A locus that influences susceptibility to 1, 2-dimethylhydrazine-induced colon tumors maps to the distal end of mouse chromosome 3.

While inheritance of mutated alleles of highly penetrant tumor suppressor genes such as retinoblastoma or p53 predisposes individuals to a greatly increased risk of developing cancer, epidemiological data indicate that the majority of sporadic tumors in humans result from interactions of environmental and host genetic factors. The host genetic factors are poorly penetrant tumor susceptibility genes that determine the likelihood that a cancer will arise from carcinogen exposure. The majority of colon tumors in humans are sporadic in nature. 1,2-dimethylhydrazine (DMH)-induced colon tumors in mice provide a useful animal model to identify genes that influence susceptibility to carcinogen-induced colon tumors in humans. A genome-wide scan of genetic crosses of relatively sensitive C57BL/6J with relatively resistant CBA mice treated with DMH revealed a linkage of DMH susceptibility with the distal end of mouse chromosome 3, suggesting that one or more tumor susceptibility genes may map to this region.

[The effect of prenatal diethylstilbestrol treatment on 1,2-dimethylhydrazine-induced carcinogenesis in C3HA female mice]. / Vliianie prenatal'nogo vozdeistviia diétilstilbéstrola na kantserogenez, indutsiruemyi 1,2-dimetilgidrazinom u myshei-samok linii C3HA.

C3HA female mice received 0.1-0.3 mg/g body weight diethylstilbestrol (DES) on day 17 of gestation. Their descendants received a total of 20 injections of 1.2-dimethylhydrazine (DMH), subcutaneously, weekly, starting from month 2. Prenatal DES significantly inhibited the development of DMH-induced clitoral gland tumors, particularly, hemorrhagic ovarian cysts which were the frequent cause of death due to their rupture into the abdominal cavity. A significant decrease in cyst incidence resulted in higher survival in mice receiving combined therapy. The results were attributed to DES-induced hyperestrogenization which was confirmed by vaginal smears examination.

1,2-Dimethylhydrazine carcinogenesis in C3HA and CBA female mice prenatally treated with diethylstilbestrol.

C3HA and CBA female mice received a single intraperitoneal (i.p.) injection of 0.1 or 0.3 mg/kg body weight (b.w.) of diethylstilbestrol (DES) at day 17 of pregnancy. The descendants, starting from the age of 2-3 months, were receiving weekly subcutaneous (s.c.) injections of 1,2-dimethylhydrazine (DMH) (8 mg/kg b.w.), total 20 injections. The survival of C3HA mice treated with DMH together with prenatal DES was considerably better than in mice treated with DMH alone, this being due to the strong inhibiting effect of DES on the induction by DMH of the hemorrhagic ovarian lesions (78.4% in DMH alone vs. 53.3 and 43.7% in groups with DES plus DMH), which frequently were the cause of animal death. Prenatal DES also inhibited the induction by DMH of clitoral gland tumors: 51.4% in the group with DMH alone vs. 26.6 and 28.1% in two groups of DES plus DMH, respectively. DES treatment, at the above doses, did not influence significantly the DMH carcinogenesis in CBA mice. Prenatal DES given to CBA mice at the dose of 1 mg/kg b.w. significantly increased the incidence of DMH-induced uterine sarcomas (42.8% vs. 73.3% in the group with DMH alone and the group receiving DMH together with prenatal DES, respectively) and accelerated their growth. The effects of prenatal DES on DMH-induced carcinogenesis correlated with the degree of hyperestrogenization produced in both strains of mice by DES.

[1,2-dimethylhydrazine induction of epithelial tumors of the kidneys in CBA strain mice]. / Induktsiia 1,2-dimetilgidrazinom épitelial'nykh opukholei pochek u myshei linii CBA.

The results of experiments on the 1,2-dimethylhydrazine (DMH) induction of epithelial renal tumours in CBA male mice are presented. The dose-response study shows a sharp increase (from 5 to 75%) of the epithelial renal tumour incidence in the range of 2, 4 and 8 injections of DMH. Higher doses induce a decrease of the tumour incidence due to the early death caused by other tumours. DMH is shown to be the most powerful renal carcinogen in mice. Serial sacrifice of mice after 5 injections of DMH is a convenient model for the study of renal carcinogenesis in mice. Main histological types of epithelial renal tumours are illustrated.

Carcinogenicity of deuterium-labeled 1,2-dimethylhydrazine in mice.

To study the effect of deuterium substitution on the carcinogenicity of 1,2-dimethylhydrazine (DMH) in mice, two comparisons were made between DMH and its fully methyl-deuterated analogue, [2H6]DMH. In a lifetime study with the CBA strain, groups of 19-30 animals of each sex were dosed s.c. weekly with 8 mg/kg of either DMH or [2H6]DMH for 8, 16, or 32 weeks. In the second study, female CF-1 mice were given DMH or [2H6]DMH in 10 weekly s.c. doses of 12 mg/kg each (13.2 mg/kg for [2H6]DMH) and examined for colon tumors 36 weeks after the first dose. Deuteration significantly decreased tumor incidence in the colon of males (P less than 0.01) and the anal tissue of both sexes (P less than 0.05) but increased that of hepatomas and lung tumors in males (P less than 0.01). Substrate deuteration did not significantly affect overall incidence of any other tumor type, however, including hemangioendotheliomas and kidney tumors in both sexes, as well as colon, uterine, ovarian, liver, and lung tumors in females. The results indicate that C--H bond breakage is kinetically important in the activation of DMH to its ultimately carcinogenic form in organs such as the male colon (relative risk in DMH-versus [2H6]DMH-treated animals approximately equal to 6), and that inhibition of this process by substrate deuteration allows a diversionary mechanism having a smaller isotope effect to become relatively more extensive. The qualitatively different effect in other organs (e.g., kidney, relative risk approximately equal to 1) supports recent suggestions that the net mechanism of activation can differ from one target tissue to another, possibly by striking a different balance between parallel metabolic pathways. The lack of a significant isotope effect on overall colon tumor incidence in females of either strain suggests that differences in relative importance among competing enzymes may also be responsible for sexual dimorphism in tumor induction by DMH.

[Influence of the rhythm and route of 1,2-dimethylhydrazine administration on its carcinogenic effect in mice]. / Vliianie ritma i puti vvedeniia 1,2-dimetilgidrazina na ego kantserogennyi éffekt u myshei.

Effects of route of administration (subcutaneous, intraperitoneal, by stomach tube and with drinking water) and dose fractionation on the carcinogenicity of 1,2-dimethylhydrazine (DMH) were studied in CBA and (C57B1/6j X CBA)F1 mice. Fractionation of DMH dose given subcutaneously exerted different effects on tumors at various sites: decrease of colon and anal tumor incidence, increase of vascular liver tumors and renal adenomas and no influence on hepatoma, lung adenoma and uterine sarcoma induction. When given with drinking water, DMH did not induce colon and anal tumors but produced high incidence of vascular neoplasms. No such effect was observed when DMH was administered weekly by stomach tube. Alteration of the organotropism of DMH given with drinking water is attributed by authors to the decrease of single DMH dose and not to peroral route of administration.

Strain differences in susceptibility of female mice to 1,2-dimethylhydrazine.

C3H, CBA, C57BL/6j, (CBA x C57BL/6j)F1, BALB/c, DBA/2, C3HA and AKR female mice were treated with 25 weekly s.c. injections of a solution of 1,2-dimethylhydrazine (DMH) in water at a dose level of 8 mg/kg body weight. BALB/c mice appeared to be most sensitive to the induction of epithelial colorectal (93.3%) and anal tumours by DMH. There was, however, a dissociation between the severity of the macroscopical tumour lesions in the colon of BALB/c mice and their relatively weak tendency to infiltrative growth. C3HA mice were more resistant to the induction of intestinal tumours (30.9%) but the tumours showed a deep invasion into the intestinal wall. There was no correlation between the strains and within a given strain between the development of colorectal and anal neoplasms. C3H and CBA mice strains developed a high incidence of uterine sarcomas (37.5 and 40.7%, respectively) which were not found at all in BALB/c, DBA/2 and C3HA mice and which appeared in C57BL/6j and AKR mice at low frequency (2.7 and 7.7%, respectively). C57BL/6j, BALB/c, DBA/2 and C3HA mice developed haemorrhagic lesions of the ovaries (35.1, 46.7, 62.9 and 85.7%, respectively). These lesions, which led to peritoneal haemorrhage, were one of the main causes of death in C3HA and DBA/2 strains. It seems that, with the exception of AKR mice, an inverse relationship exists between the occurrence of haemorrhagic ovarian lesions and development of uterine sarcomas in female mice treated with DMH.

[Effect of age on induction of intestinal tumors in mice by 1,2-dimethylhydrazine]. / Vliianie vozrasta na induktsiiu 1,2-dimetilgidrazinom opukholei kishechnika u myshei.

1,2-Dimethylhydrazine was administered subcutaneously in a dose of 8 mg/kg bw to 2-, 8- and 12-month-old female CBA mice for 25 weeks. The animals were serially killed 26-35 weeks after the beginning of treatment. The incidence of colon tumors in 2-month-old mice was always significantly lower (P less than 0.001) than in 8- or 12-month-old mice. The incidence of tumors with invasive growth in 12-month-old mice was significantly higher (P less than 0.05) than in 8-month-old mice. Mathematical evaluation allowed the conclusion about the 1.8-fold shortening of the colon tumor latency period in old mice as compared to the young mice.

[Pararenal angiosarcoma as a manifestation of sexual dimorphism in carcinogenesis]. / Pararenal'naia angiosarkoma kak proiavlenie polovogo dimorfizma v kantaserogeneze.

Pararenal angiosarcoma developed in 42% of CBA male mice injected subcutaneously 1.2-dimethyl hydrazine (DMH) in a dose of 8 mg/kg body weight within 30 weeks. None of 176 CBA female mice given the same treatment developed such tumors. Histologically, the tumors represented various angiosarcomas characterized by a marked invasive growth into the renal parenchyma.

Non-epithelial uterine tumours induced in CBA mice by 1,2-dimethylhydrazine.

In CBA mice treated with weekly subcutaneous injections of 1,2-dimethylhydrazine an unusually high incidence of uterine sarcomas was observed in two successive experiments. The tumours are easily transplantable. The description of their histological structure is presented and their histogenesis is discussed.

[Tumors in CBA line mice caused by 1,2-dimethylhydrazine]. / Opukholi myshei linii CBA, vyzvannye 1,2-dimetilgidrazinom.

Female CBA mice were treated weekly with subcutaneous injections of 1,2-dimethyl-hydrazine (8 mg/Kg b. w.) for 38--40 weeks. All animals but one developed tumors, mainly of the uterus, and region and intestine. Uterine tumors were most likely endometrial sarcomas, although myometrial and vascular components were also present. Large tumors of the anal region were squamous cell or baso-squamous carcinomata, while small growths were sebaceous adenomas or basal-cell tumors. 1.2-dimethylhydrazine appears to be a more multipotent carcinogen for mice than for the rat. Uterine sarcomas are of special interest in view of their rarity in mice.