[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.

[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.

[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.

[Diethylstilbestrol-induced uterine sarcoma in mice]. / Sarkomy matki myshei, indutsirovannye diétilstil'béstrolom.

Female mice of CBA strain received diethylstilbestrol (DES) 1 g body weight intraperitoneally. High incidence of histiocytic uterine sarcoma was observed in parents (25%), first generation (F1), descendants (10.9%), and generation F2m (through F1 males mated with females in control) (17.8%). Morphologically, tumor cells examined through light and electron microscopy were referred to as histiocyte-like elements. Half of the animals had metastases in the liver, kidneys, lungs, spleen, pineal and adrenal glands and stomach. The development of tumors in generation F2m, which was not exposed to DES, might be accounted for by "transgeneration" carcinogenesis, i.e. passage of carcinogenic effect through a generation.

[Carcinogenic effects of single total-body irradiation with accelerated charged particles and gamma rays]. / Kantserogennye éffekty odnokratnogo obshchego oblucheniia uskorennymi zariazhennymi chastitsami i gamma-luchami.

The study deals with the frequency of tumorigenesis in the endocrine glands, skin, soft tissues and internal organs of sexually mature female rats, exposed to accelerated charged particles with low LPE, such components of cosmic radiation as 645 MeV and 9 GeV protons and 4 GeV/nuclon ions of helium. The experiment continued until the animals' natural death. We established a high frequency of endocrine and uterine tumors and a comparatively wide range of localizations in rats which had received sufficient doses of gamma radiation. There were no intestinal or renal tumors, while very few tumors of the skin and soft tissues were detected in unexposed animals.

[Comparison of risk of mammary tumors developing in rats exposed to high-energy accelerated particles and gamma-ray radiation]. / Sravnitel'nyi risk razvitiia opukholei molochnykh zhelez u krys, obluchennykh uskorennymi zariazhennymi chastitsami vysokikh énergii i gamma-luchami.

The frequency of tumorigenesis was investigated in the mammary glands of noninbred female rats and Wistar rats, after total-body exposure to a single dose of 60CO gamma radiation, 645 MeV and 9 GeV protons and 4 GeV/nuclon ions of helium. It was found that the relative biological effects of accelerated charged particles was significantly higher. This finding was obtained from calculations of the frequency of mammary tumors.

[Consideration of the deuterium-free water supply to an expedition to Mars]. / Vozmozhnost' ispol'zovaniia bezdeiterievoi vosy v marsianskoi ékspeditsii.

Interplanetary missions, including to Mars, will put crews into severe radiation conditions. Search for methods of reducing the risk of radiation-induced cancer is of the top priority in preparation for the mission to Mars. One of the options is designing life support systems that will generate water with low content of the stable hydrogen isotope (deuterium) to be consumed by crewmembers. Preliminary investigations have shown that a decrease of the deuterium fraction by 65% does impart to water certain anti-cancer properties. Therefore, drinking deuterium-free water has the potential to reduce the risk of cancer consequent to the extreme radiation exposure of the Martian crew.

Effect of myelopeptide-2 on the development of spontaneous and urethane-induced tumors in mice.

We studied the effect of endogenous immunoregulatory myelopeptide-2 on the development of spontaneous and urethane-induced lung adenomas. Long-term treatment with myelopeptide-2 (25 injections) in parallel with urethane poisoning decreased animal mortality caused by this carcinogen. Short-term treatment with myelopeptide-2 decreased the number of spontaneous and urethane-induced lung tumors in mice. Myelopeptide-2 delayed the appearance of urethane-induced tumors irrespective of the number of injections.

[Determination of the effective number of animals to be used in oncologic experiments, and in testing for carcinogenicity, in particular]. / Opredelenie éffektivnogo chisla zhivotnykh v onkologicheskikh éksperimentakh, v chastnosti pri testirovanii na kantserogennost'.

An effective number of animals used in oncological experiments in general and carcinogenicity testing in particular is usually calculated as that of animals which have survived by the time a first tumor of any type (epithelial, mesenchymal, fatal, incidental etc.) is detected in any group, including control, throughout the whole experiment. This is justified for the determination of total number of tumors or the incidence of early tumors which are detected first. It is assumed that tumors of different histologies and in different organs, on the one hand, and early tumors, on the other, are detected at the same time. However, such approach may be misleading as far as tumors detected at later stages are concerned when the number of animals is much lower than that when the first rapidly-growing tumor was found. It seems advisable to compute effective numbers for all tumor patterns individually or for a given pattern in each organ. Hence, in either experimental situation, an effective number will refer to animals surviving till a first target tumor is detected.

[Rapid progression of passaged mouse hepatocarcinoma associated with the loss of cell polarity]. / Skachkoobraznaia progressiia perevivaemoi gepatokartsinomy myshei , sopriazhennaia s utratoi poliarnosti kletok.

Two transplantable differentiated mouse hepatocarcinomas were obtained in B6 D2 F1 mice from primary tumors induced by initiation (NDEA)-promotion (phenobarbital) protocol. Both HC were slowly growing with time from passage to passage of 5-7 months (s-HC). A fast-growing variant with time between passages of 2-3 weeks appeared in one mouse on the third passage (f-HC). The three HC strains constantly retained their phenotype. The s-HCs were characterized by prominent cell polarity according to organization of the cytoskeleton and distribution of domain-specific membrane-associated markers. Cell polarity was completely destroyed in the fast-growing variant. Cell adhesion in the latter tumor was very low. An in vitro growing strain of f-HC was easily obtained enabling experimental study of regulation of progression in HCs.

Nongenotoxic (epigenetic) carcinogens: pesticides as an example. A critical review.

The following groups of pesticides are considered in this review by supposed mechanisms of their carcinogenicity: hepatocarcinogenic pesticides, pesticides - peroxisome proliferators, pesticides as endocrine disruptors, goitrogenic pesticides, pesticides producing sustained cell proliferation and some others. With very rare exceptions, pesticides do not react with DNA directly and the mechanisms of their carcinogenicity are, in general, similar to those of other nongenotoxic (epigenetic) carcinogens, namely: promotion of spontaneous initiation, cytotoxicity with sustained cell proliferation, oxidative stress, formation of activated receptors and some others. Genotoxicity of pesticides varies from its complete absence (propiconazol as an example) to a very pronounced one (captafol) with remaining compounds in between. These two compounds demonstrate full correlation between genotoxicity and carcinogenicity (or their absence). Many pesticides give positive results in some tests for genotoxicity but these results are frequently controversial, not readily reproducible, or obtained only at toxic dose levels. The weak genotoxicity of the majority of pesticides is easily explainable by their rather severe testing before their introduction into practical use. The above mechanisms are threshold-based and therefore pesticides are regulated through NOEL/safety factor. There exist examples of lack of correlation between genotoxicity and carcinogenicity: some pesticides are genotoxic (although not strongly) but noncarcinogenic, others are considered as nongenotoxic but are strongly carcinogenic (chlorothalonil, acetochlor). The general scheme of the promoters' effect is presented in which an important role is attributed to the cytochrome P-450 induction (some pesticides are the cytochrome P-450 inducers), formation of reactive oxygen species and peroxitome proliferation. Teratogenesis Carcinog. Mutagen. 20:229-240, 2000.

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.

[Effect of prenatal treatment with diethylstilbestrol on 1,2-dimethylhydrazine-induced carcinogenesis in male CBA mice]. / Vliianie prenatal'nogo vozdeistviia diétilstil'béstrola na katserogenez, indutsiruemyi 1,2-dimetilgidrazinom u myshei-samtsov linii CBA.

Female CBA mice were injected 1 mg/kg diethylstilbestrol (DES) on day 17 of gestation. Their male progeny received 15 weekly injections of 1,2-dimethylhydrazine (DMH) starting from the age of 2 months. Prenatal treatment with DES was followed by a significant acceleration and higher frequency of DMH-induced renal adenomas and renal capsule sarcomas in males. Tumor-induction was significantly enhanced by androgen effect. This was matched by a higher frequency of induced tumors of the large bowel. The increased frequency of androgen-dependent renal malignancies, served as indirect evidence of hyperandrogenization being stimulated in CBA male mice by prenatal treatment with DES.

Predominant p53 G-->A transition mutation and enhanced cell proliferation in uterine sarcomas of CBA mice treated with 1,2-dimethylhydrazine.

Mouse uterine tumors were examined for genetic alterations in the ras proto-oncogene and p53 tumor suppressor gene and for other biologically relevant immunohistochemical markers that may increase our understanding of the events that occur in uterine cancer. Fourteen dimethylhydrazine (DMH)-induced uterine sarcomas, including 3 primary malignant fibrous histiocytomas (MFH), 7 transplanted MFH, 3 stromal sarcomas, and 1 undifferentiated sarcoma, were first screened by immunohistochemistry for p53 missense mutations, followed by single strand conformation polymorphism analysis and DNA sequencing for the identification of point mutations. There was 100% correlation between p53 protein immunopositivity and subsequent detection of p53 mutations in DMH-induced malignant fibrous histiocytomas. All MFH had a characteristic p53 G:C-->A:T transition mutation, consistent with O6-methylguanine mispairing with thymine, the most common DNA lesion caused by alkylating agents. DMH-induced uterine MFH with p53 mutations also had a higher proliferative rate (qualitatively evaluated by immunohistochemical detection of proliferating cell nuclear antigen) when compared with other DMH-induced sarcomas. Uterine sarcomas were further evaluated for biological end points, such as estrogen receptor and desmin. Neoplastic cells from stromal sarcomas (SS), undifferentiated sarcomas (US), and MFH did not stain for desmin. The estrogen receptor was detected in normal uteri and a small portion of MFH, SS, and US. Our data suggest that DMH-induced uterine sarcomas are not consistent with smooth muscle cell origin and that a subset of these tumors, specifically DMH-induced malignant fibrous histiocytomas, have unique p53 G:C-->A:T transitions and a high proliferative rate.

Hygienic classification of pesticides in the Russian Federation.

Hygienic classifications of pesticides used in the Russian Federation are presented. The classifications cover both technical products and preparative forms of pesticides. Four classes of hazards are distinguished: extremely hazardous, hazardous, moderately hazardous, and slightly hazardous. These four classes are used for classifying general toxicity (peroral, skin, inhalation), cumulative, allergic, teratogenic, embryotoxic, reproductive, mutagenic, carcinogenic effects, and the stability in soil. The class of the hazard is determined on the basis of toxicohygienic evaluation of a pesticide, taking into account a limiting criterion of the hazard.

Renal cell tumours in mice: electron microscopy versus immunohistochemistry.

15 renal cell tumours induced in CBA male mice by 1,2-dimethylhydrazine were studied electronmicroscopically (EM). All these tumours earlier were investigated histochemically and immunohistochemically with the use of gamma-glutamyltranspeptidase (GGT) as a marker of the proximal tubules and antigen A6 as a marker of distal tubules and/or collecting ducts. One of the tumours was GGT-positive and antigen A6-negative and ultrastructurally well developed brush border was found. This correlation between immunohistochemistry and EM data allowed to conclude that the site of origin of this tumour were the cells of the proximal tubules. All other tumours were GGT-negative and antigen A6-positive, i.e. the development of these tumours from the distal tubules (and not from the proximal tubules) could be suspected. However in 5 of these neoplasms reduced brush border was found. Microvilli were of a smaller size than in normal proximal tubules and were frequently located not on the apical cell surface but in the narrow spaces between two cells. Invaginations and apical vesicles typical for the normal proximal tubules were also found in some tumour cells. EM and immunohistochemical data combined allow to suggest the origin of these tumours from the common precursor cell capable of differentiation, in the course of tumour progression, into the cells with properties of proximal and/or distal tubules.