Comparative Analysis of the Pharmacological Activity of Bis(3,5-di-Tert-Butyl-4-Hydroxyphenylthiolate)Dimethylol in Different Modes of Administration on a Mouse Model of Melanoma B16 Tumor Growth.

We performed a comparative analysis of the pharmacological activity of the hybrid organotin compound bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) administered in different modes to mice with transplanted melanoma B16 to identify the most effective dosage regimen. Three modes of administration were used: preventive (before transplantation of tumor cells), classical according to Z. P. Sof'ina (48 h after transplantation of tumor cells), and delayed (7 days after transplantation of tumor cells, after formation of nodules of the primary tumor node). Compound Me-3 was administered at a total dose of 375 mg/kg intraperitoneally once a day for 5 days. The classical mode of administration was identified as the most effective, which indicates the preventive antimetastatic activity of Me-3 on the model of the transplanted mouse tumor melanoma B16.

Effect of Hybrid Organotin Compound on Activity of LPO and Antioxidant Protection of the Liver Tissues in Animals with Melanoma B16.

The central element of the "metastatic organotropism" is a shift of the pro/antioxidant balance in cells and activation of oxidative stress and protective antioxidant systems. We studied the effects of bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) in the maximum effective and toxic total doses on the level of markers of oxidative stress and antioxidant protection in the liver of mice with melanoma B16 before the appearance of macroscopic metastases. In 48 h after tumor inoculation, Me-3 was administered intraperitoneally once a day for 5 days in total doses of 375 and 500 mg/kg according to the classical method. Administration of the hybrid organotin compound Me-3 produced different effects on the pro/antioxidant state of the microenvironment of liver tissue as the target of melanoma B16 metastasis. The results suggest that inversion of the anti/prooxidant profile of Me-3 is determined by its dose.

[Diabetes mellitus and cancer: a system of insulin-like growth factors].

Diabetes mellitus and malignant tumors are among the most common and complex diseases. Epidemiological studies have shown a strong relationship between these pathologies. The causality of this relationship has not yet been unambiguously established, but a number of probable biological mechanisms have been proposed to explain it through the effects of hyperglycemia, hyperinsulinemia on the process of oncogenesis. An important role in this is played by the axis of insulin-like growth factors, their receptors and binding proteins (IGF / IGFR / IGFBP). The review provides data on the structural elements of the insulin / IGF / IGFR / IGFBP signaling axis and their internal relationships in diabetes mellitus and in the development of malignant tumors. Significant changes in the axis that occur during the formation of the diabetic environment prepare the background, which, under certain conditions, can lead to the stimulation or inhibition of tumor development. The considered signaling system, playing a significant role in the physiology of normal cells, often functions as a decisive factor in the survival of tumor cells, providing fine context-dependent regulation of many cellular processes associated with oncogenesis. However, despite many years of in-depth studies of the pathogenesis of diabetes mellitus and malignant tumors, the molecular mechanisms of the relationship between these pathologies are still largely unclear, and the internal heterogeneity of pathologies complicates research and interpretation of the results, leaving many questions.

Method to Create Multiple Primary Malignant Neoplasms with Stimulation of Tumor Growth under Conditions of Primary Immunodeficiency in Experiment.

The experimental model of synchronous multiple primary malignant tumors (MPMT) was created. B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline) and sarcoma 45 (0.5 million tumor cells in 0.5 ml saline) were simultaneously subcutaneously inoculated to male BALB/c nude mice. In the model of synchronous MPMT, the tumors appeared faster by 2.4 times and had greater volumes: melanoma by 2.2 times and sarcoma by 3.2 times; melanoma metastasized into sarcoma in 71.4% cases; the survival of mice with MPMT was lower. The altered dynamics of malignant growth in the MPMT model is based on the mutual influence of tumors, which results in the exchange of "structural information".

Method for Stimulation of Malignant Growth by Chronic Pain in Rat Lungs.

We developed a method of reproducing malignant process in the lungs of rats with stimulation by chronic neurogenic pain. In white outbred male rats, chronic neurogenic pain was modeled by bilateral ligation of the sciatic nerves and in 45 days, a suspension of M1 sarcoma cells (106 cells/liter in 0.3 ml physiological saline) was injected into the subclavian vein. In almost all rats receiving transplantation of tumor cells against the background of chronic neurogenic pain, tumor foci in the lungs were detected in 1.5-2.0 months and led to the death of the animals.

[Influence of malignant growth and chronic neurogenic pain on neurosteroid levels in rat brain]. / Vliianie zlokachestvennogo rosta i khronicheskoi neirogennoi boli na uroven' neirosteroidov v mozge krys.

The aim of the study was to determine the level of sex steroid hormones in white matter of the brain of rats with tumors combined with chronic neurogenic pain (CNP), which was modeled by bilateral sciatic nerve ligation. The study included albino male rats (n=74). In the main group, M1 sarcoma was transplanted subcutaneously (n=11) or into the subclavian vein (n=11) 45 days after CNP modeling. Two comparison groups (n=13 each) included sham operated animals (without CNP) with M1 sarcoma transplanted subcutaneously and intravenously. Control groups included animals with CNP and sham operated animals. Rats were euthanized on day 21 of the carcinogenesis. Levels of total and free testosterone (T), estrone (E1), estradiol (E2), estriol (E3) and progesterone (P4) in the brain white matter were measured using ELISA kits ("Cusabio", China). CNP caused a decrease in the total and free T by 1.5 times (p<0.05), E2 and P4 by 1.9 and 3 times, respectively, E3 by 1.6 times (p<0.05), as well as an increase in E1 by 1.4 times (p<0.05) as compared to the corresponding levels in the brain white matter of rats without CNP. CNP stimulated M1 sarcoma growth in both subcutaneous and intravenous transplantation. Regardless of the tumor site, the dynamics of total T, E2 and E3 in the brain had similar features, but the dynamics of free T, P4 and E1 differed. Thus, changes in the level of neurosteroids in the white matter of rat brain with CNP and tumor growth alone or associated with CNP are a reaction to stress.

[A role of diencephalic monoaminergic dysfunction in chronic neurogenic pain].

Changes in catecholamine pool (epinephrine, norepinephrine, dopamine) and 5-oxyindoles (serotonin, 5-oxyindolacetic acid) in the diencephalic structures were studied in 2, 15, 40 days of neurogenic pain syndrome development in rats with double-sided entrapment of N. ischiadicus. The main manifestations of monoamine diencephalic dysfunction in the period of neurogenic pain chronization were described: the reduction of catecholamine pool, most evident in the thalamus; absolute and relative serotonin increase (especially in the hypothalamus); "minimization" of thalamus monoamine potential and shift of diencephalic balance to the hypothalamic MA-ergic component domination. The possible mechanisms of the imbalance and its role in the deformation of noci-antinociceptive interaction in the neurogenic pain process are discussed.