Vol 22, No 3 (2017)

There was given a review of data on pharmacology of fentanyl with focus on transdermal formulation. In the first part of the article improvements in technology of fentanyl transdermal patches were reviewed and advantages of the membrane-matrix system that are of practical use were highlighted. The results obtained from bioequivalence and therapeutic equivalence studies of traditional and improved transdermal fentanyl systems were given. Clinical trials with fentanyl transdermal patches as well as systematic reviews and meta-analyses on the efficacy and safety of transdermal fentanyl were summarized. The second part of the article will focus on factors contributing to the variability in pharmacokinetics and pharmacodynamics of fentanyl including pharmacogenetics; the taking into account the whole spectrum of these factors would allow to escaped the majority of errors during the administration of the drug e.g. transdermally. A special attention will be paid to basic principles and issues of the application of fentanyl transdermal therapeutic systems.

Objective. To study the relapse-free overall survival in metastatic renal cell carcinoma (mRCC) patients after the targeted therapy and to develop optimal approach to the treatment shedule. Material and methods. The research included 88 mRCC patients of mean age of 55.5 + 9.6 years, 63 (71.6%) men and 25 (28.4%) women. 42.0% patients had a favorable prognosis, 52.3% - intermediate one and 5.7% of the cases had poor prognosis. First line targeted therapy was carried out in 88 patients, the second line - in 26 patients, and the third line - in 7 patients. Results. The one or several lines of targeted therapy allowed to achieve 20 months of a median in survival without progression of the disease. Several lines of treatment increased a median of general survival up to 42 months in comparison with the patients who were involved in the one line of treatment (a median = 30 months), p = 0.001. Side effects of targeted therapy were reversible. In the first line targeted therapy the preference was given to sunitinib, in the second line - to sorafenib. Sorafenib had an advantage in case of not light-cellular forms of renal carcinoma. In cases with favorable prognosis factors, metastases into organ parenchyma, targeted therapy with bevacizumab was carried out.

Ovarian carcinoma is the leading cause of death from gynecological cancer. Aim of the study is to reveal the role of VEGF-C comparing to VEGF-А in the progression of ovarian cancer. Material and methods. Tissue samples obtained from 76 patients with epithelial ovarian cancer (serous cystadenocarcinoma: T1N0M0; T2N0M0; T3NxM0; T4Nx-1M0) and 47 patients with cystadenoma were studied. Histological control was performed in all cases. Ovaries of 20 patients obtained during the surgery for uterine myoma were used as the intact tissue. All patients were 50.9 ± 2.9 years old. Levels of the growth factor as VEGF-A and its receptor VEGF-R1, as well VEGF-С and its receptor sVEGF-R3 - were measured by ELISA with the use of standard test systems. Results. VEGF-А levels in cystadenomas and intact tissue were similar, while in cystadenocarcinomas VEGF-А was significantly higher at all stages of the tumor development. sVEGF-R1 receptor in cystadenomas was lower in comparison with the intact tissue, in the contralateral ovary in T1N0M0 and in the tumorous ovary in T4Nx-1M0. VEGF-С level was higher significantly in all tumors, in cystadenocarcinomas it was higher if compared to cystadenomas. Its increase in the contralateral ovary in T1N0M0 differed from other tissue values being average. sVEGF-R3 receptor increased significantly at the later stages of ovarian cancer - T3NxM0 and T4Nx-1M0; its level was low only in the contralateral ovary in T1N0M0, and the values in other tissues were similar to the intact ones. Conclusion. The results show a high rate of lymphatic vessel formation in benign tumors at all stages of the development of the malignant tumor. The significant increase in VEGF-C level in the contralateral (non-tumorous) ovaries, compared to the intact tissue, allows considering VEGF-C, along with VEGF-А, as a pathogenetic factor of ovarian tumor development.

Oncolytic viral therapy is a promising approach to targeted therapy of malignant tumors. In this article we consider the therapeutic potential of a non-pathogenic Coxsackie A7 virus (CA7V) with neurotropic properties on a model of human neuroblastoma. Purpose to study in vitro/in vivo sensitivity of human neuroblastoma HNB (from cell line JMR-32) to Coxsackie virus A7 (CA7V). Objectives: еvaluation of cytolytic activity in vitro on NB cells verified by cytomorphology and assessment of dynamics of the growth of subcutaneous neuroblastoma xenografts in Balb/c nude male mice exposed to CA7V multiple i.v. injections. Material and methods. CA7V was produced in the cells of line-producer С-33А. Cell culture and the strain of transplanted NB (JMR-32) were obtained from the Collection of N.N. Blokhin Russian Cancer Research Center. Cytomorphologic verification of neuroblastoma and CA7V cytolytic activity were executed with the use of standard cultural methods, TCID50 and IC50 criteria. Experiments «in vivo» were performed on immunodeficient Balb/c nude male mice bred and reared in the N.N. Blokhin Russian Cancer Research Center. The experiments were made at day 6 when neuroblastoma subcutaneous xenografts developed to the Vmean = 79-82 mm3 by day 6. The treatment with CA7V at the i.v. single dose of 1×108 cells per mouse was performed 3 times with 72-hours intervals; evaluation of the efficacy was made according to standard criterion Т/С ≤ 42%; and control of the tumor growth rate (Vt/V0) in the dynamics. Statistical assessment was made with the software Excel for Windows 2007 with the use of T-test under p ≤ 0.05. Results. Cytolytic effect of CA7V on neuroblastoma cells was registered similar to basic parameters of the original line-producer С-33А: TCID50 = 0.99×10-4 pfu/cell, and IC50 = 1.11×10-4 pfu/cell; 48 and 72 hours after virus reproduction in NB cells the rate was 2.0 and 1.5-fold higher than in the line-producer cells. СA7V inhibiting effect on the growth of large subcutaneous neuroblstoma xenografts is registered after the first i.v. injection at the minimal level of T/C = 67% (criterion ≤ 42%) with the 1.5-fold decrease of the tumor growth rate and cancellation of early mice death by day 22 vs day 15 in the control group of untreated mice (n = 8). Conclusion. The obtained results allow to consider human neuroblastoma (JMR-32) to possess the low sensitivity to oncolytic effect of in vitro/in vivo. In order to obtain significant effect in vivo the treatment should be started in mice with 2-fold smaller tumors and a higher initial dose of the oncolytic agent.