THE EFFECTS OF THE COMBINATION OF RAPAMYCIN WITH DOXORUBICIN AND PACLITAXEL ON THE MODELS OF TRANSPLANTABLE TUMORS IN MICE

The study aimed to assess combined treatment with mTOR inhibitor rapamycin and cytotoxic drugs (doxorubicin and paclitaxel) on two models of transplantable tumors - mammary adenocarcinoma in male HER-2/neu transgenic FVB/N mice and solid Ehrlich carcinoma in male 129/Sv mice. Rapamycin (total dose of 3.6 mg kg), doxorubicin (total dose of 15 mg/ kg), paclitaxel (total dose of 6 mg/kg) or their combination were intraperitoneally injected to mice with developed tumor node. Rapamycin showed its own antitumor activity by tumor growth inhibition up to 42% in mammary adenocarcinoma model and up to 57% in Ehrlich carcinoma model. A tendency to an increase in the antitumor activity of chemotherapeutic drugs with the addition of rapamycin was revealed. The cyto-protective effect of the mTOR inhibitor was observed during therapy with doxorubicin and paclitaxel, expressed in a significant decrease in the level of apoptosis in normal epithelium of jejunum crypts. Thus, revealed protective effect of mTOR inhibitor on jejunum epithelium could be applied for reduction of chemotherapeutic drugs enterotoxic effect without any efficiency reduction. Thus, in perspective that could expand the possibilities of standard chemotherapeutic treatment and improve the quality of life of cancer patients.

VEGF dynamical changes in laboratory rodents with transplanted experimental tumors of various histological types

Vascular endothelial growth factor (VEGF) is one of the most important cytokines in charge of proliferation, migration and differentiation of endothelial cells in physiological and pathological processes. Because of this they are involved in pathogenesis of neoplasmatic process namely mechanisms of neoangiogenesis – development of blood-vessels’ network in the tumor as well as adjoining intact tissues. Almost all contemporary antiangiogenic medicines are targeted at either VEGF or its receptors. However, there are practically no conventional models of oncologic pathology nowadays described in detail and recommended for preclinical studies. The present study focuses at changes of VEGF concentrations at va rious stages of disease using experimental tumors of different histological types, intensity of neoplasmatic growth and localization. Development of experimental transplantable tumors of various histological types and locations has been demonstrated to be usually accompanied by increased VEGF blood serum concentration in experimental animals; the dynamic of this increase depending upon the intensity of the tumor growth. A statistically valid decrease of VEGF level in comparison with the previous control point of the study has been demonstrated in BALB/c male mice with subcutaneously transplanted colonic adenocarcinoma on the background of active development of the tumor at the 45th day of the study. Pliss’ Lymphoma, and Lymphocytal Leukemia Р-388 models have been demonstrated to be optimal for the assessment of medicines’ aimed at VEGF elimination pharmacological activity.

Tumor-associated fibroblasts predominantly come from local and not circulating precursors

Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a mouse expressing green fluorescent reporter protein (EGFP) under control of the type I collagen (Col-I) promoter (COL-EGFP) had green stroma, whereas we could not find COL-EGFP+ cells in tumors developing in the parabiotic partner lacking the fluorescent reporter. Lack of incorporation of COL-EGFP+ cells from the circulation into tumors was confirmed in parabiotic pairs of COL-EGFP mice and transgenic mice developing autochthonous intestinal adenomas. Second, transplantable tumors developing in chimeric mice reconstituted with bone marrow cells from COL-EGFP mice very rarely showed stromal fibroblasts expressing EGFP. Finally, cancer cells injected under full-thickness COL-EGFP skin grafts transplanted in nonreporter mice developed into tumors containing green stromal cells. Using multicolor in vivo confocal microscopy, we found that Col-I–expressing fibroblasts constituted approximately one-third of the stromal mass and formed a continuous sheet wrapping the tumor vessels. In summary, tumors form their fibroblastic stroma predominantly from precursors present in the local tumor microenvironment, whereas the contribution of bone marrow-derived circulating precursors is rare.