The pharmacology and clinical uses of tamoxifen

In this chapter, we discuss the diseases and related pathologic alterations that may be encountered in the gastrointestinal tract and associated organs of various species of laboratory animals, birds, fish, reptiles, and amphibians. Diseases of various segments of the gastrointestinal tract, the salivary glands, liver, and pancreas are discussed and categorized as inflammatory, parasitic, neoplastic, or miscellaneous. The latter category includes developmental anomalies and metabolic lesions. Due to space limitations, this presentation is not an all-inclusive review, but it does provide a rather extensive review of these lesions. We have also included a rather comprehensive literature review, with a list of references for those readers who want more detailed information with respect to specific diseases.

The Digestive System

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.20408

Human prostate cancer risk factors.

Transformed epithelial cells were isolated by using tissue culture techniques from an irradiated human submandibular salivary gland which showed no neoplastic lesion. These cells, carrying colony-forming ability in semisolid agar, formed a semiconfluent monolayer with occasional tubular arrangement. All transformed clones were demonstrated by electron microscopic examination to be only one type of cells having fine structure similar to intercalated duct cells. Of six clones isolated, one clone with stable growth was cultured within the sponge matrix, resulting in formation of duct-like structure with mucinous eosinophilic substance. Moreover, inoculation of the cloned cells into nude mice resulted in a production of adenocarcinoma with solid and trabecular pattern. These findings indicate that a human intercalated duct cell line carrying tumorigenicity is established from a human submandibular salivary gland with an exposure to irradiation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819810801%2948%3A3%3C745%3A%3AAID-CNCR2820480314%3E3.0.CO%3B2-7

A neoplastic epithelial duct cell line established from an irradiated human salivary gland.

In contrast, the prostate is a rare site of tumor development in carcinogenesis bioassays in rodents (2,3) and in aging male laboratory rodents, with the exception of ventral prostatic neoplasms in some rat strains (4–9). Prostate cancer is also rare in male farm and companion animals, with the notable exception of the dog, which is the only species besides man that develops this malignancy. As will be discussed in this overview, steroid hormones can induce and can substantially enhance prostate carcinoma development in rodents, and this phenomenon has been exploited to further our knowledge about the involvement of hormonal factors and mechanisms in prostate cancer etiology. In this overview, the epidemiologic evidence for a role of steroid hormonal factors in prostate carcinogenesis is summarized first, followed by review of experimental data, a discussion of the possible mechanisms whereby steroid hormones, androgens as well as estrogens, may be involved in prostate cancer causation, and overall conclusions and suggestions for future research. As will be demonstrated, there is no lack of hypotheses about the role of steroid hormones in prostate cancer etiology, but the available data are often contradictory and incomplete, and an in-depth overall mechanistic understanding of how steroid hormonal factors are involved in prostate carcinogenesis is very limited.

/pdf/the-role-of-steroid-hormones-in-prostate-carcinogenesis-3g8apgkkxa.pdf

The role of steroid hormones in prostate carcinogenesis.

A pathological investigation was undertaken in Hiroshima on cases seen between 1945 and 1971 to determine the relationship between salivary gland tumors and exposure to atomic (A) bomb radiation. Of the 208 cases of histologically confirmed salivary gland tumors, 62 were A-bomb survivors and 146 were nonexposed. The relative risk based on the rate in the nonexposed for malignant tumors of salivary glands among the exposed in Hiroshima Prefecture was 11.0, while that of the submaxillary gland was 13.8 and that of the parotid gland was 9.8. They were all highly significant by X/sub 2/ test (P less than 0.001). The latent period of malignant salivary gland tumors was shorter in the exposed than in the nonexposed. Four cases of benign salivary gland tumor, all being benign mixed tumors of the parotid gland, were observed in children whose parents had been exposed. The incidence of mixed tumors of the salivary gland among the exposed in Hiroshima City was 2.0 times higher than that among the nonexposed and showed a tendency to increase with proximity to the hypocenter (P less than 0.01).

Salivary gland tumors in atomic bomb survivors, Hiroshima, Japan. II. Pathologic study and supplementary epidemiologic observations

An epidemiologic investigation was undertaken in Hiroshima to study the relationship of salivary gland tumors to exposure to ionizing radiation. Two hundred and eleven cases examined between 1953-1971 were confirmed by a review of histologic specimens. Of these, 66 cases occurred in residents of Hiroshima City who were born before the A-bomb: 30 among A-bomb-exposed, and 36 in non-exposed individuals. The incidence of salivary gland tumors among the exposed individuals was significantly higher, 2.6 times greater than that among the nonexposed individuals for all tumors, and 10 times greater for malignant tumors. The incidence increased with proximity to the hypocenter for the directly exposed. An increased incidence was also found among early entrants, particularly those entering the city within 3 days of the A-bomb.

Salivary gland tumors in atomic bomb survivors, Hiroshima, Japan. I. Epidemiologic observations.

Induction of gastric adenocarcinoma in mice by localized x-irradiation.

Summary A 31-month-old female mongrel dog was orally administered with 50 mg or 100 mg of N-nitrosobutylurea (NBU) in gelatin-capsule 3 times per week for 19 months with interposing periods of complete suspension.Thirty-four foci of signet ring cell carcinoma were found in the antral region of the stomach.The majority of the foci (31 foci) were early cancer, and the remaining foci were invasive cancer.In addition to these lesions, there was “a single gland cancer” in which a row of cancer cells was confined to a single gland.The whole gland was composed of two cell layers; the inner layer facing the lumen was normal gastric cells and the outer layer was atypical or neoplastic cells underlaid by the basement membrane.Mitosis was frequently observed on the bottom of the gland.Atypical or neoplastic cells seemed to mature gradually through a process of upward migration with increase in cytoplasmic Alcian blue-PAS and HID-AB positive mucin.Some of the cells rich in mucin moved into the lamina propria.The other cells remained in the flow of the regular cell renewal system of the normal gastric cells and reached the top of the gland.This observation revealed a mode of incipient gastric cancer growth, which starts and spreads within a single gland, before it invades the surrounding lamina propria.

A Mode of Incipient Growth in Chemically Induced Signet Ring Cell Carcinoma of the Canine Stomach

Subcutaneous injection of W/Fu rat stomach antigen emulsified with an equal volume of Freund's complete adjuvant at 1 week interval for a total of 2 administrations induced atrophic gastritis in A/HeJ mice. From the second week after the last injection the parietal cell mass decreased. At the same time, Alcian blue-PAS positive cells and Paneth-like cells appeared. Furthermore, the activity of alkaline phosphatase and disaccharidase of the small intestinal mucosa was biochemically demonstrated in the atrophic glandular stomach.

Fumio Hirose

Papers

Salivary gland tumors in atomic bomb survivors, Hiroshima, Japan. II. Pathologic study and supplementary epidemiologic observations

Salivary gland tumors in atomic bomb survivors, Hiroshima, Japan. I. Epidemiologic observations.

Induction of gastric adenocarcinoma in mice by localized x-irradiation.

A Mode of Incipient Growth in Chemically Induced Signet Ring Cell Carcinoma of the Canine Stomach

Morphological and biochemical changes in the gastric mucosa of A/HEJ mice injected with a xenogeneic stomach antigen