High Antimetastatic Activity of Platin Liposomal Form after Lyophilization and Storage.

Antimetastatic activity of Platin in lyophilized liposomes stored for 7 years after fabrication was evaluated. The main flaw of liposomes as vehicles for drug delivery to the tumors is their high affinity for the liver, which accumulates a great amount thereof. This property of liposomes can be used for adjuvant therapy of operable primary tumors metastasizing to the liver. It is shown on the model of mouse GA-1 tumor metastases in the liver that platinum(II) complex compound Platin in phosphatidylcholine-cholesterol liposomes, stored for 7 years after lyophilization, causes complete cure of 40% animals, while free Platin prolongs the lifespan of mice with tumors by only 31.7% vs. control (no treatment).

Stimulation of Diethylnitrosamine Metabolism Reduces Its General Toxic and Hepatocarcinogenic Effects.

The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.

Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver.

Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms.

Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice.

Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone.

Sex-Related Differences in the Sensitivity to Carcinogenic Effect of Urethane on the Lungs in Mice Are Reversed after Neonatal Androgenization.

Experiments on male and female CC57BR/Mv mice differing by the sensitivity to carcinogenic effect of urethane on the lungs showed that castration 1 week before carcinogen challenge reduced the number of lung adenomas caused by it in males and somewhat increased the number of tumors in females. Exogenous testosterone after urethane injection caused virtually no changes in urethane effect in males and females. By contrast, elevation of testosterone concentrations in newborn male and female mice by injections or its decrease in feminized males receiving sodium glutamate during the neonatal period reduced the sensitivity to the carcinogenic effect of urethane in adult males and to its increase in females.

PT/Y Mice Are Sensitive to the Inhibitory Effect of o-Aminoazotoluene on Glucocorticoid Induction of Tyrosine Aminotransferase and Its Hepatocarcinogenic Effect.

PT/Y mice used for studies of the effects of mutagens are characterized by the absence of spontaneous tumors of the liver, but often develop these tumors in response to chronic oaminoazotoluene treatment. The level of glucocorticoid induction of adaptive hepatic enzyme tyrosine aminotransferase decreases by more than 70% 24 h after acute injection of o-aminoazotoluene to these animals. These mice can serve as a model for studies of the relationship between the effect of carcinogens on the regulation of activity of adaptive hepatic enzymes and their capacity to induce the development of liver tumors.

Dual effects of indoleamine 2,3-dioxygenase inhibitors on the therapeutic effects of cyclophosphamide and cycloplatam on Ehrlich ascites tumor in mice.

Ethyl pyruvate, an inhibitor of indoleamine 2,3-dioxygenase, slightly suppressed the growth of transplantable Ehrlich tumor in mice and significantly potentiated the therapeutic effect of cyclophosphamide. Another inhibitor amidoxime produced a similar effect. However, both ethyl pyruvate and amidoxime significantly reduced the effect of cycloplatam therapy. The observed changes can be stipulated by different effects of cyclophosphamide and cycloplatam on the subpopulations of lymphoid cells taking part in the formation of antitumor immunity and resistance to tumors.

[Mutagenic activation and carcinogenicity of aminoazo dyes of ortho-aminoazotoluene and 3'-methyl-4-dimethylaminoazobenzene in experiments on suckling mice].

It is found that after administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB,) which was hepatocarcinogenic to rats, in suckling mice, the number of neoplastic lesions in the liver of mice was 3 times higher than after analogous administration of equimolar dose of ortho-aminoazotoluene (OAT)). However, in the Ames test (TA-98 strain of Salmonella typhimurium) with activation by hepatic enzymes (S-9 fraction) of both intact and Aroclor-1254-induced mice and rats OAT contributed by an order of magnitude to revertant colonies compared to 3'-Me-DAB. In vivo inhibition of sulfotransferase activity, the enzyme which catalyzes the final stage of the mutagenic activation of aminoazo dyes, had no effect on carcinogenicity of 3'-Me-DAB but more than 4 times elevated that of OAT. It was concluded that the mechanism of carcinogenic action of aminoazo dyes studied is not genotoxic and that the carcinogenic potential of OAT is lost in the process of mutagenic activation.

Immunomodulating effect of ethyl pyruvate on nonsyngenic transplanted tumor in mice.

Indolamine-2,3-dioxygenase, a tryptophan-catabolizing enzyme, creates local conditions suppressing immune lymphocytes. Expression of this enzyme in tumors protects them from immune mechanisms, while its inhibition partially reduces tumor immunoresistance. This effect is attained by multiple subcutaneous or intraperitoneal injections of ethyl pyruvate, an indolamine-2,3-dioxygenase inhibitor. Experiments on mouse nonsyngenic tumor have demonstrated the immunomodulating effect of chronic oral ethyl pyruvate administered with drinking water.

[Influence of age and sex on hepatotoxic and hypothermic effects of estrogole in mice].

Some physiological effects of estragole under a single intraperitoneal injection in oil solution were studied in GR mice; elevation of blood aminotransferases activity, body temperature and animals lethality were registered. At a dose of 600 mg/kg, estragole killed 100% sucklings of both sexes and 90% adult females but no any adult male. The males aquire resistance to estragole at the time of maturation. Exogenous testosterone administered at the dose of 50 mg/kg 4-2 days earlier increases the resistance of female mice to estragole up to its level in males. However, neonatally androgenized females are as sensitive to the toxic action of estragole as the males. At the dose of 900 mg/kg, estragole defeats adult males as well: significant elevation of aminotransferase activities in their blood is indicative of this. In this case, the enzyme activity reaches its peak after 2-3 days, not at the 1st day as in the case of carbon tetrachloride administration. We have discovered a strong hypothermic effect of estragole which appears to be unrelated to its hepatotoxicity and testosteron level.

OXYS rats as a model of senile cataract.

Changes in the lens appear by the age of 2 months in early aging OXYS rats, at the age of 6 months these changes are detected in 100% animals, and by 12 months both eyes are involved. According to biomicroscopy findings, predominant forms of cataract are vesicular, annular, and dendritic, located in the cortical layer and/or nucleus of the lens. Light and electron microscopy showed morphological changes involving all structural components of the lens: epithelial degeneration progressing with age, deformation of fiber architectonics, and appearance of uneven condensations. Cataract in OXYS rats corresponds to senile cataract, which makes this rat strain a unique model for studies of the pathogenesis of involutive cataract and elaboration of methods for its prevention and correction.

[Cyclophosphamide-induced apoptosis of murine lymphosarcoma cells in vivo]. / Tsiklofosfamid-indutsirovannyi apoptoz kletok myshinoi limfosarkomy v usloviiakh in vivo.

The antitumor action of combination chemotherapy (cyclophosphamide + adriamycin + vincristin + prednisolone) for transplantable nitrosomethylurea-induced lymphosarcoma was studied in male CBA mice. Single injections of the mixture were followed by complete regression of tumors of up to 2 cm in diameter. The effect was shown to be caused by cyclophosphamide (CP) alone, by inducing apoptosis. The other components failed to potentiate the CD effect. Being useless, they are likely to cause harm by contributing to the overall toxic effect of therapy. The nature and duration of CP-induced remission appeared dose-dependent: on day 50 of the administration of 50, 100 and 150 mg/kg body, tumors were detected in 100, 55 and 0% of the animals, respectively. Such means of apoptosis induction as glycocorticoid treatment and ionizing radiation did not cause complete regression.

[Lower urethane carcinogenicity for the lungs of thymus-free nude mice in comparison with immunologically normal littermate mice]. / Bolee nizkaia kantserogennost' uretana dlia legkikh bestimusnykh myshei nude po sravneniiu s odnometnymi immunologicheski normal'nymi myshami.

Lung adenomas arose in 2 of 10 nude mice injected twice with urethane in a dose of 1 mg/g of body weight; these tumours were revealed in 7 of 10 immunologically normal littermates treated in the same way. Mean adenoma numbers were 0.2 +/- 0.13 per nude mouse and 1.2 +/- 0.36 per normal mouse (P less than 0.05). The data obtained do not agree with the immunological surveillance concept which predicts greated number of tumours in the nude mice in comparison with the normal ones.

[Characteristics of hematopoiesis in athymic nude mice]. / Kharakteristika krovetvoreniia u bestimusynkh myshei nude

The bone marrow, peripheral blood and spleen state was studied from the age aspect in Nude mice characterized by recessive nu mutation. A number of blood system peculiarities were revealed in homozygotic (nu/nu) mice by which they differed from the heterozygotic (nu/+) animals: low peripheral blood, bone marrow and spleen lymphocyte count, erythropoiesis depression in the bone marrow and erythroid element hyperplasia in the spleen.

[Development of a rat subline with symptoms of hereditary galactosemia and study of its biochemical characteristics]. / Poluchenie sublinii krys s priznakami nasledstvennoi galaktozemii i issledovanie ikh biokhimicheskikh osobennostei

It was established earlier that the maintenance of rats on a galactose-rich diet induced in rat liver a sequental induction of enzymes, converting galactose to glucose (galactokinase, galactoso-1-phosphaturidytransferase and uridyndiphosphogalactose-4-epimerase); this was followed by the repression of these enzymes. Against the background of the enzyme repression, the continuation of galactose treatment leads to the development of galactosemia symptoms; cataracts, liver lesions growth retardation. Animals with the increased susceptibility to galactose were found in population of Wistar rats; in these animals rapidly developing enzyme induction is followed by sharp repression of enzymes of the galactose metabolism and in them cataracts appear 17-19 days after the start of feeding a galactose-rich diet. A part of the population is resistant to the galactosemic effect of galactose and in these animals cataracts develope only 40-44 days after the beginning of the galactose feeding. By inbreeding of individuals extremely susceptible to galactose and those resistant to it, new substrains of rats were obtained. It is found that in the rats of the galactose-susceptible substrain a number of galactosemic features develope spontaneously and that these features are inheritable. Thus, 85% of the animals of the age of 2.5-6 months have cataract, lens opacities and other lens impairments. In the galactose-resistant substrain no cataracts or lens opacities develope and only slight changes of the lens are observed in 15% of the animals. In the susceptible substrain other features characteristic of galactosemia occur: an increase in the size of thymus, spleen and liver. It is established that in 3.5-5 month old rats of the galactose-susceptible substrain the galactoso-1 phosphaturidyltransferase activity in blood hemolysates is 15 times lower than in rats of galactose-resistant substrain, and in liver the activity of this enzyme is 1.4 times lower. The activity of liver galactokinase and uridyldiphosphogalactose-4-epimerase is slightly higher in rats of galactose-susceptible substrain than in galactose-resistant 1.

[Higher nervous activity in rats with symptoms of hereditary galactosemia]. / Issledovanie vysshei nervnoi deiatel'nosti krys, obladaiushchikh priznakami nasledstvennoi galaktozemii

The patterns of behaviour and neural processes in rats with symptoms of hereditary galactosemia were investigated. Certain impairment of neural processes, particularly of the internal inhibition process in galactosemic rats was established. This is evidenced by low conditioning rate and lower level of responding in 2-way shuttle-box avoidance achieved by galactosemic rats in comparison with galactose-resistant rat substrain. Significant changes in motor activity and emotionality level in the course of repeated open-field testings were not found in galactosemic rats. The pecularities of the active avoidance acquisition, an analysis of the capacity to the retention of acquired task demonstrated an impaired mechanism of long-term memory storage in galactosemic animals.