Metastasizing tumors in rats treated with alkylating carcinogens

Tumors induced in approximately 2000 F344 rats by a number of carcinogenic N-nitroso compounds have been examined for their propensity to metastasize. The objective was to discover relations between the structure of the carcinogen, the tumor induced and the proportion of tumors that formed metastases. Treatments consisted of multiple doses of one of 16 nitrosamines or 19 alkylnitrosoureas, which were administered in drinking water, by gavage or by the intravesicular route. Male and female rats were included. Most of the carcinogens were mutagens in bacteria, but some were not; this had no bearing on the tendency of induced tumors to metastasize, nor did the extent of alkylation of DNA produced in vivo. Fewer malignant tumors appeared in the rats treated with nitrosamines than with alkylnitrosoureas, but more than twice as many of the former metastasized; many were carcinomas or hemangiosarcomas of the liver, of which very few were induced by alkylnitrosoureas. Tumors of the liver, lung, mammary gland and forestomach metastasized most commonly, whereas those of the esophagus, nasal mucosa, Zymbal gland, kidney mesenchyme, thyroid, urinary bladder and mesotheliomas seldom formed metastases; none of the tumors of the brain or intestines metastasized; no differences between males and females were noted. Some rare tumors, osteosarcomas and thymus lymphomas, metastasized frequently. The lungs and lymph nodes were the most common sites for metastases, but less frequently liver, heart, kidney, adrenal gland, omentum, peritoneum, esophagus and pancreas were involved. Higher doses were associated with greater numbers of metastasizing tumors among mutagenic or non-mutagenic carcinogens, as has been reported elsewhere. It appears that directly alkylating alkylnitrosoureas are no more likely (and probably less likely) to induce tumors with metastatic properties than are nitrosamines that require metabolic activation to form reactive proximate carcinogens.