[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.

[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.

[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.

[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.

[Specific features of spontaneous carcinogenesis and survival in female mice 129/Sv PARP-1+].

Spontaneous carcinogenesis and survival were compared in female mice 129/Sv PARP-1+ and PARP-1++ controls. Survival of all animals, including that of the last 10% of mice PARP-1+ (p<0.0002), was relatively lower. It was matched by a significant rise in aging rate. Spontaneous tumor incidence was identical in both groups, although experimental animals revealed tumors at an earlier stage (612+19.2 and 706+17.6 days, respectively, (p<0.0002). The death rate of mice PARP-1+ was 67% as compared with controls (47%) (p<0.05). Tumors of uterus, ovary, liver, lung, mammary gland and soft tissues as well as malignant lymphoma were detected. Malignant tumors contributed 72% among experimental animals versus 49% in control (p<0.05). Those differences were mostly observed among uterine malignancies, adenocarcinomas of the lung and hepatocellular carcinomas. Hence, the switching-off of PARP-1+ involved accelerated aging, shorter survival and earlier and more aggressive tumor development which is in agreement with the existing views on the role played by DNA reparation in mechanisms of carcinogenesis and aging.

[Poly(ADP-ribosa)polymerase--the relationships with life span and carcinogenesis].

Poly(ADP-ribose) polymerases (PARP) is enzyme family repairing single or double DNA strand breaks induced by different alkylating agents, ionizing- or UV-irradiation as well as by oxidative stress. Poly(ADP-ribose) polymerase-1 (PARP-1) is the most studied enzyme involved in a number of pathways including DNA replication and repair, recombination, gene transcription, cell proliferation and death. A positive correlation between the PARP-activity and the life span of different mammalians has been detected. PARP inhibition in vitro with inhibitors of PARP activity (3-aminobenzamide, nicotinamide, picolinamide e.t.c.) in cells from wild type or PARP-1(-/-) mice was followed by high genomic instability (i.e. aneuploidy, gene amplifications and deletions, micronuclei formation, sister chromatic exchange, cell ploidy and centrosome number increase) and increased sensitivity to mutagens. Life span reduction, latency period of spontaneous tumors development shortening and the increase in susceptibility to carcinogens have been observed in PARP-knockout mice. Treatment with PARP inhibitors stimulated chemical and radiation carcinogenesis in animals. The PARP-1(-/-) mice being additionally disrupted in WRN, p53, DNA-PKcs or Ku80 genes the promotion of spontaneous carcinogenesis was observed as compared with a single gene-disrupted mice. Available data suggest a significant role of PARP in maintenance of genomic stability, preventing of aging and carcinogenesis.