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An investigation of fluorescent diagnosis possibility in the near infrared range was performed on a rat model of the Pliss lymphosarcoma (30 rats) with the use of indocyanine green (ICG) as a fluorescent marker and photosensitizer. For conju- gates of ICG there were used bovine and human albumins as these proteins in solution strengthened and stabilized fluorescence and in intravenous administration promoted improving diagnosis while the diagnostic contrast after administration during the optimum time was no less than 6. It permitted to easily detect a pathological focus (tumor or inflammation).

The critical analysis of preclinical testing of anticarcinogenic and antitumor activity of biguanides presented in this paper. Experiments have been conducted using in total more than 20 models of carcinogenesis including models of spontaneous , chemically- , radiation- and virus-induced carcinogenesis, as well as carcinoigenesis induced by special fat diets and by genetic modification in rodents. Cancer preventive effect of buiguanides has been studied in relation to total tumor incidence and to 17 target organs in animals of 3 species, including 25 various strains of mice, 4 strains of rats and 1 strain of hamsters using various routs of administration and doses. In the majority of cases (86%) the exposure to biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed, however there was no any case of stimulation of carcinogenesis by antidiabetic biguanides., Metformin suppressed tumor growth in the majority of in vitro studies conducted in 46 different cell lines originated from malignant tumors of 15 localization as well as in athymic mice with xenografts of 31 tumor lines. It was concluded that there are sufficient experimental evidences of anticarcinogenic and antitumor effects of antidiabetic biguanides revealed in a number of models of induced and spontaneous carcinogenesis.

Malignant glioma is the most frequently occurring primary brain tumor. Despite significant progress in the diagnostics and treatment of neoplastic diseases the prognosis for patients with III-IV grade gliomas, remains extremely unfavorable. Rapidly developing area in oncology is the employment of therapeutic viruses with natural or genetically engineered oncolytic activity. In the present study we demonstrated the oncolytic potential of a recombinant influenza A virus vector with impaired interferon antagonism function of NS1 protein in treatment of malignant glioma. Recombinant influenza A virus (HA-DS-GFP) expressing green fluorescent protein from the NS1 open reading frame was used as a model vector. HA-DS-GFP virus has shown infectivity towards glioma cells both in vitro, and in vivo (experimental glioma model in rats). Intratumoral inoculation of HA-DS-GFP resulted in a substantial inhibition or complete regression of tumor growth. Our data demonstrate that recombinant influenza vectors have promising potential in therapy of malignant gliomas.

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.

Historical essay devoted to the life and work of Professor Tamara Alexandrovna Korosteleva (1913-1991), the former Head of the Laboratory of Oncoimmunology at the N.N. Petrov Research Institute of Oncology, St. Petersburg.

An experimental technology of normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet has been elaborated to treat abdominal carcinomatosis in ovarian cancer. Antitumor effects of the treatment were evaluated for the duration of animal life. Normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet in comparison with the standard intraperitoneal administration significantly increased the median life expectancy by 75-92%. Hyperthermic intraperitoneal chemoperfusion with dioxadet demonstrated potentiation of antitumor effect of hyperthermia and dioxadet. Experimental technology is recommended for testing new drugs and methods of chemoperfusion for malignant tumors affecting the peritoneum.

In experimental animals with tumors it was studied antitumor activity of spirocyclic hydroxamic acids which could be classified as targeted agents as their target was enzyme histonedeacetylase, which was involved in the neoplastic process. The results showed that the hydroxamic acids were chemosensitizers for anticancer agents increasing their efficacy and enabling the researchers to reduce significantly the therapeutic dose. Also it was showed that hydroxamic acid, containing nitrogen mustard, was effective in the action on tumors with phenotype and genotype of multidrug resistance.

For the first time, the biodistribution of recombinant heat shock protein in rhHsp70 rats with grafted intracranial C6 glioma was evaluated. It was assessed using the fluorescent antibody accumulation chaperone rhHsp70 conjugated with fluorochrome Alexa Fluor 555 in tumor cells by intratumoral or intravenous administration. Assessment of the distribution and accumulation of labeled protein was carried out on the model of subcutaneous B16/F10 melanoma in C57BL/6 mice with the use of single-photon emission computer tomography. After 60 minutes after intravenous administration rhHsp70-I123 (20 MBq, 5 mg chaperone) accumulation of the drug mainly in the liver and tumor tissue was showed. The coefficient of the differential accumulation of the labeled protein KDN(tumor/background) was 3.14. It was turned out that comparing the level of fixation of rhHsp70-I123 in the liver and the tumor KDN(tumor/ liver) = 0.76. After 24 hours from the time of injection of rhHsp70-I123 it was observed increase the level of fixation of the labeled protein in the liver and melanoma: KDN(tumor/background) = 3.43; KDN(tumor/liver = 0.78.

Data are presented on the results of photodynamic treatment (PDT) of mice DBA2 with transplantable lympho-leukemia P-388. Different regimens of photosensitizer Dimegin and emission were used. Both intravenous PDT and in combination with local PDT should be recommended.

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.

When used separately, diethylnitrosamine (DENA) initiates 4-6 times more neoplastic lesions in the liver of suckling mice than ortho-aminoazotoluene (OAT) lower. However, after combined treatment with either carcinogen the total number of hepatic lesions was significantly than that in mice injected with DENA only. Similar inhibition of DENA-induced hepatocarcinogenesis was observed when OAT was administered 8-12 hrs after DENA. Our findings cannot be adequately explained except by competition of the carcinogens for supposedly target molecules of protein origin, presumably, transcription factors, which contribute to generation of genetic information. They have different affinities for different compounds and, therefore, suffer different damage from the latter functioning.

DNA unprotected by protamine immediately degraded to fragments of a 200 bp size in the blood flow of experimental animals to be delivered to the innermost compartments of tumor cells. Once absorbed by protamine, DNA fragment remained unchanged in size. For intravenous injection of 1-2 microg, the amount delivered to the cells of intramuscularly grafted tumor RLS was well below several copies on a basis of 1,000 bp. There was no correlation between the amount delivered and DNA-protamine linkage. Protamine protection did not affect DNA's ability to inhibit experimental tumors.

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.

Influence of low-dosage pre-irradiation on xanthine oxidase levels in Guerin's carcinoma was studied with particular emphasis on free oxygen generation and free sulphohydrils in a fraction of proteins characterized by xanthine oxidase activity. Enhanced growth of tumor correlated with that of xanthine oxidase activity involving higher levels of enzymatic O-form due to thiol groups oxidation. Under similar conditions, xanthine oxidase and free oxygen generation levels were higher due to SH-group oxidation than in intact animals. Terminal stages involved dropping xanthine oxidase levels and enzymatic protein degradation.

The investigation is concerned with effects of lighting--12hr light/12hr dark (standard), natural lighting in the Russian North-West, constant illumination and light deprivation--on life span and spontaneous tumor development in female LIO rats. Constant and North-West lighting involved premature aging, shorter mean (13.5 and 25%) and maximum life span (by 9 and 7 months, respectively) and a significant increase in spontaneous tumor development rate as compared with standard lighting. Light deprivation resulted in a longer maximum life span and significant (2.1 times) drop in tumor incidence.

Anticarcinogenic action of dietary supplement Pheocarpin and its active component Natural Coniferous Complex (NCC), in particular, has been studied. Pheocarpin and NCC efficiently inhibited tumorigenesis in the mammary gland, large bowel, skin, cervix uteri and lungs. Pheocarpin offers considerable advantage as a means of reducing the risk of malignant disease.

Non-inbred SHR/u 3-month old mice were injected a single dose of urethane 1 g/kg, intraperitoneally. Beginning from day I after injection, they received melatonin 20 mg/l or 2 mg/l with drinking water at nighttime. After 28 days of the experiments, mice were sacrificed, lung adenomas counted and examined morphologically. Samples of blood and ling tissue were taken from each group and assayed for malonic dialdehyde (MDA) and catalase level. Tumor count of lung adenomas in the untreated group (control) was 23 +/- 2.63, melatonin 20 mg/l--14 +/- 1.2 (p0.01) and melatonin 2 mg/l--11 +/- 0.72 (p0.01). Urethane-treated mice revealed increased levels of MDA (62%) and catalase (70.7%) in blood-serum and in lung tissue (36.5%) as compared with control. Melatonin treatment significantly lowered concentrations of MDA in blood-serum and catalase (blood-serum and lung) rather than in the lung bearing urethane-induced tumor. Antitumor and antioxidant effect of relatively low dosage of melatonin appeared to be more effective than those of a larger one.

An enzymoassay of levels of Mg2+-dependent alkaline endoDNAase of protein spectrum of blood serum of noninbred albino mice by SDS-electrophoresis in 10% PAAG established a fairly high heterogeneity of the enzyme. The variety of alkaline endoDNAases must be due to the limited proteolysis of their high-molecular precursor by specific proteases as described in the literature. No alkaline endoDNAase activity was identified by analysis of 10-150 kDa protein spectrum in A/smail line mice without ascites hepatoma. It was detected (pH 8.3) in the 25-45 kDa range on day 10 after tumor transplantation. Considering the gravity of disease (pre-lethal stage), on day 10, it was suggested that the level be accounted for by decay of diseased cells. The lack or extremely low level of endoDNAase activity in original blood serum expressed a mechanism of enhancing sensitivity to tumor cell effects. In mice bearing ascites hepatoma, the enzyme levels (pH 8.3) were much higher on day 10. DNAase activity (pH 7.5) was not induced in response to the heterogenous DNA. Our data point to possible defects in the induction of Mg2+-dependent alkaline endoDNAases (pH 8.3) and DNAses (pH 7.5) as well as their role in raising sensitivity to transplantable ascites hepatoma.

The effect of preliminary irradiation on DNA-ase activity and DNA fragmentation degree in the nuclei of Guerin's carcinoma was evaluated. It was found that effective growth of malignant cells involved higher concentrations of acid DNA-ase matched by decreased levels of alkaline one which in turn lowered the rates of DNA fragmentation. Low-dose preliminary irradiation stimulated relevant processes.

The potential of increased antitumor effect of cyclophosphane used in conjunction with low-energy infra-red laser radiation was studied in sarcoma-45--bearing rats. Exposure to certain modes stimulated non-specific antitumor resistance and enhanced antitumor influence of the drug by reducing its damaging effect. Also, it inhibited refractory leukopenia and marked intoxication induced by antistressor reactions.

Ortho-toluidine carcinogenicity has been tested in chronic experiments using mice, rats and dogs. Tumors were induced in 19% of mice (lung and kidney adenomas, leukemia), rats--40% (subcutaneous fat tumors, mammary fibroadenomas, leukemia, renal tumors and hepatic sarcoma). Bladder tumors developed in two dogs after 9 and 10 years of experiment. Both literature and experimental evidence point to o-toluidine as a hazard to humans.

Twenty five female HER-2/neu transgenic mice (FVB/N), aged 2 months, were surgically deprived of lighting; 30 intact transgenic mice, kept under standard conditions, were in control. Light deprivation was followed by inhibited intake of feed, decreased body mass and delayed age-associated estral disorders, as compared with control. Mean survival rate among experimental mice was higher by 13.5% than in control (p 0.001). Mean life span among the last surviving 10% of the experimental mice was longer than in control by 21.5% while maximum life span--by 21%. Although the number of tumor bearers under 7 months in the study group was twice that in control (p0.05), they had almost equalized by the end of the experiment. The number of multiple malignancies and the size of tumor and metastases to the lung increased too.

Formation of specific immune response of Geren's carcinoma (GC) versus its biological properties was studied in non-inbred rat spleen. GC growth was accompanied by mounting immune response to tumor-associated antigens (TAA) which was evaluated by macrophage adherence inhibition test. Increase in cell-mediated response to such antigens passed through stages determined by the peculiarities of GC growth in spleen tissues. Immune response to TAA was reported in half the animals as the cells were taking. Enhanced proliferative pool of tumor, aneuploidy and DNA index offset by the low level of apoptosis were characteristic of tumor progression stage. The combination of those factors served as a backdrop for immunologic tolerance development in all the animals. Immune response resurfaced as apoptosis intensified during generalized tumor growth when cell proliferation in the parenchyme declined.

Peripheral blood was sampled for cytochemical assay of cationic proteins from three groups of animals--intact ones, those with tumor C45 and bearers of the same tumor treated with helium-laser radiation and chemotherapy. Radiotherapy involved such manifestations of enhanced nonspecific antitumor resistance and, in particular, mobilization of the cellular component, as increased number of neutrophils containing cationic protein granules and relatively high levels of such proteins in them. Cytochemical assay of cationic proteins in neutrophil granules may serve as a criterion of nonspecific antitumor resistance assessment.

Inhibition of experimental tumor growth, life-span, mitotic activity and cytologic damage have been studied in cells of ascitic and solid carcinoma of Ehrlich in the course of biotherapy with vaccines of Venezuelan encephalomyelitis virus, mumps and influenza viruses. Summing up, it is concluded that the vaccine of Venezuelan encephalomyelitis virus looks most promising as far as further research in development of an antitumor viral drug is concerned.

An additional criterion is suggested for description of effectiveness of therapy of experimental tumors--tumor growth index. It is a ratio of area covered by the kinetic curve of tumor growth in the study group and that in control. The index is intended to describe the efficacy of therapy in terms of degree and duration of the effect.

A neoplasm in cranial bone of an early Triassic amphibian has been investigated. Although no tissue has survived, the cranial flat bone is similar to that in living animals of the same class. Evidence is presented in support of a hypothesis that the neoplasm is a skeletal tumor which consists of non-functional bone and looks like an atypical tumorous bone of skeletal origin. It was identified as a parostotic osteosarcoma on the basis of macro- and microscopic and X-ray examination.

A significant delay in benz(A)pyrene-induced tumorigenesis was obtained following three series of parenteral injection of xenogenic leukocytic interferon alternating with irradiation at 3-4 day intervals. Radiation was delivered from a red low-energy laser through a puncture in the peritoneal wall of the spleen. When each of said procedures was performed separately similar effects were recorded but the changes were not significant.

The potential of therapy with vaccinal strain of Venezuelan encephalomyelitis virus (VEL) in conjunction with cytostatics (cyclophosphamide) or immunomodulators (T-activin) has been studied. It was found that VEL in conjunction with cyclophosphamide inhibited the antitumor action of the drugs while T-activin potentiated the same effects of the virus and its oncolysate.

Since the methods of investigation of carcinogenicity of different agents have changed drastically, relevant manuals need to be revised and supplemented. A new concept of carcinogenic agents evaluation, criteria for their selection and study are discussed. Working out of criteria for establishing priorities of hazardous substance selection is of vital importance.

Olipiphat is an original lignin-based mix developed by special technology. It showed antitumor action against carcinoma of Ehrlich, breast adenocarcinoma Ca 755, melanoma B 16, lung carcinoma of Lewis, lymphosarcoma of Pliss, Walker's carcinoma, sarcoma 45 (tumor growth inhibition by 83-92%, increase in survival by 42-54%) and spontaneous murine tumors (the total of 9 pathologies). The drug was administered by 3-5 injections at 2-3 day intervals. No immediate cytotoxic or cytostatic effects were registered.

Fifty female CBA mice were given melatonin with drinking water (20 mg/l) for 5 consecutive days monthly, beginning from the age of 6 months, until natural death. Another 50 intact mice were used as controls. Melatonin failed to significantly influence body weight or food consumption. Age-related switching-off of estrus function was delayed, body temperature decreased. Somewhat decreased motor activity did not affect physical one or endurance. Increase in life span led to higher spontaneous tumor incidence. Another experiment using 20 animals of the same line showed melatonin to inhibit free-radical processes. A conclusion was drawn that caution should be exercised before melatonin is recommended for long-term administration as a geroprotector.

Cohort analysis of life span in a uniform LIO rat population established a correlation between death cause and age-related death force parameters. It also demonstrated certain sex-related differences involved. The life span of males which had tumors at the time of death, whatever the real cause of death, was significantly longer than that in tumor-free animals. The life span of tumor-free females and those which died from cancer was shorter while the longest-surviving group bore non-fatal tumors. It is suggested that prognosis of individual survival be based on a combination of traditional procedures of mathematical evaluation of population mortality rates and complex assessment of individual health. This approach envisages formation of cohorts characterized by maximum differences in aging dynamics.

The biological activity of cycloferon (CF) used in interferon manufacture has been investigated for its therapeutic and prophylactic properties which may be used for radiotherapy of glioma. It was demonstrated in experiments on rats that use of CF is most effective at an early stage of irradiation due to decrease in tumor mass which does not occur in case of irradiation alone. When used at a later stage, CF caused certain hematological indices of immunity to rise. CF did not produce an antitumor effect of its own. It successfully competed with Leukomax when used to bring blood indices in irradiated tumor-bearing animals back to normal.

The study of neoplastic growth capacity in gag-myc F3-F4 transgenic mice showed that they retain the capacity to develop hyperplasia and benign and malignant tumors same as F0-F2 transgenic mice do. However, the histological spectrum of tumors was much narrower, chiefly, due to the absence of rare patterns. The tumors in F3-F4 transgenic mice were mainly lymphomas and epithelial tumors of endocrine or exocrine glands. The incorporation of gag-myc in the genome of F3-F4 transgenic mice failed to tell on the variation of such quantitative polygenic characteristics as body mass and growth.

The influence of cycloferon and its combinations with cyclo-phosphamide on the growth of transplantable tumors was studied in rats with lymphosarcoma of Pliss and CBA and NMRI mice bearing Ehrlich's carcinoma and leukemia L1210. While cycloferon alone failed to significantly influence tumor growth, treatment with 100 mg/kg of the drug was followed by longer survival in mice with transplantable Ehrlich tumor. The highest inhibitory effect of combined cycloferon and cyclophosphamide was recorded on day 10 when tumor growth inhibition was as high as 90%. Mitotic activity of tumor was inhibited following multiple treatment with cycloferon, in combination with cyclophosphamide and cyclophosphamide alone. Survival longer than in control was registered only in animals with L1210 receiving cyclophosphamide alone or in combination with cycloferon. Cycloferon administration was shown to inhibit the growth of Pliss lymphosarcoma only within a short period after the start of the study. Combined treatment with cycloferon and cyclophosphamide produced the highest inhibition. The antitumor effect of cycloferon varied depending on tumor pattern, species and line of animals and dose and modality of administration.

The report discusses whether transcranial electrostimulation in cancer patients can be accepted. A number of tumors were inhibited in an experiment using 120 rats. The procedure used in 80 cancer patients was followed by favorable changes in the concentration of several hormones. The antinociceptive action of electrostimulation is similar to that of narcotic analgetics.

Subcutaneous injections of 21 mg/kg 1,2-dimethylhydrazine were given weekly to 134 female LI0 rats. In the first series, 73 rats received 15 injections while 63 animals--5 injections (series 11). Some rats were also fed Aqualen (0.1 or 1.0 g/kg b.w.) during the whole experiment (6 months). In run 1, all animals developed malignant tumors of the colon. However, multiple tumors in Aqualen-fed rats were significantly less frequent than in those receiving carcinogenic agent alone. Also, Aqualen appeared to inhibit the development of carcinoma in the small intestine. In run 11, Aqualen treatment was followed by decreased incidence and multiplicity of tumors both in the entire large intestine and ascending and descending colon. Rectal tumor incidence was lower, too. In both runs, tumor size in enterosorbent-fed animals was smaller than in controls. All intestinal tumors were adenocarcinomas. No pathology was observed in Aqualen-fed rats untreated with the carcinogenic agent.

Male and female SHR mice were exposed to irradiation from the display terminal of a personal computer, 1 hr, 5 times a week for 2 weeks. Then the animals were mated and tumor yield in the progeny was studied. The descendants of intact mice were used as control. A significant increase in total tumor incidence was recorded in males and females in the experimental group. Adenocarcinoma of the mammary gland highly featured in females while lung tumors--in males.