[Light-induced disruption of the circadian clock and risk of malignant tumors in laboratory animals: state of the problem].

There were obtained sufficient experimental evidence of the stimulating effect on the development of tumors (transplanted, spontaneous and induced by various carcinogenic agents), disorders of circadian function of the pineal gland (light-induced desynchronosis) caused by knockout or mutation of clock genes, pinealectomy, content in conditions of constant light or natural light regime of the North, as well as jetlag modeling in laboratory rodents. In experiments on various models of carcinogenesis it was found that sympathectomy (removal of the superior cervical ganglion), light deprivation, hibernation and application of melatonin, the natural hormone of the pineal gland, had an inhibitory effect on the development of transplanted, spontaneous and induced tumors of different histogenesis.

[Experimental study of the effect of benzidinsulfon, included in the group of diaminodifenils, with potential carcinogenic effects].

There was performed a study of carcinogenicity of benzidinsulfon (4.4'-diaminodiphenil sulfone) in rats and mice. Experimental animals (99 mice and 99 rats, approximately equally divided by sex) received the drug throughout the life by subcutaneous injections (once a week) or addition to food (5 times a week). A single dose per animal in rats was: subcutaneous administration--50 mg (in females it was reduced due to the toxicity after beginning of the experiment to 25 mg) in 0.5 ml of oil, while feeding--20 mg in 0 5 ml of oil; in mice--respectively 5 mg in 0.2 ml of oil, and 2 mg in 0, 2 ml of oil. The maximum amount of a substance when administered subcutaneously to male rats was 5.65 g, to female rats--2, 68 g, when fed to rats 12.44 g, when injected subcutaneously in mice--380 mg, when fed--737 mg. The survival of experimental animals was significantly reduced as compared to the intact control because of the toxic effect of the drug, preferably chronic nephrosis with nephritic component and secondary nephrosclerosis and as well as miocardiosclerosis and aortic sclerosis. Frequency and timing of detection of tumors in experimental animals was not significantly different from that observed in the control that indicated the absence of carcinogenic features of benzidinsulfon.

[Effect of epsilon-aminocaproic acid, cyclophosphamide and their combination on the growth of autochthonous sarcomas of mice induced by benzo(a)pyrene].

Antifibrinolytic drug epsilon-aminocaproic acid as a therapeutic form (5% solution in saline) was tested for antitumor activity in the autochthonous subcutaneous tumors of mice, induced by benzo (a) pyrene, in monotherapy mode (instead animals received drinking water) and in combination with cyclophosphamide, which was administered once intraperitoneally in the dose of 200 mg/kg. In the control groups, treated with drinking water and saline solution instead of water, there was no stabilization and reduction in tumor volume, while in the groups receiving epsilon-aminocaproic acid, cyclophosphamide and their combination statistically significantly in comparison with the control groups there was increased the proportion of tumors with not changed or reduced volume; epsilon-aminocaproic acid enhanced the antitumor effect of cyclophosphamide. The data obtained are for further study of the antitumor effect of epsilon-aminocaproic acid.

[The effect of sodium fluoroacetate and metformin on the antitumor activity of cyclophosphamide on the autochthonous mice sarcoma model].

Previously it was found that sodium fluoroacetate (SF) inhibited the growth of the Ehrlich cancer by means of monotherapy and enhanced the antitumor effect of cyclophosphamide (CP) in experiments with autochthonous subcutaneous tumors induced by benzo (a) pyrene. In this study a comparison of the antitumor activity of SF and metformin showed that both substances did not have significant effect in monotherapy but enhanced the effect of CP, increasing the percentage of tumors with the same or reduced volume. Besides, SF, unlike metformin increased the average duration of effect. The data obtained promoted further study of the mechanism of the antitumor effect of SF and the search effective combination with already known antitumor drugs.

[Effect of plastoquinone derivative SkQ1 on benzo(a)pyrene-induced soft tissue carcinogenesis].

Ninety female SHR mice were subcutaneously injected with a single dose of 2 mg benzo(a)pyrene (BaP) dissolved in 0.2 ml of vegetable oil. Since the next day after BaP injection mice were started to treat with mitochondria-targeted antioxidant SkQ1 at the doses of 5 and 50 nmol/kg/day in drinking water. Control animals received tap water. Study was finished by 358th day. Number of tumor-bearing mice increased in all groups exposed to BaP but retarded since 20th week in SkQ1-treated groups in comparison with control. Maximal tumor volume gain was observed in control mice resulting in premature death. By the 30th week of study only 20% of control animals survived, whereas SkQ1 treatment increased survival up to 30% at the dose of 5 nmol and 40% at the dose of 50 nmol. By the 40th week mean tumor volume in 5 and 50 nmol SkQ1-treated mice was 13 and 21 cm3 respectively, whereas in control--40 cm3. In SkQ1-treated mice pneumonia was observed rarely as compared with controls. It could be supposed, SkQ1 at the doses of 5 and 50 nmol/kg/day retarted BaP-induced soft tissue carcinogenesis in SHR mice.

[Effect of sodium fluoroacetate on Ehrlich solid tumor and autochthonous sarcoma growth in mice].

Due to biochemical characteristics of toxic action of fluoroacetate on energetics and metabolism of cells, including tumor cells, it was interesting to testify sodium fluoroacetate (SFA) for its antitumor activity in vivo. We have estimated that SFA significantly inhibits growth of Ehrlich tumor carcinoma. In experiments with autochthonous induced by benzo[a]pyrene subcutaneous tumors, SFA was not active in monotherapy regime, though potentiated antitumor effect of cyclophosphamide, significantly increasing the relative number of mice with stabilized or decreased tumor volume as well as the duration of this effect. The data obtained render basis for additional studies of mechanism of antitumor effect of SFA.

[Hyperplastic skin growth on the head of goldfish--comparative oncology aspects].

Dynamics of development and morphology of hyperplastic skin lesions ("hoods") on the head of goldfish, which were bred using artificial selection for more than thousand years, were studied. During monitoring of hundred fishes, at the age of 6 months "hoods" were found in 39.5%, among 14 months-old fishes in 60,7%. Morphologic examination of "hoods" on various stages of development revealed epithelial hyperplasia with increased clear mucous cells number, dermis thickening and oedema. On later stages developed papillomatous outgrowth and areas of epithelial intrusion. The comparative oncology analysis allow to hypothesize these skin growth to be a genetically determined benign neoplasm. This is the first example of artificially selected neoplasm described in the literature. It supports our hypothesis of the possible evolutionary role of tumors.

[The effect of SSH&H on the lifespan and spontaneous cancer development in transgenic mice with HER-2/neu mutation].

10 months old mice receiving SSH&H with daily food increased the lifespan in comparison to the control group. The maximal lifespan was increased by 1,6 months. For the long-living 10% group the mean lifespan increased by 8,7% compared to the control group (p<0,05). The mammary gland neoplasia rate was the same in both groups. The mean latent tumor development period duration, number and size of the tumors were also similar. There was a tendency to lower lung metastases rate in the experimental group. The cumulative neoplastic frequency curve for the experimental group was shifted to the right in comparison to the control group curve giving evidence to the inhibitory effect of SSH&H on the neoplastic rate in transgenic mice with HER-2/neu mutation.

[Light pollution increases morbidity and mortality rate from different causes in male rats].

The influence of different light regimes (constant light--LL; constant darkness--DD; standard light regime--LD, 12 hours light 12 hours darkness; natural lightening of the North-West of Russia--NL) on the dynamics of life's morbidity rate, spontaneous tumorigenesis and frequency of some kinds of non-tumor pathology revealed at the post-mortem examination of male rats was studied. It was found out that the maintenance of animals at LL and NL conditions led to the increase of the number of infectious diseases, substantially faster development of spontaneous tumors and the increase of non-tumor diseases in comparison with the animals kept at LD (standard light) regime. Light deprivation (DD) led to substantial reduction of development of new growth, of non-tumor and infectious diseases in comparison with the similar parameters in standard light regime.

[Morbidity and mortality rate from tumors and other causes in female rats under different light regime].

The influence of different light regimes (constant light--LL; constant darkness--DD; standard light regime--LD, 12 hours light/12 hours darkness; natural lightening of the North-West of Russia--NL) on the dynamics of life's morbidity rate, spontaneous tumorigenesis and frequency of some kinds of non-tumor pathology revealed at the post-mortem examination of female rats was studied. It was found out that the maintenance of animals at LL and NL conditions led to the increase of the number of infectious diseases, substantially faster development of spontaneous tumors (2,9 and 3,3 diseases per one rat, respectively) and the increase of non-tumor diseases in comparison with the animals kept at LD (standard light) regime (1,72 diseases per one rat). Light deprivation (DD) led to substantial reduction of development of new growth, of non-tumor and infectious diseases (1,06 diseases per one rat) in comparison with the similar parameters in standard light regime.

[Metformin effect on urethane-induced tumorigenesis in mice].

Sixty one male 129/Sv mice were exposed to a single intraperitoneal injection of 1 g per kilo of urethane dissolved in 0.9% normal saline. Starting the next day from the injection the study group mice were given 1200 mg metformin per liter of drinking water 5 days a week for 26 weeks. The control group mice received pure drinking water. Six months after the urethane treatment the mice were killed and the morphology samples were taken. Twenty five of 31 (96.7%) control group mice developed tumors (lung adenomas and thymic lymphomas), while tumor development was observed in 25 of 31 (80.7%; p<0.05) mice exposed to metformin. Solid or trabecular lung adenomas developed in 90% of the control group mice and in 77% of the metformin group mice (p=0.119). Therefore, it is a first evidence of tumor-inhibitory effect of metformin in mice.

[The effect of mithochondria targeted antioxidant SkQ1 on aging, life span and spontaneous carcinogenesis in three mice strains].

Female outbred SHR mice, inbred 129/Sv mice and transgenic HER-2/neu mice were given mitochondria targeted antioxidant SkQ1 with drinking water in the various doses (0,5-2500 nmol/kg day) since the age of 2 months, whereas control animals received tap water. Age-related dynamics of the body weight and temperature, the amount of drinking water and consumed food, estrous function, as well as parameters of the life span and spontaneous carcinogenesis were estimated. As compared with controls, no difference in the parameters of body weight and temperature or amount of consumed food and water in the treated mice of all studied mice strains was revealed. In SkQ1-treated SHR mice, the tendencies of inhibition of the age-dependent disturbances of estrous function and aging appearance were observed. No effect of SkQ1 on estrous function and external view in inbred and transgenic mice was shown. SkQ1 treatment significantly decreased locomotor activity (in 12-15 months old SHR and 129/Sv mice) and exercise tolerance in old (20 months) SHR mice. The treatment with SkQ1 (0,5-50 nmol/kg day) increased parameters of the life span in SHR mice (mean life span, mean life span of the last 10% of survival, median and maximum life span) without significant effect on the life span in 129/Sv and HER-2/neu mice. There was no reliable difference in tumor development in all SkQ1-treated mice strains as compared with the control. The drug considerably inhibited the incidence of age-associated non-tumor pathology in SHR mice. Our data suggest geroprotective activity of SkQ1, and a lack of toxic or carcinogenic activities during long term use.

[Features of carcinogenesis and aging in knockout male mice PARP-1].

Poly(ADP-ribosyl)ation polymerase-1 (PARP-1) is a major factor of DNA repair. Age-related parameters such as body weight and blood cholesterol in knockout male mice PARP-1 were more pronounced as compared with controls. Mean life span was shorter (486 +/- 31.7 and 723 +/- 22.6 days, respectively, (p = 0.000005) while initial risk of death (beta) was 8 times as high as in mice PARP-1(+/+). Mean latency of all tumors in knockout and control mice was 656 +/- 43.5 and 782 +/- 33.8 days, respectively, (p < 0.05). Among the most frequent neoplasms were tumors of the liver (experimental--22% and control--8%, respectively) (p = 0.03) and lungs (8% and 12%, respectively). Hence, mice PARP-1(-/-) revealed certain typical charhacteristics of accelerated aging, shorter life span, earlier carcinogenesis and higher rates of liver tumor incidence as compared with mice PARP-1(+/+). Our evidence highlights the role of DNA repair in carcinogenesis and aging.

[Effect of additional administration of iron ions on the efficacy of radiotherapy of glioma-bearing animals].

Our analysis failed to establish any antitumor effect of treatment of rats with transplantable glioma-35 with iron-containing mineral drinking water (ICMW). The latter treatment combined with irradiation (15 Gy) was followed by enhanced genotoxic effect in white blood cells. Post-irradiation administration of ICMW did not influence glioma growth significantly as compared with radiation alone. Pre- and post-iradiation drinking of ICMW resulted in marked leukopenia 24 hrs after exposure as well as to significant decrease in tumor size (20-40 days after of experiment) as compared with control.

[Models and methods of evaluation of geroprotective activity of pharmacological drugs].

Current approaches to evaluation of efficacy and safety of potential life span extending drugs (geroprotectors) are reviewed in the paper. The methods and protocol of evaluating the effect of pharmacological drugs on aging and life span in mice which have used by the authors are described in details. Principles and criteria of evaluation of degree of evidence the experimental studies in rodents as well as a possibility of extrapolation to humans are discussed.

[Diethylnitrosamine-induced carcinogenesis in PARP-1(-/-) and PARP-1(+/+) mice].

Our study is concerned with comparative analysis of diethylnitrosamine (DENA)-induced carcinogenesis in PARP-1 knock-out female mice PARP-1(-/-) and wild type animals PARP-1(+/+). No difference was recorded in relation to total tumor incidence (88 and 95%, respectively): cardia (87 and 84%, respectively), liver (80 and 66%, respectively). However, experimental animals PARP-1(-/-) tended to reveal incidence of cardia tumors with invasion as deep as the serosa higher than in PARP-1(+/+) mice (100 and 81%, respectively) and metastases to the liver and lung--27 and 7%, respectively. Relative incidence of angiosarcoma and holangiocarcinoma among liver tumors from PARP-1(-/-) mice was higher than that in wild type mice. Hence DENA induced the most aggressive tumors in PARP-1(-/-) knockout mice more often than in PARP-1(+/+) ones. Our results confirm the significance of the role of DNA repair in carcinogenesis.