Sindbis viral vectors target hematopoietic malignant cells.

Sindbis viral vectors target and inhibit the growth of various solid tumors in mouse models. However, their efficacy against blood cancer has not been well established. Here, we show that Sindbis vectors infect and efficiently trigger apoptosis in mouse BW5147 malignant hematopoietic T-cells, but only at low levels in human lymphoma and leukemia cells (Jurkat, Karpas, CEM, DHL and JB). The Mr 37/67 kD laminin receptor (LAMR) has been suggested to be the receptor for Sindbis virus. However, JB cells, which are infected by Sindbis at low efficiency, express high levels of LAMR, revealing that additional factors are involved in Sindbis tropism. To test the infectivity and therapeutic efficacy of Sindbis vectors against malignant hematopoietic cells in vivo, we injected BW5147 cells intraperitoneally into (C3HXAKR) F1 hybrid mice. We found that Sindbis vectors targeted the tumors and significantly prolonged survival of tumor-bearing mice. We also tested the Sindbis vectors in a transgenic CD4-Rgr model, which spontaneously develop thymic lymphomas. However, infectivity in this model was less efficient. Taken together, these results demonstrate that Sindbis vectors have the potential to target and kill hematopoietic malignancies in mice, but further research is needed to evaluate the mechanism underlining the susceptibility of human lymphoid malignancies to Sindbis therapy.

Advanced oxidation protein products in obese women: its relation to insulin resistance and resistin.

Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, is thought to take a part in the development of insulin resistance and T2DM. The aim of this study was to characterise the changes in circulating levels of resistin and proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in diabetic and prediabetic obese patients and to explore their relationship to insulin resistance. Attempts were also made to see whether resistin levels are related to the degree of oxidative stress, as determined by the measurement of advanced oxidation protein products (AOPPs). The study groups consisted of obese diabetic (BMI: 30-42 kg/m(2), n=28) and prediabetic (BMI: 29-41 kg/m(2), n=23) women. Fourteen healthy women, with BMI in the range 21.5-25.5 kg/m(2), were taken as controls. Serum levels of TNF-a, IL-6, resistin, glucose, insulin and AOPPs were measured. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). Diabetic and prediabetic obese patients had increases in serum resistin and TNF-alpha levels (P<0.01 and P<0.001, respectively). IL-6 levels in diabetic patients were significantly higher than in prediabetics (P<0.05). AOPP levels were also significantly higher in diabetics than prediabetics and controls (P<0.05 and P<0.001, respectively); and positively correlated with blood glucose. Insulin was significantly associated with circulating resistin and TNF-alpha. The development of insulin resistance may contribute to the elevation of circulating resistin or vice versa. Determination of AOPPs may be helpful for monitoring the impaired glucose metabolism in obesity.

Coadministration of melatonin and estradiol in rats: effects on oxidant status.

This study was designed to investigate the effects of melatonin and estradiol (E2) on lipid peroxidation and antioxidant defense enzymes in blood and liver tissue when administered in vivo. Wistar albino rats were divided into three experimental groups and treated with either estradiol (25 mg/kg bw, s.c.), melatonin (i. p.), or melatonin plus E2, whereas control animals had diluent injections only. Melatonin was given 10 mg/kg bw x 2 intraperitoneally 30 min before and 60 min after E2 treatment to the melatonin plus E2 group. Animals were sacrificed three hours after the estradiol injection, and their blood and liver tissues were prepared for biochemical analyses. Tissue malondialdehyde (MDA) levels and antioxidant enzyme activities--superoxide dismutase (SOD) and glutathione peroxidase (GPx)--were determined in the postmitochondrial fraction, and the results were compared. Estradiol injection caused significant increases in both MDA levels and GPx activity in liver. When melatonin was administered in combination with E2, the effect of estradiol on MDA levels was abolished. A significant decrement in SOD activity occurred in melatonin-treated animals. GPx activity in the blood of E2 plus melatonin-injected animals was significantly higher than those in control animals. Melatonin-treated animals exhibited relatively lower levels of SOD activity than those from the control and E2 plus melatonin groups. This indicates that estradiol could exert oxidant action resulting in an increment in tissue malondialdehyde levels. Enhanced activity of GPx in both liver and blood following melatonin injection may indicate the contribution of this neurohormone on the antioxidant defense.

Response in DNA ploidy of hepatocytes to tamoxifen and/or melatonin in vivo.

Tamoxifen is known to induce hepatocarcinogenesis in experimental animals and reversible chronic liver diseases in humans. Melatonin has been recently introduced as an oncostatic agent, especially for hormone-dependent tumors. This study was designed in order to investigate whether melatonin has an effect onthe tamoxifen-induced hepatotoxicity. Wistar albino rats were injected tamoxifen citrate intraperitoneally in three different doses (10 mg/kg and 20 mg/kg bw for 26 days; and 45 mg/kg bw for three days). Another group of animals were treated with melatonin once a week in addition to daily tamoxifen injections, whereas the third group received melatonin only. The control animals were injected an equal volume of diluent at corresponding intervals. At the end of the experimental period, the animals were sacrificed and the livers were prepared for the flow cytometric DNA analysis. DNA histograms were analyzed using the multicycle program. In experimental groups, all animals had aneuploid cell population. The difference in the diploid/ aneuploid ratio of each experimental group as compared to the control group according to Fischer's exact test was found to be highly significant (p < 0.002 MEL vs control; and p < 0.0001 for both TAM vs control and MEL+TAM vs control). Among the tamoxifen-injected animals, the proportion of multiploidy to aneuploid cell population was 17, similar to those treated solely with melatonin. Although the melatonin plus tamoxifen group had higher multiploidy percentage (38%), the difference was not statistically significant as compared to the tamoxifen (or melatonin) groups. No significant difference was noted between the animals which were treated with three different doses of tamoxifen. S-phase fraction percentage was significantly different in melatonin- and melatonin plus tamoxifen-injected animals with regard to controls, the degree of significancy being < 0.05 for both. According to our data, tamoxifen injections induced DNA aneuploidy, but did not stimulate proliferation in the liver as estimated by S-phase fraction. Melatonin, whether alone or in combination with tamoxifen, stimulated cell proliferation and produced aneuploidy.

Acute effects of estradiol and of diethylstilbestrol: pro- or antioxidant potential?

This study was aimed to examine the effects of a single high dose of natural and synthetic estrogens on the antioxidant defense enzymes in liver and blood. Female Wistar albino rats, four to six months old, were divided into three groups, and received either i.p. injections of diethylstilbestrol (DES ; 150 mg kg(-1) b.w.) or s.c. injections of estradiol (E2; 25 mg kg(-1) b.w.), and the third group (control) was injected the solvent. Animals were killed under light ether anesthesia three hours after injection. Cu-Zn superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (Cat) enzyme activities and fluorometric malondialdehyde (MDA) determination were performed in liver tissue homogenates and in blood. Acute estradiol injection caused a significant increase in both MDA levels and GPx activity in liver tissue when compared to the controls, (p <0.05 and p <0.02; respectively). Changes in both enzyme activities and MDA concentration were unremarkable following acute DES injection. In blood, only Cu-Zn SOD activity was significantly altered in blood following E2 injection. Although the significance of alteration in GPx activity remains unclear, it is most likely related to enhanced generation of lipoperoxides. A significant increase in MDA concentrations in liver tissue is indicative of pro-oxidative damage rather than an antioxidant action by E2.