Temporal advancement of diethylnitrosamine carcinogenesis in aging mice.

Female BALB/c mice were given diethylnitrosamine (DEN) in their drinking water beginning at 2.5, 9.5, and 17 months of age (cumulative dose approximately 300 to 400 mg/kg body weight) or were untreated. Median times of death for the treatment groups were 193, 168, and 125 days, respectively, after cessation of DEN treatment and were significantly different (p less than .01). Induced tumors in the three respective age groups were of squamous forestomach (88, 87, and 84%), vascular tumors of the liver (11, 13, and 16%), and adenomas of the lung (65, 56, and 54%). Controls had no forestomach or liver tumors and relatively low incidences of lung tumors. The fact that aging mice have similar incidences and types of tumors of the same size and in the same tissues, but at an earlier time, shows that (1) DEN is carcinogenic in aging BALB/c mice; (2) age at treatment does not alter the tumor-susceptible tissue nor types of tumors after DEN treatment; (3) tumor incidences are not affected by age at time of treatment; (4) mice die earlier with induced tumors with increasing age at time of treatment; (5) age-matched non-DEN-treated mice die from different diseases (leukemias) than do DEN-treated mice (stomach and liver tumors). These observations may be related, in part, to an identified age-dependent decrease in immunocompetency or to other age-related changes, such as vascular or hormonal, which could explain temporal advancement in the tumorigenic process.

A positive correlation between declining immune competence and early mortality associated with diethylnitrosamine carcinogenesis in aging mice.

The effect of age (2.5, 9.5, and 17 months) at time of treatment upon diethylnitrosamine (DEN) carcinogenesis and immune competence has been assessed in female BALB/c mice. Median times of death were 193, 168, and 125 days, respectively, after termination of DEN treatment. Immune competence as a measure by both cell-mediated and humoral immune parameters immediately after DEN treatment was not significantly different among treated and age-matched non-treated control animals. In contrast, a significant age-related decline in immune competence was seen in both DEN-treated and non-treated controls, thereby demonstrating a direct and positive correlation between the natural age-related decrease in immune competence and cancer-induced advanced mortality.

Selective sex-related modification of diethylnitrosamine-induced carcinogenesis in BALB/c mice by concomitant administration of butylated hydroxytoluene.

Tumor induction in BALB/c mice by diethylnitrosamine (DENA) was shown to be sex related. Female mice killed 13.5 months after DENA exposure generally had higher incidences of forestomach and lung tumors than did males and also had higher numbers of lung tumors per tumor-bearing mouse. Although neither sex developed stomach tumors spontaneously, males had higher incidences of spontaneous lung tumors than did females (45 vs. 26%). When butylated hydroxytoluene (BHT) was given concomitantly with DENA treatment, females had an increased survival (68 vs. 43%) and a reduced incidence of forestomach squamous cell carcinomas (77 vs. 100%) compared with females given DENA alone. No such protective effect on survival or on the occurrence of stomach tumors was seen in males given BHT and DENA or on lung tumorigenesis in either sex. In males, BHT given alone increased survival of treated mice over that of untreated controls, but it had no such effect on the females. The results of this study suggested an as yet unexplained hormonal influence and/or dependence for this BHT modification of DENA tumorigenesis.

Diseases of aging untreated virgin female RFM and BALB/c mice.

Diseases of untreated, virgin female barrier-maintained RFM and BALB/c mice used as controls in a large radiation aging experiment were necropsied after natural death. The spectrum and incidence of neoplastic and nonneoplastic diseases were somewhat different in the two strains. Both strains show a high incidence of neoplasma (largely reticulum cell sarcomas and lung tumors) and of glomerulosclerosis. A wide variety of other diseases was noted in much lower incidence. The findings in the RF were briefly compared with those in earlier experiments with that strain in this laboratory.