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In undertaking a quantitative estimation of carcinogenesis risk, it is essential to keep in mind that carcinogenesis is a multistage process, and that each stage can be affected by different classes of risk factors. Furthermore, different mechanisms are involved in the various stages of carcinogenesis. Thus, a dose-response analysis of one given factor cannot provide an accurate estimation of carcinogenic risk. Carcinogenic risk estimation is usually undertaken for a specific chemical or group of chemicals; however, the concept of multistage carcinogenesis is based on biological processes and not on the mechanisms of action of the agents involved. It is therefore important to consider three related, but different, factors involved in carcinogenesis: stage, agent, and activity of agent. This is especially important in developing a short-term test for stage-related risk factors, such as tumor-promoting agents. For this reason, carcinogens should not be classified according to only one chemical activity. This article briefly reviews the cellular and molecular mechanisms involved in multistage carcinogenesis, and discusses their implications for risk estimation. Special consideration is given to the effect of treatment frequency on the response of tumor-promoting agents, as seen in long-term tests in experimental animals. It is proposed that exposure frequency be taken into account together with exposure dose.
Cancer Metastasis Rev 1988 Apr
PMID:Multistage carcinogenesis: implications for risk estimation. 329 32

Mice were given i.v. injections of various tumor cell lines and, beginning 24 h later exposed for 3 weeks to 70% oxygen. Hyperoxia reduced the number of lung colonies derived from MT-7 cells (originally a mammary carcinoma) and of the lung-tumor derived cell lines 498 and Line-1 early passage. Lung colonies derived from Line-1 late passage, lines M109, B16-F10 and Lewis lung carcinoma were oxygen resistant. Lung metastases following i.m. injection of MT-7 cells were oxygen-sensitive and metastases derived from B16-F10 cells or Lewis lung carcinoma were oxygen resistant. Pre-exposure of mice for 48 h to 100% oxygen enhanced colony formation for all cell lines examined whereas exposure to 100% oxygen after i.v. injection only curtailed the growth of the cell lines previously shown to be sensitive to 70% oxygen. There was no correlation between oxygen sensitivity or resistance and the levels of total glutathione or activities of superoxide dismutase (SOD), glutathione reductase or peroxidase or glucose 6-phosphate dehydrogenase in the cell lines. However, upon injection in mice a resistant cell line increased its anti-oxidant defense mechanisms while growing in vivo whereas a sensitive cell line failed to show such adaptation.
Carcinogenesis 1988 Mar
PMID:Effects of hyperoxia on growth of experimental lung metastasis. 334 81

Diminished blood selenium levels have been associated with increased risk of gastrointestinal cancers in man, while dietary selenium supplementation reduces the incidence of experimental colon cancer in rats. However, no previously published data are available concerning selenium and the evolution of colon cancer from benign neoplastic colonic polyps through localized and metastatic cancer. To assess any influence of selenium on this polyp to cancer sequence, we measured plasma and erythrocyte selenium levels in colonoscopically and histologically evaluated patients with adenomatous polyps (group I), locally resectable colon cancer (group II), metastatic colon cancer (group III), and selected colonoscopy negative controls (group IV). We found no difference in selenium levels between groups IV versus groups I or II. Likewise, within group I, no difference in selenium was present for different polyp histologies or numbers of polyps. However, selenium levels did drop progressively (p = 0.028, ANOVA) from polyp (group I) to local cancer (group II, p = NS vs group I) to metastatic cancer (group III, p less than 0.05 vs group I or group II). Parallel changes were seen in both plasma and erythrocyte levels, suggesting that these selenium abnormalities are of long duration, reflecting tissue stores, and therefore capable of influencing cancer risk. We conclude that selenium stores may not be an important factor in the de novo formation of benign neoplastic colonic polyps. Although these data suggest that selenium does not affect the polyp-cancer sequence, it is possible that a subset of patients with polyps and the lowest selenium levels are at higher risk for malignant transformation. However, these human data do not support a significant role for selenium in colon carcinogenesis.
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PMID:Selenium status and the polyp-cancer sequence: a colonoscopically controlled study. 338 7

This investigation was based on an epidemiologic association of milk consumption and decreased intestinal cancer risk. Furthermore, there is also some indirect evidence that calcium supplementation in humans and animals may decrease colon cancer risk and that calcium, by inference, may be the protective factor in milk. In order to investigate these associations in a controlled laboratory setting, dietary supplementation of low fat dried milk (37 g/kg diet; N = 18) and calcium carbonate (40 mg/kg rat/day; N = 17) were compared separately to regular diet controls in the rat-dimethylhydrazine colon carcinogenesis model. The results of this investigation showed that neither milk-supplemented rats nor calcium carbonate-supplemented rats had fewer DMH-induced colorectal (P = .374) or total gastrointestinal tumors (P = .291) than did regular diet controls (N = 10; by analysis of variance [ANOVA]). Milk supplementation did result in a significant decrease in tumor burden when measured by incidence of metastases (P = .035) and of intestinal obstruction (P = .011; by chi-square test), when compared with calcium-supplemented and control rats. Though this implies that milk supplementation provides protection against some aspects of carcinogenesis of the colon, in rats fed low fat diets, this does not appear to be mediated through the calcium content of milk.
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PMID:The effect of dietary milk and calcium on experimental colorectal carcinogenesis. 369 Dec 67

Carcinogenic potency (TD50) estimated from the results of 88 NCI/NTP carcinogenesis bioassays was examined by common target sites in rats and mice. Other indicators of a chemical's hazard were investigated, including whether tumors were induced at more than one site in a single sex-species group of test animals, whether tumors may have caused the death of the animal or were found at sacrifice, and whether metastases of induced tumors occurred. These hazard indicators are sometimes interrelated; however, the potency (TD50) values of chemicals which are hazardous by each of these measures spanned a wide range. Carcinogens which caused some type of fatal tumor were more likely than other carcinogens to cause tumors in multiple organ sites and multiple sex-species groups. Since these other hazard indicators were not related to carcinogenic potency, they should be included along with potency estimates such as the TD50 in summarizing the potential dangers of human exposures to a carcinogen and in comparisons of hazard among carcinogens.
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PMID:Association between carcinogenic potency and tumor pathology in rodent carcinogenesis bioassays. 371 36

Among the nitro-naphthofurans, 7-methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) has been proved to be a very potent mutagen. The purpose of this study was to demonstrate the carcinogenicity of a R 7000 to male Wistar rats initially 6 weeks old. R 7000 was dissolved in olive oil at a concentration of 1 mg/ml for injection. A S.C. injection of 0.5 ml containing 0.5 mg of R 7000 was given once a week in the neck of each animal tested. Ten control animals were not injected and 10 animals received a 0.5 ml injection of olive oil every week to serve as control. The remaining 70 animals were divided into five groups. Four groups of 10 animals received a total of either 2.5 mg, 5 mg, 7.5 mg or 10 mg of R 7000; the fifth group of 30 animals received 12.5 mg of R 7000. In animals which did not receive R 7000, no malignant tumor was observed. In those to whom R 7000 was administered tumors began to appear at the site of the injection after the third month. At the sixth month of the experiment, most of the animals injected had a tumor at the injection site. The number of tumor-bearing animals and the time between the first injection and the tumor appearance were closely related to the dose of R 7000 injected. These tumors were high grade fibrosarcomas, one animal developed a salivary fibrosarcoma. No other tumors or metastases were found in the autopsied animals. The high carcinogenicity of R 7000 in vivo is analogous to that of methylcholanthrene. The exact mechanism of action of 2-nitro-naphthofurans as carcinogens remains to be explained.
Carcinogenesis 1985 Jan
PMID:Induction of sarcomas in rats by subcutaneous injection of 7-methoxy-2-nitro-naphtho[2,1-b]furan (R 7000). 396 29

The most important target in pharmaceutical therapy against cancer is complete suppression of metastases and recurrence after curative surgical operation. It is fundamentally, a growth inhibition and regression of small number of autochthonous tumors scattering in the host, and coexistence between tumor and host is also important. As immunosuppressive anticancer drugs have detrimental effects for patients in such cases, application of strong immunopotentiators such as lentinan should be expected. Lentinan showed a prominent effect on suppression of metastases in experimental systems of clinical models using MH-134 hepatoma, Madison-109 lung carcinoma and DBA/2.MC.CS-1 fibrosarcoma. Suppression of carcinogenesis may be considered as one of experimental methods to prevent metastases in a viewpoint of regression of small number of autochthonous tumor cells. Lentinan given at suitable timing and schedule showed marked prophylactic effect on chemical and viral carcinogenesis. Mode of action of lentinan as T-oriented adjuvant in its antitumor and metastases-inhibitory effects is also discussed. Considering excellent end-point results of Phase III with advanced and recurrent gastrointestinal cancer, lentinan is the most hopeful substance to prevent micrometastases.
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PMID:[Experimental studies on growth inhibition and regression of cancer metastases]. 400 87

The development of a satisfactory rodent model for cancer of the large intestine began with the discovery by Laqueur and associates in 1962 that the plant product, cycasin (methylazoxymethanol glycoside), is a potent carcinogen for rodents. Soon after that, DMH, AOM, and MAM were found to be even more efficient intestinal carcinogens in rats. These three compounds, plus two direct acting carcinogens (MNNG, MNU) are used almost exclusively in current animal investigations. Although all these chemicals have some degree of activity in all rodents, they are most effective in rats. Various rat strains differ somewhat in susceptibility, Sprague-Dawley being the most sensitive to these carcinogens. Cancers of the large intestine in the animal model resemble adenocarcinomas in humans, and they spread in a similar manner except that metastases to the liver and lung are very uncommon in animals. Animal studies support epidemiological and human experimental observations of dietary factors involved in colorectal cancer formation. Most physicians believe that the majority of colorectal cancers develop from preexisting adenomas. Morson has shown that large adenomas and villous adenomas have a greater risk of developing cancer than small adenomas. Hill has theorized that there are different factors responsible for the formation of small adenomas from normal mucosa, for the growth of small to large adenomas, and for the development of cancer from large adenomas. Animal studies provide some support for this concept. Weak intestinal carcinogens tend to induce more benign adenomas than carcinomas. Very small doses of strong carcinogens also induce some adenomas and a few early polypoid intestinal cancers after a long latent period. Moderate to large amounts of DHM, for example, induce only malignant lesions even when these lesions are as small as 1 mm. These observations suggest a relationship between adenomas and carcinomas. There is also biochemical evidence to support the staged progression of carcinogenesis. An example is the graded increases in ODC activity that occur in tissues undergoing tumorigenesis.
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PMID:Animal model for colorectal cancer. 403 97

To lay the groundwork for subsequent chapters in this monograph of multiple primary cancers in Connecticut and Denmark, we present a description of the historical significance of previous studies, focusing on key surveys that have enhanced our understanding of the origins of multiple cancers. Case reports, hospital series, and cancer registry studies have progressively sharpened our perspective on the patterns and causes of multiple cancers. These findings in turn have generated hypotheses about host and environmental determinants of various combinations of cancer and have provided clues to the actual mechanisms of carcinogenesis. The registries of Connecticut and Denmark which began in the 1930s and 1940s, respectively, afford investigators a unique opportunity to analyze the cancer experience of well-defined populations, followed for long periods. The major contribution of this monograph is the evaluation of second cancer risks among long-term survivors of cancer, including relatively rare tumors about which little information currently exists. For patients with a particular cancer, the number of observed second cancers are tabulated over time and compared with those expected if the patients experienced the same rates prevailing in the corresponding general population. We have discussed problems in distinguishing statistical artifacts from biologically plausible associations in light of the potential biases inherent in follow-up surveys of cancer patients; for example, heightened medical surveillance and mistaken metastases could result in false indications of elevated risk. Several differences in the reporting, follow-up, and coding practices between the Connecticut and Denmark registries are described and probably account for many differences in the reported findings.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Introduction to the study of multiple primary cancers. 408 4

Human epithelial cells contain, intermediate-sized filaments formed by polypeptides related to epidermal alpha-keratin ("cytokeratins") which are expressed in different combinations in different epithelia. Using cytoskeletal proteins from human biopsies and autopsies we have examined, by two-dimensional gel electrophoresis and immunoblotting experiments, the cytokeratin polypeptide patterns of diverse primary and metastatic carcinomas and have compared them with those of corresponding normal epithelial tissues and cultured cells. Five groups of carcinoma cytokeratin patterns can be discriminated. (1) Cytokeratins typical of simple epithelia (polypeptides Nos. 7, 8, 18, 19) are expressed, in various combinations, by many adenocarcinomas, for example those of gastrointestinal tract. (2) Cytokeratins typical of stratified epithelia (Nos. 1, 5, 6, 10, 11, 14-17) are found, in various combinations, in squamous cell carcinomas of skin and tongue. (3) Complex patterns showing polypeptides Nos. 7, 8, 18, 19, and one basic component (No. 5 or 6) are detected in certain carcinomas of the respiratory tract and the breast. (4) Complex patterns containing cytokeratins widespread in stratified epithelia (Nos. 4-6, 14-17) as well as components Nos. 8 and 19 occur in diverse squamous cell carcinomas derived from non-cornified stratified epithelia, with or without additional small amounts of cytokeratin No. 18. (5) Patterns of unusually high complexity can be found in some rare tumors as is shown for a cloacogenic carcinoma. No significant qualitative changes of expression of cytokeratins were found when primary tumors and metastases were compared. When compared with cytokeratin patterns of normal epithelia, carcinomas of the first type usually display a high degree of relatedness to the tissue of origin. Other carcinomas do not express some of the cytokeratins present in the tissue of their origin and, vice versa, certain components which are minor or apparently absent in normal tissue are major cytokeratins in the corresponding tumor. These differences may be explained by cell type selection during carcinogenesis, but changes of expression during tumor development cannot be categorically excluded. The possibility of cell type heterogeneity within a given tumor is also discussed. Similarly complex patterns of cytokeratin polypeptides have been noted in certain cultured human carcinoma cell lines (e.g., A-431, RPMI 2650, Detroit 562, A-549) and can also be observed in cell clones. The possible value of analyses of cytokeratin patterns, by gel electrophoresis or specific monoclonal antibodies, in distinguishing different carcinomas by non-morphologic criteria is discussed.
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PMID:Complex cytokeratin polypeptide patterns observed in certain human carcinomas. 618 57


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