[Influence of dichlorodiphenyldichloroethylene on 1,2 dimethylhydrazine-induced androgen-dependent renal capsule angiosarcoma development].

The study was concerned with the influence of dichlorodiphenyldichloroethylene (p,p'-DDE) on 1,2 dimethylhydrazine (DMH)-induced androgen-dependent renal capsule angiosarcoma (RCA) in male CBA mice. p,p'-DDE was shown to significantly decrease the incidence of DMH-induced RCA (69.0% vs. 44.1%). That could be accounted for by the anti-androgen affinity of p,p'-DDE. It is suggested that exposure to p,p'-DDE might inhibit androgen-receptor containing tumors.

[Cancinogenic effects of fast helium ions with energy of 4 GeV/nucleon in rats].

The study was made of carcinogenic efficiency of 4 GeV/nucleon helium ions (LET = 0.88 keV/um) in comparison with gamma-radiation 60Co (LET = 0.23 keV/um). Adult outbred female rats underwent a single whole-body irradiation with helium ions in doses 0.25-4.0 Gy at the Synchrophasotron of the Joint Institute for Nuclear Research and with gamma-rays at "PX-gamma-30" irradiator in doses ranged from 0.5 to 4.0 Gy. The yields, histology and occurrence time of hemoblastoses and tumours in mammary glands, in endocrine glands, in soft tissues and in other organs were determined. Histological study was made using conventional methods. The irradiation of experimental animals with accelerated helium ions and standard radiation was shown to result in an increase in the yield of growths of various localizations with decreasing occurrence time and expanding histological spectrum as compared with intact rats. However, helium ions possess a higher carcinogenic efficiency. The coefficients of relative biological effectiveness of helium ions calculated by the nonparametric method appeared to increase with decreasing the radiation dose.

Morphology and histogenesis of anal region and clitoral gland tumors induced in mice by 1,2-dimethylhydrazine.

Ninety-seven tumors induced in the anal region in female CBA and BALB/c mice by 1,2-dimethylhydrazine were examined histologically. Tumors originated mainly from the following sources: epidermis (papillomas and basal cell neoplasms), pilosebaceous complexes of the anal region (keratoacanthomas, cystic squamous cell tumors, and adenomas of the perianal sebaceous glands), and clitoral (preputial) glands (adenomas and adenoacanthomas). A subcutaneous location and late ulceration were characteristics of many tumors originating from the pilosebaceous complexes and clitoral glads. From 31 to 43% of all anal tumors were of sebaceous gland (perianal or clitoral) origin. Cystic squamous cell tumors were morphologically similar to type II keratoacanthomas of rodents. Squamous cell tumors of any origin finally became squamous carcinomas.

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.

Contribution of aflatoxin B1 and hepatitis B virus infection in the induction of liver tumors in ducks.

The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus (DHBV) infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to DHBV infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by i.p. injection once a week from the third month posthatch until they were sacrificed (2.3 years later). Two control groups of ducks not treated with AFB1 (one of which was infected with DHBV) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with DHBV and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with DHBV and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All DHBV carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No DHBV DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected. The metabolism of AFB1 in infected and noninfected duck liver was also examined. The study on the role of DHBV infection and AFB1 in the etiopathogenesis of liver tumors may help to clarify some of the basic mechanisms of carcinogenesis.

[The mutagenic and carcinogenic activity of chemical compounds].

The article presents data on the association between the mutagenicity and carcinogenicity of chemical compounds. Genotoxic carcinogens, which universally act via interaction with DNA, are positive in tests for mutagenicity. The mechanisms of the carcinogenicity of non-genotoxic carcinogens include promotion, cytotoxicity and oxidative stress. As mutagenicity tests do not allow determination the carcinogenicity of chemical substances, long-term experiments on rodents should be considerred the only reliable method of carcinogenicity detection.

[Low-deuterium water effect on transplantable tumors].

Such models of transplantable tumors as Lewis sarcoma, uterine sarcoma-322 and uterine carcinoma-5 were used to study possible inhibitory effect by low-deuterium water. Such water was given to experimental animals (20 mice in each group). Controls (30 in each group) received tap water with standard deuterium concentrations. Low-deuterium water treatment resulted in significant inhibitory effect on volume of all tumor patterns concerned: it delayed nodule formation at transplantation site. However, no increase in survival time was obtained.

Sarcomatous lesions in CBA female mice treated with 1,2-dimethylhydrazine: independent primaries or metastases?

CBA female mice treated with 1,2-dimethylhydrazine (DMH) alone or in combination with oestradiol dipropionate (EP) or ascorbic acid (AA) developed, as expected, a high incidence of uterine sarcomas. In addition, sarcomatous lesions at unusual sites (mainly in the forestomach) were evident. The incidence of sarcomatous lesions at other sites was 53/220 in mice having uterine sarcomas and 0/186 in mice treated with DMH but without uterine sarcomas. The difference between the two groups was highly statistically significant (P < 0.001) and demonstrates non-coincidental association of the above sarcomatous lesions with uterine sarcomas. Uterine sarcomas which presented in association with lesions at other sites were of a larger size than those found in isolation, and the difference in weights in three out of four groups was statistically significant (P = 0.008, 0.035 and 0.011). Histologically, sarcomatous lesions were similar in structure to those of uterine sarcomas, i.e. were of a fibroblastic-histiocytic nature with admixture of giant cells. On the basis of the above data the sarcomatous lesions described appear to represent uterine sarcoma metastases rather than independent primary tumours. AA did not have any influence on carcinogenesis induced by DMH alone but inhibited the growth of uterine sarcomas (whether or not they were associated with other sarcomatous lesions) induced by DMH combined with oestradiol dipropionate.

Modifying effect of aging on chemical carcinogenesis. A review.

The age-associated elevation in tumor incidence is generally attributed to the age-related accumulation of a total effective dose of carcinogenic agents and/or time of exposure, or is regarded as a consequence of disturbances of the hormono-metabolic pattern and the decline in immunity vigor with increasing age. This review deals with the data available on the peculiarities of realization of the effect of different carcinogenic chemicals in various tissues of young mature and old animals. The results of the analysis of the literature data show that aging may involve either an increase or a decrease in the sensitivity of tissues and the whole organism to the action of carcinogenic chemicals or no changes at all. These differences are due to the specific characteristics of the age-associated dynamics of activity of drug-metabolizing enzymes and the proliferative activity of target tissue controlled by hormonal factors and chalones.

Tumours of the anal region induced in mice by 1,2-dimethylhydrazine.

CBA female mice treated with 1,2-dimethylhydrazine developed a high incidence of benign and malignant tumours in the anal region. Many of these tumours originated from the perianal glands rather than the epidermis.

Modifying effect of ascorbic acid and sodium ascorbate on the promoting stage of uterine sarcomogenesis induced in CBA mice by 1,2-dimethylhydrazine and estradiol-dipropionate.

Administration of estradiol-dipropionate (EP) after the cessation of 1,2-dimethylhydrazine (DMH) treatment increased the incidence of uterine sarcomas in CBA mice from 32.5 (DMH alone) to 62.5%. Ascorbic acid (AA) (0.3% in drinking water) given simultaneously with EP decreased the tumour incidence to 35%. Sodium ascorbate did not exert an inhibiting effect. AA inhibited the increase of uterine weight produced in mice by EP and did not influence the growth of mouse transplantable uterine sarcomas. The mechanisms of the antiestrogenic effects of AA are discussed.

Increased multiplicity of lung adenomas in five generations of mice treated with benz(a)pyrene when pregnant.

The effect of benz(a)pyrene (BP) given to female mice of A strain on the 18 and 19th days of pregnancy was studied in 5 consecutive generations. As expected there was a high incidence of lung tumours (TBA%) in the F1-generation of mice treated with BP (53.9 vs. 15.4% in control in females and 77.6 vs. 8.0% in control in males). The percentage of TBA was not increased (with one exception) in both males and females of F2-F5 generations which were not directly exposed to carcinogen. Tumor multiplicity increase occurred not only in the F1 generation of BP-treated mice but in both males and females of F2-F5 generations of mice which were not in direct contact with the carcinogen. This increase was statistically significant. There was a slight negative trend within F2-F5 generation of BP-treated mice which however was not significant. Thus the transgenerational carcinogenic effect manifested in a greater tumour multiplicity persisted for four unexposed generations.

Estrogen modification of 1,2-dimethylhydrazine carcinogenesis in C3HA mice.

Considerable strain differences were reported in our previous studies in the induction by 1,2-dimethylhydrasine (DMH) of uterine sarcoma and hemorrhagic ovarian lesion (HOL) in mice: the incidence of the former was high and that of the latter was low in CBA mice while the reverse was observed in C3HA mice. The present study confirmed the above observation in that C3HA mice treated with DMH developed high incidence (59%) of HOL and no uterine sarcoma. Combined treatment of C3HA mice with DMH and estradiol dipropionate (EP) completely inhibited the induction of HOL and increased the incidence of uterine sarcomas from naught to 28%. EP significantly decreased (from 61 to 19%) the incidence of clitoral gland tumors and somewhat increased the frequency of liver epithelial tumors and colon tumors. It is suggested that the strain differences in the induction by DMH of uterine sarcoma and HOL may be due rather to differences in the strain hormonal status than to the differences in the susceptibility to carcinogen.

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.

Tumour incidence in the progeny of male rats exposed to ethylnitrosourea before mating.

BDVI male rats were given a single i.p. dose of 80 mg/kg b.w. ethylnitrosourea (ENU), and each rat was then mated at weeks 1, 2, 3, 4 and 5 after treatment with 3 untreated females. A decrease in the fecundity of the treated males was observed, particularly when they were mated 5 weeks after ENU treatment. The average litter size was lower in the treated group, especially for females mated in week 4. No significant differences in pre- or post-weaning mortality were noted between control and treated groups. A slight, non-significant increase in the incidence of brain tumours was observed in the progeny of treated males compared with the controls. The incidence of thyroid tumours was significantly higher in controls but this difference disappeared when adjustment was made for litter effect and intralitter dependence.

Nephroblastoma and renal mesenchymal tumor induced in rats by N-nitrosoethyl- and N-nitrosomethylurea.

Rats treated prenatally with N-nitrosoethylurea or with N-nitrosomethylurea developed nephroblastomas, renal mesenchymal tumors and epithelial tumors (adenomas and carcinomas) of the kidneys. 15 nephroblastomas and 59 mesenchymal tumors were examined histologically. Nephroblastomas were encapsulated growths composed of dark cells, forming primitive tubules similar to those seen in the rat embryonal kidney and in human Wilms' tumor. Mesenchymal renal tumors showed an infiltrative growth and consisted of fibroblast-like cells, smooth muscles and angiomatous areas with the engulfed pre-existing tubules. These growths are similar to the mesenchymal renal tumors induced in the rat by N-nitrosodimethylamine. Nephroblastoma and mesenchymal renal tumor are considered to be separated entities, the first corresponsing to the epithelial variant of human Wilms' tumor and the second to congenital mesoblastic nephroma.

[Experimental models of 2-stage carcinogenesis]. / Eksperimental'nye modeli dvukhstadiinogo kantserogeneza.

The regularities observed in the experiments carried out by the two-stage scheme (initiation-promotion) are considered. Apart from the mouse skin in which these regularities are established, the phenomenon of initiation-promotion is reproduced on the epithelial tumours of the liver, bladder, colon, thyroid, mammary gland, epithelial and mesenchymal tumours of the uterus. The following properties of the promoters are listed: lack of mutagenicity; weak carcinogenicity towards the target organ; threshold of the promoting effect; cessation of carcinogenesis after the promoting treatment has been stopped; organotropism. Approaches and principles of chemical compound testing for cocarcinogenic and promoting activity are considered.

[Effect of dose fractionation on the carcinogenicity of chemical substances]. / Vliianie fraktsionirovaniia dozy khimicheskikh soedinenii na kantserogennyi éffekt.

Interrelations between single and total doses of chemical carcinogens are considered. On the basis of the data published and the author's own works a conclusion is drawn on the single dose as a decisive factor determining the organotropism (cytotropism) of certain pluripotential carcinogens (DMNA, DENA, DMH). Fractionation of the dose enhances the effect of polycyclic aromatic hydrocarbons, probably decreases the effect of directly acting carcinogens. Tumours of different histogenesis may respond to the dose fractionation in a different way.

[Histogenesis of endocardial tumors in rats]. / O gistogeneze éndokardial'nykh opukholei krys.

10 endocardial tumours (two tumours induced by N-nitrosoethylurea and eight spontaneous) of BD VI rats were examined for protein S-100 using specific antiserum in an immunoperoxidase reaction. The presence of protein S-100 in tumour cells is demonstrated in all cases and is considered as a proof of Schwann cell origin of these tumours.

1,2-Dimethylhydrazine carcinogenesis in CBA male mice prenatally treated with diethylstilbestrol.

CBA female mice, at the 17th day of pregnancy, received single intraperitoneal injection of diethylstilbestrol (DES) at the dose of 1 mg/kg body weight (b. w.). Their descentands at the age of 2 months started receiving subcutaneous injections of 1,2-dimethylhydrazine (DMH) at the dose level of 8 mg(base)/kg b. w., total 15 weekly injections. Prenatal DES treatment of male mice considerably accelerated the development and increased the incidence of DMH-induced androgen-dependent renal adenomas and, notably, renal capsule angiosarcomas (RCA). In males receiving prenatal DES (without subsequent DMH-treatment), there was a statistically significant increase of renal adenomas and 9% of RCA were observed which are exceedinly rare in untreated mice. The enhancement of androgen-dependent tumourigenesis may be considered as an indication, even though indirect, of the hyperandrogenization produced in male mice by the prenatal DES treatment.