Tirapazamine has no Effect on Hepatotoxicity of Cisplatin and 5-fluorouracil but Interacts with Doxorubicin Leading to Side Changes in Redox Equilibrium.

Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anticancer therapy of tirapazamine with a routinely used anticancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in this study, the effect of tirapazamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5-fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were killed, and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose-6-phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG-CoA-reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5-fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anticancer activity in similar schedules.

The influence of a thyroxine supplemented diet on selected hepatic redox equilibrium markers, liver morphology and the serum lipid profile in rats treated with doxorubicin.

INTRODUCTION: Cytotoxicity of doxorubicin (DOX) - an anticancer drug, mostly results from reactive oxygen species (ROS) generation. Some enzymes catalyzing this process and enzymes of antioxidant defense are regulated by iodothyronine hormones. Thus, disorders in iodothyronine hormone status may affect doxorubicin-induced redox imbalance and anabolic/catabolic disorders. The aim of this study was to evaluate the influence of doxorubicin and thyroxine (T4) associated treatment on liver morphology, markers of oxidative stress and plasma lipid parameters. MATERIALS AND METHODS: Rats were intraperitoneally treated with doxorubicin (1.5 mg/kg) once a week for ten weeks. Thyroxine was simultaneously given in drinking water (0.2 or 2.0 mg/l) for 14 weeks. RESULTS: There were higher hepatic level of malonyldialdehyde (MDA) of all tested groups and at the same time in rats treated with DOX plus T4 lower concentrations of total glutathione compared to controls were observed. Morphology of liver did not show any features of necrosis or steatosis but a decrease of glycogen content in T4+DOX groups compared to DOX treatment was observed. The concomitant administration of a lower dose of thyroxine and doxorubicin decreased triglycerides (TG) and increased LDL level compared to the DOX group. DISCUSSION: Thyroxin supplementation caused redox equilibrium disorders and oxidative stress in liver of rats receiving DOX. The study revealed the normalizing influence of thyroxin on glycogen deposits that were observed after doxorubicin treatment. Apart from an adverse impact of thyroxine administration on LDL in rats treated with doxorubicin, a beneficial effect of lower dose of thyroxine on serum TG level was revealed.

Intensification of doxorubicin-related oxidative stress in the heart by hypothyroidism is not related to the expression of cytochrome P450 NADPH-reductase and inducible nitric oxide synthase, as well as activity of xanthine oxidase.

Cytochrome P450 NADPH-reductase (P450R), inducible synthase (iNOS) and xanthine oxidase play an important role in the antracycline-related cardiotoxicity. The expression of P450R and iNOS is regulated by triiodothyronine. The aim of this study was to evaluate the effect of methimazole-induced hypothyreosis on oxidative stress secondary to doxorubicin administration. 48 hours after methimazole giving cessation, rats were exposed to doxorubicin (2.0, 5.0 and 15 mg/kg). Blood and heart were collected 4, 48 and 96 h after the drug administration. Animals exposed exclusively to doxorubicin or untreated ones were also assessed. The hypothyreosis (0.025% of methimazole) significantly increased the doxorubicin effect on the cardiac carbonyl group and they may increase the glutathione level. An insignificant effect of methimazole was noticed in case of the cardiac lipid peroxidation product, the amount of DNA oxidative damages, iNOS and xanthine oxidase-enzymes responsible for red-ox activation of doxorubicin. However, the concentration of P450R was affected by a lower dose of methimazole in rats administered with doxorubicin. Since in rats receiving doxorubicin changes in oxidative stress caused by methimazole were not accompanied by elevation of bioreductive enzymes, it may be concluded that these changes in the oxidative stress were not related to the tested enzymes.

Unusual interleukin-1 and -6 expression in fetal cartilage is associated with placental abnormalities.

Unusual expression of interleukin-1alpha, -1beta and -6 was previously found in the epiphyseal cartilage of rat fetuses prenatally exposed to various non-steroidal anti-inflammatory drugs (NSAID, i.e., ibuprofen, piroxicam, tolmetin) and selective cyclooxygenase-2 inhibitor (DFU). The aim of the present study was to evaluate the role of placenta in such phenomenon. Morphology of the organ, thickness of basal and labyrinth layer, immunoexpression of COX isoenzymes were examined, and confronted with maternal biochemical data and fetal developmental parameters. Higher maternal urea level, as well as lower placental weight and labyrinth thickness were found in the group of fetuses who revealed expression of genes coded the selected interleukins, when compared with the xenobiotic-exposed pups without the selected genes expression and untreated control. A significant correlation between placental weight and maternal total protein or urea level was revealed. Histological changes like inflammatory infiltration and calcification were observed sporadically. Location and intensity of COX-1 staining was similar in all cases. However, more intense COX-2 staining for majority of cells of the basal zone and in dispersed giant cells of the labyrinth was found in inflamed organs. It could be concluded that abnormal expression of the selected interleukins is associated with low placental weight and decrease of its thickness, especially labyrinth zone, as well as with high maternal urea level.

[The diagnosis of anthracycline-induced cardiac damage and heart failure]. / Diagnostyka uszkodzen i dysfunkcji miesnia sercowego wywolanych antracyklinami.

Routine examinations during chemotherapy containing anthracyclines evaluate heart function before treatment and monitor cardiotoxic effects during and after therapy. A number of methods are useful in cardiac assessment, including electrocardiography, radiology techniques (RTG, CT, MRI,PET-CT, PET-MRI), echocardiography, radioisotope imaging techniques (scintigraphy, MUGA,PET), and ultra-structure evaluation in biopsy samples. Nevertheless, there is a continuous need for new methods to predict future damage at the initial stages of cardiac changes. In recent years the therapeutic usefulness of biochemical blood parameters in anthracycline-treated patients has been assessed. The levels of cardiac troponins (cTnI, cTnT), natriuretic peptides (ANP, BNP), and endothelin 1 have been included in the studies. Heart-type fatty acid binding protein (H-FABP) is another promising factor showing cardiomyocytic impairment. However, the clinical use of biochemical parameters in diagnosing anthracycline-related cardiotoxicity is still a controversial issue.