In a past decade became evident that phosphatidylinositol-3-kinase controlled signal transduction cascade (PI3K/Akt/PTEN/mTOR) is implicated in resistance of tumor cells to anticancer drugs. Another well studied mechanism of multidrug resistance is associated with the activity of drug transporters of ABC superfamily (first of all P-glycoprotein (Pgp), MRP1, BCRP). Several mechanisms of cell defense can be turned on in one cell. The interconnections between different mechanisms involved in drug resistance are poorly studied. In the present study we used PC3 and DU145 human prostate cell lines to show that PTEN functional status determines level of cell resistance to some drugs, it correlates with expression level of MRP1 and BCRP proteins. We showed that Pgp is not involved in development of drug resistance in these cells. Transfection of PTEN into PTEN-deficient PC3 as well as rapamycin treatment caused the inhibition of PI3K/Akt/mTOR signaling and resulted in cell sensitization to the action of doxorubicin and vinblastine. We showed that PTEN transfection leads to the change in expression of MRP1 and BCRP. Our results show that in prostate cancer cells at least two mechanisms of drug resistance are interconnected. PTEN and mTOR signaling were shown: to be involved into regulation of MRP1 and BCRP.

The Val-Val-Tyr-Pro-Asp bone marrow peptide (MP-5) and an analogue (MP-5-Lys) were synthesized. Fluorescent derivatives, Ftc-MP-5 and MP-5-Lys(Ftc), were prepared. The biological activity of MP-5 and MP-5-Lys was studied in vitro and in vivo. The MP-5 peptide caused 60-84% inhibition of growth of the following mouse cancers: lymphatic leukemia P-388, melanoma B-16, and cervical carcinoma CUC-5. These peptides also restored functional activity of T lymphocytes that was inhibited by metabolic products of the HL-60 leukemic cell line. MP-5-Lys(Ftc) was shown to preserve the functional properties of MP-5 toward T lymphocytes, but Ftc-MP-5 was practically inactive.

In this study, we have examined the organization of the mitotic spindle poles in CHO-K1 cells dividing after treatment with the etoposide (1 h, 25 microM). We studied at various periods after the treatment: 1) the distribution of gamma-tubulin in mitotic cells by immunofluorescent staining; 2) the level of posttranslational modification of a-tubulin in the spindle microtubules by immunoelectron microscopy; 3) the ultrastructure of the mitotic apparatus poles by standard electron microscopy. In 48 h after the addition of the agent we identified considerable changes in the ultrastructure of poles in etoposide-treated CHO-K1 cells with bipolar and multipolar spindles. The number of centrioles increased. The centrioles were unevenly distributed among the poles, and some centrioles were not explicitly involved in the organization of mitotic spindle, furthermore they can differ in the number of outgrowing microtubules. Most centrioles were without fibrillar halo. In 48 h after the addition of etoposide, electron microscopy of cells after immunoperoxidase staining with antibodies to acetylated and tyrosinated alpha-tubulin has shown that different poles of a multipolar spindle within the same cell are stained differently for tyr-tubulin but not for acet-tubulin. Immunofluorescence staining for gamma-tubulin also points to different organization of poles in the same spindle. Our findings provide the first evidence that the pattern of immunostaning and the ultrastructure of mitotic apparatus poles differ in the cells dividing at various periods after etoposide treatment.

Etoposide (1 h, 25 microM) causes interphase arrest in CHO-K1 after which cells resume mitotic division and die due to apoptosis after a certain time period. Accumulation of apoptotically dying cells in the culture follows a gradual increase in the number ofmultipolar mitoses. Our findings provide the first evidence that the pattern of immunostaning for alpha-tubulin, acetylated alpha-tubulin and tyrosinated alpha-tubulin in cells dividing at various periods after etoposide treatment. Moreover, some parts of the multipolar mitotic spindle differ in the presence of antigenic determinants accessible to anti-tyrosinated alpha-tubulin antibodies. It is noteworthy that these abnormalities are aggravated just before the increase in the number of apoptotically died cells. Our findings also suggest that some cells pass through at least two mitotic cycles prior to a sharp increase in the number of apoptotically died cells in the cell culture.

The topical problem of experimental neurobiology is the development of pharmacological models to search for correlation between induced brain pathology and changes in behavioral phenotype. Cytosine arabinoside (Ara-c) is an antiproliferative agent, exposure to which in the critical period of the embryonic formation of the cortex results in the abnormality of its development. This study was aimed at estimation of the somatic and sensorimotor aspects of the early postnatal maturatrion of behavioral acts in mice with developmental abnormalities of the cortex induced by Ara-c. Pregnant C57BL/6 mice were injected with the substance on the 12.5th 13.5th gestation days. Offspring behavior was studied using a modified Fox battery on the 1st-21st postnatal days. Severe disorders of the sensorimotor development with slight somatic changes were revealed in the offsprings of Ara-c-treated mice. Features of these pathological changes point to a correlation between the developmental changes in behavioral phenotype and irregularities of the cortex formation. This experimental model can be applied to neurobiological and pharmacological studies.

We studied efficacy of a combination of intraosseous and systemic administration of drugs in patients with invasive cancer of the urinary bladder (UB). A total of 20 patients aged 54-79 years with verified had recurrence, 2 had tumors with continuous growth. T2N0M0 UB carcinoma was diagnosed in 7 patients, T3N0M0--in 12, T6N0M0--in 1 patient. All the patients received systemic chemotherapy with gemzar in a single daily dose 800-1000 mg/m2 on day 1, 7 and 14. On day 2 a single intraosseous 100 mg eloxatin was given. A total of three courses of combined chemotherapy with 4-week interval was used. Intravenous gemzar administration was accompanied with mild leukopenia in 4 patients, moderate leukopenia--in 1, allergic reaction--in 2 patients. This required gemzar discontinuation. No side effects were seen in response to intraosseous administration of eloxatin. The combined chemotherapy produced complete regression of UB cancer in 3 of 18 patients, partial regression--in 12, stabilization--in 3 patients. Neither local nor long-term tumor progression was found. Short-term therapeutic efficacy of combined therapy was 70%. Fifteen patients with partial regression or stabilization have undergone transurethral resection. Duration of a recurrence-free period reached 5 to 72 months (mean 17 months). The neoadjuvant chemotherapy proposed by us allows achievement of a high percentage of regression in patients with invasive UB cancer located in UB cervix and provides concervative surgery including patients over 70 years of age.

The review analyses contemporary data on the role of the interferon-alpha in the central nervous systems. Interferon-alpha is one of the key polyfunctional cytokines providing integrative activity of the neuro-immuno-endocrine complex. The emphasis is made on the molecular mechanisms of anti-viral, anti-proliferative and neuromodulating actions of the interferon-alpha in the brain. Mechanisms of its involvement in regulation of pain, sleep, body temperature, circadian rhythms, food consumption etc. are considered. Based on the literature and our data we hypothesized a dose-dependent action of exogenous interferon-alpha on the nervous system. We suggest that optimal schemes of chronic application of small interferon-alpha doses can be more expedient for treatment of viral or oncologic diseases than large doses causing neuropsychiatric disorders.

The aim of the work was the investigation of pharmacological activity of unique dihydroflavonol glycoside, micranthoside, extracted from the leaves Eupatorium micranthum Less. introduced into Georgia. Mature human T-cell leukemia cell lines (Jurkat) were analyzed in the study under the modeled oxidative stress. For modelling of oxidative stress 30% hydrogen peroxide (H(2)O(2)) (Sigma) (100 microM) was added to Jurkat cell incubation suspension with subsequent incubation for 24, 48 h. Under the effect of H(2)O(2) there was significant elevation of superoxide and peroxyl radical levels, as well as free NO levels, and reduced antioxidant enzyme SOD activity. It was shown that dihydroflavonol glycoside, micranthoside, extragated from Eupatorium micranthum Less., has marked antioxidant properties, it inhibits hyperproduction of reactive oxygen species, and protects cells against oxidative damage, stimulates cell proliferation and inhibits necrosis in cell line.

The basidiomycetes Ganoderma lucidum, Hericium erinaceus, Lentinus edodes and Trametes versicolor were used for preparation of aqueous extracts. A polysaccharide preparation (VPG) was isolated from the G. lucidum aqueous extracts. The mycelium was grown under submerged conditions according to an original procedure. Preliminary exposure of mice with tumors to cyclosphosphamide in a low dose for prolonged elimination of T-suppressors and rapid recovery of T-killers induced an increase in the efficacy of the H. erinaceus and L. edodes extracts. Investigation of the aqueous extracts and VPG on different tumor strain lines for the potential Modifiers of Biological Response (Ca755, s/c P388, s-180) demonstrated antitumor activity and satisfactory tolerabily after oral administration. Inhibition of the tumor growth by the H. erinaceus and T. versicolor extracts and VPG amounted to 88-99% and that of s-180 treated with the L. edodes aqueous extract amounted to 66-75%. Compositions 1, 2, 4 amd 5 were significantly more active by the duration and value of the effect on the animal tumor nodes as compared to the aqueous extracts and VPG included to the compositions and composition 4. Composition 5 (T. versicolor + H. erinaceus + G. Lucidum) proved to be the most efficient by all the criteria. The results of the design of the technologies for cultivation of the mycelum of the medicinal basidiomycetes, investigation of the antumor properties of the extracts and polysaccharide fraction of the mycelium and development of efficient compositions on their basis are summarized. Composition 5 proved to be the most promising for the clinical trials.

The authors summarize in the article experience of a new anticancer drug Polyplatillen use in the chemotherapy of advanced pancreatic cancer. Polyplatillen use in the palliative chemotherapy in the patients with advanced pancreatic cancer permits to realize a control of pain and stabilize an ECOG status. Tendency to the improvement of total survival during an early period was registered in the group of patients with advanced pancreatic cancer who were treated with Polyplatillen.

Mexidol therapy inhibited cyclophosphamide-induced myelosuppression in C57B1/6 line mice with Lewis lung carcinoma without affecting antitumor action of the latter. Mexidol plus cyclophosphamide proved more effective in prophylaxis of metastasis as compared with the cytostatic alone.

The report reviews the experience gained with radio- and chemotherapy-related injuries suffered by bladder cancer patients. It corroborates the opinion of most European specialists that indications for radical cystectomy be extended with due considerations of up-to-date potential in anesthesiology, extensive care and pharmacology. Possible untoward side effects of radiation and intravesical chemotherapy as well as means of solution of the problem are discussed. It is urgent considering the constantly growing number of such patients, their age and associated somatic problems.

Transcatheter treatment for liver metastases from breast cancer was given to 55 patients (1995-2006): hepatic artery infusion (HAI) with 5-fluorouracil, doxorubicin and carboplatin--11; hepatic artery oil chemoembolization (HAOC) with doxorubicin--14; taxotere (Docetaxel)--17; HAI+HAOC--13. Partial response was reported in 18%, stabilization--27%, metastatic progression--55%. Mean survival (MS) of all deceased patients--11.9 +/- 1.5; 1-, 2- and 3-year survival--40, 20 and 0%, respectively. HAOC: partial response and stabilization--42%, progression--58%. As of January 2007, 7 patients survived 8-22 months (mean 14.3 months); 24 deceased had survived 16.8 +/- 3.3 months. HAOC+HAI: complete response--8%, partial--23%; stabilization--44%; progression--25%. Three patients have survived 24, 33 and 82 months; mean survival of 10 deceased--19.9 +/- 4.5 months, their 1-, 2- and 3-year survival was 90, 60 and 20%, respectively.. Mean survival of doxorubicin-treated patients was 18.9 +/- 1.6, taxotere--24.8 +/- 5.1 months (p < 0.05); 1-, 2- and 3-year survival- 57, 29 and 7%, and 88, 35 and 24%, respectively. HAOC+HAI was the most effective while application of taxotere was followed by longest mean survival.

The paper discusses the advantages offered by two regimens of therapy of Hodgkin's disease in children and adolescents (139)--DAL-HD (versions 87 and 90) (83) and SPbHD-05 (56). Survival rates were fairly high (OS--94.3%; DFS-- 90.0% and EFS--81.2%); they differed depending on risk group. Both the potential of a largen choice of prognostic criteria used in risk grading and the hazards from akylating drugs and anthracyclines were demonstrated.

The overexpression of a new cytokine-induced apoptosis inhibitor 1 (CIAPIN1) gene has been shown previously to promote a multidrug resistant phenotype in gastric cancer cells through the upregulation of MDR1 and MRP1. In the present study, we constructed the siRNA eukaryotic expression vectors of CIAPIN1 and transfected them into SGC7901/VCR cells to examine whether the down regulation of CIAPIN1 increased cell sensitivity towards chemotherapeutic drugs. After transfection, the expression of CIAPIN1 was dramatically decreased in CIAPIN1 siRNA transfectants compared with that in parental cells and empty vector control cells. The down-regulation of CIAPIN1 significantly enhanced the sensitivity of SGC7901/VCR cells to vincristine (VCR), adriamycin (ADR) and etoposide (VP-16), but not to 5-fluorouracil (5-FU) and cisplatin (CDDP). Cell capacity to efflux adriamycin decreased markedly in CIAPIN1 siRNA transfectants, and correlation between CIAPIN1 down regulation and decreased MDR1 transcriptional activity were observed. CIAPIN1 siRNA could significantly down regulate the expression of Bcl-2, and up-regulate the expression of Bax, but not alter the expression of PTEN in gastric cancer cells. These observations suggested that the siRNA constructs of CIAPIN1 we obtained could effectively down-regulate the expression of CIAPIN1 and reverse the resistant phenotype of gastric cancer cells. The further study of the biological functions of CIAPIN1 may be helpful for understanding the mechanisms of multidrug resistance of gastric cancer and developing possible strategies to treat gastric cancer.

The present review summarises the data obtained by analysing the publications dedicated to using paclitaxel-eluting stents in management of coronary heart disease. The stents containing paclitaxel (taxol) proved to have high clinical efficacy in both single and multiple stenoses of the coronary arteries. The feasibility of using taxol-eluting stents in patients suffering from diabetes mellitus and in patients diagnosed with chronic coronary occlusion does not admit of any doubt. However, the rate of restenoses development following implantation of the paclitaxel-eluting stents is higher than that after using the syrolimus-releasing stents. Unsolved as yet remains the issue concerning the efficacy of the paclitaxel-eluting stents intended for treatment of restenoses inside the stent, as well as concerning the feasibility of using these stents for stenting the main trunk of the left coronary artery.