Publisher Summary This chapter provides information on lung tumors in mice, with emphasis on the use of mouse lung for quantitative investigations in carcinogenesis, especially bioassay of chemicals for carcinogenic activity. The lung-tumor response in strain A mice is easily and clearly positive to all major types of chemical carcinogens. Strain A mice are the most susceptible to a wide variety of carcinogens, in terms of the earlier appearance and greater multiplicity of tumors. The lung-tumor response in strain A mice is easily and clearly positive to all major types of chemical carcinogens. Estrogenic and other steroid hormones, with the targets of endocrine-regulated tissues, are an exception. The lung tumor of the mouse has demonstrated its ability to pick up undetected, unpredicted neoplastic responses such as to urethane and to isoniazid. The carcinogens picked up by the lung tumor system have been shown to be carcinogenic for other tissues and in other species of animals. The mouse lung tumor is a reproducible, stable, and rapid biological model for a wide variety of quantitative investigations in carcinogenesis. It provides a three-dimensional lattice of the lung in which a known, identifiable subpopulation of cells—the type 2 alveolar pneumocytes—can be accelerated into conversion into neoplasms.

Lung tumors in mice: application to carcinogenesis bioassay.

Nitrosoureas form O6-alkylguanine-DNA adducts that are converted to G to A transitions, the mutation found in the activated ras oncogenes of nitrosourea-induced mouse lymphomas and rat mammary tumors. These adducts are removed by the DNA repair protein O6-alkylguanine-DNA alkyltransferase. Transgenic mice that express the human homolog of this protein in the thymus were found to be protected from developing thymic lymphomas after exposure to N-methyl-N-nitrosourea. Thus, transgenic expression of a single human DNA repair gene is sufficient to block chemical carcinogenesis. The transduction of DNA repair genes in vivo may unravel mechanisms of carcinogenesis and provide therapeutic protection from known carcinogens.

https://science.sciencemag.org/content/sci/259/5092/219.full.pdf

The prevention of thymic lymphomas in transgenic mice by human O6-alkylguanine-DNA alkyltransferase.

At a level which was effective as a skin tumor promoter, croton oil increased the rate of incorporation of tritiated precursors into mouse skin macromolecules. After a single application of croton oil, the early 2- to 3-fold stimulation of RNA and protein synthesis and the 60% inhibition of DNA synthesis was followed by a 3-fold stimulation of DNA synthesis at 18 hr. The rates of macromolecular synthesis returned to normal levels within 7 days. A single application of cantharidin, a weak tumor promoter, stimulated both DNA and RNA synthesis in mouse skin. Treatment with either croton oil or cantharidin stimulated the synthesis of rapidly labeled RNA when measured 2 hr after treatment; stimulation of RNA synthesis may be important in the process of promotion. When an incision was made in initiated skin, tumors developed along the line of wound healing. Because croton oil, cantharidin, and other promoters cause hyperplasia and because wound healing causes a local stimulation of mitosis, a stimulation of cell division may be involved in promotion. A possible molecular mechanism of skin carcinogenesis is discussed.

https://cancerres.aacrjournals.org/content/canres/30/2/312.full.pdf

Studies on the mechanism of skin tumor promotion.

Mutagenic and carcinogenic N-nitroso compounds: possible environmental hazards.

Publisher Summary Although the field of chemical oncogenesis in culture depends upon the fundamentals and advances in cell biology, virology, biochemistry, and other related disciplines, it is clearly impossible to cover these other fields. Although most of the work has been done with cell cultures, but organ cultures are also considered in this chapter. Organ cultures consist of small 3-dimensional pieces of differentiated tissues that are usually maintained on top of the nutrient medium. Cell cultures consist of individual cells submerged in the medium that grow either on a glass or plastic substrate or in suspension. The more important systems, such as 3T3-like systems, other cell systems, and liver cell systems are described in the chapter, followed by some of the major generalizations that can be drawn from the various researches involving these systems. The many advantages of studying biological phenomena in cell cultures, rather than in intact animals, include the ability to control the environment, to do quantitative bookkeeping of the cells, to vary the exposure to chemicals, to synchronize the cells, and to be free of the immunological milieu of the host.

Chemical oncogenesis in culture.

The toxic and carcinogenic actions of four methylnitrosamine or -amide compounds, given as a single intraperitoneal injection to newborn and adult inbred Swiss mice, were examined.

Toxicity was approximately directly proportional to the stability of the three compounds capable of methylating macromolecules in vitro .

Methylnitrosourea induced a high incidence of thymic lymphomas in adults and newborns of either sex. Dimethylnitrosamine induced a high incidence of hepatomas in newborns only. These two drugs, as well as methylnitrosourethan and methylnitroso- p -tolylsulfonamide, induced a high incidence of pulmonary adenomas.

Mice given a single sublethal intraperitoneal injection of methylnitrosourea underwent cell depletion of the thymolymphoid and myeloid systems, followed by recovery. These events occurred more rapidly in the myeloid systems than in the thymolymphoid system. These events may represent steps in the genesis of lymphomas induced by methylnitrosourea.

Toxicity, Tissue Changes, and Tumor Induction in Inbred Swiss Mice by Methylnitrosamine and -amide Compounds

Comment on epidermal hyperplasia and tumor promotion

Influence of Methylnitrosourea on Malignant Transformation of Mouse Embryo Cells in Tissue Culture

Summary Because of the possibility of cocarcinogenic effects of substances to which many people are exposed, the mechanism of action of one such agent was examined in 2-stage tumor induction experiments. The appearance of new tumors was studied at the end of a series of croton oil treatments, or between treatments given at long intervals in mouse epidermis given a single pretreatment with a carcinogen. During a series of treatments with croton oil, the tumor-enhancing effect of any single treatment persisted for 2 to 3 weeks. Tumors were enhanced by as few as 2 croton oil treatments when given 3 weeks apart, and it was also demonstrated that the concentration of croton oil was more important in tumor enhancement than the absolute amount.

/pdf/features-of-tumor-enhancement-by-croton-oil-8w8at8hiya.pdf

J. V. Frei

Papers

Toxicity, Tissue Changes, and Tumor Induction in Inbred Swiss Mice by Methylnitrosamine and -amide Compounds

Comment on epidermal hyperplasia and tumor promotion

Influence of Methylnitrosourea on Malignant Transformation of Mouse Embryo Cells in Tissue Culture

Features of tumor enhancement by croton oil.

Initial cell cycle delay and depression of macromolecular synthesis of primary mouse embryo cells treated with methylnitrosourea in mass culture