oestrogens, progestogens and combinations of these hormones are given in high doses throughout their life span. The susceptibility to tumour induction by hormonal contraceptives is not consistent in different strains of mice and rats, and if there is little or no predictive value in rodents it is difficult to see how they can provide useful information of the potential carcinogenicity of any of these compounds in women. Ideally, carcinogenic testing of oral contraceptives should be conducted in animal species which have a similar metabolic disposition of the drugs and similar feedback mechanisms which control ovulation and menstruation to that of women: subhuman primates and guinea pigs possess some of these characteristics. Many previous studies indicate that carcinogenic tests in rodents have not been carried out in a very satisfactory manner. Improvements which are suggested include the use of strains with a low spontaneous tumour incidence, strains which are free of oncogenic viruses, and standardised diet. The use of extremely high doses should be avoided. To date there is no convincing evidence that oral contraceptives are carcinogenic in women, but further epidemiological studies following prolonged treatment will provide the most meaningful evidence.

Effect of Vitamin E on Carcinogenicity of Methylcholanthrene.

Discussion and conclusionsThe C57 mice have a low incidence of spontaneous tumors, but respond uniformly well to carcinogens. Age does not seem to be a prominent factor, though more primitive sarcomas are produced in very young mice (10). Mineral oil and tricaprylin, if critically purified, apparently have little or no specific influence on carcinogenesis when used as a vehicle in a subcutaneous depot. Alpha tocopherol appreciably inhibited the carcinogenic activity of methylcholanthrene in the first experiment, and failed to produce tumors in the controls. In the second experiment, which had a bascially similar plan, though differing in the sex and substrain of mice, dosage of Vit. E, and vehicle used for the carcinogen, inhibition of the carcinogenic activity of methylcholanthrene by alpha tocopherol was confirmed.The significance of these results approximates the 93% level(11, 12).

The Skin of Hairless Mice: II. Ageing Changes and the Action of 20-Methylcholanthrene

INTRODUCTION Notwithstanding the low incidence of spontaneous tumors (7), the skin o hairless mice is very sensitive to carcinogenic agents. Numerous elevated skin growths appear soon after one topical application of methylcholanthrene. In spite of the many peculiarities of the skin of these animals (20), most of the induced growths develop directly from the surface epidermis and from the sebaceous glands. The many epidermal and sebaceous cysts stranded in the dermis are not involved in hyperplastic changes. As in the formation of cysts, the development of skin growths in these animals demonstrates further the pluri-potentiality of epidermal cells. For example, typical papillomas, which in other animals are said to arise only from hair follicles, in hairless mice grow on the scars of biopsy wounds which contain neither sebaceous glands nor hair follicle remnants.

Steroid Hormones and Tumors. Tumorigenic and Anti-tumorigenic Actions of Steroid Hormones and the Steroid Homeostasis. Experimental Aspects

Steroid Hormones and Tumors. Tumorigenic and Antitumorigenic Actions of Steroid Hormones and the Steroid Homeostasis. Experimental Aspects. By ALEXANDER LIPSCHUTZ, M.D. , Formerly Professor of Physiology, Hon. M. Roy. Soc. Med. (Endocrinol.), Director of Depar tment of Experimental Medicine, National Heal th Service of Chile. 309 pp., I l l figs. $6.00. Balt imore: The Williams & Wilkins Company, 1950. The monograph Steroid Hormones and Tumors by Alexander Lipschutz summarizes the contributions of the author and his collaborators to the subject of experimental tumori genesis. From the study of experimental conditions which permit the reproducible development of neoplasms by steroids in animals the author seeks for a bet ter comprehension of some of the elements which give rise to tumors, the ult imate goal being an understanding of the origin and approach to t reatment of neoplasm in the human. Dr . Lipschutz and his group were concerned primarily with the steroids of the estrogenic series. Under given conditions the administration of these compounds to guinea pigs is followed by the appearance of fibromata scattered throughout the peritoneal cavity. Analysis of these conditions confirms classical concepts of neoplastic origin obtained by other experimental approaches. Since continuously absorbed estrogen, even in small amounts, can give rise to these tumors, Dr . Lipschutz seeks to explain the action in terms of disturbed physiologic consequences. However, it becomes clear t ha t our understanding of hypophysealgonadal-adrenal-liver relation is only hazy enough for us to reach a stage of conjecture rather than theory relative to this problem. Compounds like progesterone and testosterone can prevent the appearance of fibromata following estrogen administration. This leads the author to the opinion tha t the relatively low incidence of spontaneous tumors of this type in various species may be due to normal secretion of these substances during the reproductive period. The fact tha t Lipschutz was able to dissociate tumorigenic and ant i tumorigenic action from the so-called physiologic actions of the various steroids might suggest tha t the observed physiologic changes were secondary to pharmacologic effects. This volume, although more limited than its ti t le suggests, is a provocative and stimulating treatise expressively written by an author engaged completely by the subject a t hand.