The teratogenic effects of 6-mercaptopurine on chick embryos in ovo.

Fertilized eggs of single-combed White Leghorn hens were each injected through a shell window directly beneath the embryo at 70 or 96 h of incubation with 2 mg of the sodium salt of 6-MP dissolved in 0.1 M phosphate buffer, and at 11 days of incubation the embryos were examined for gross morphological abnormalities. Various gross malformations and growth retardation were found, the most frequently and severely affected structures being limbs, beak, and eyes. Treatment at 70 h caused more severe abnormalities than at 96 h, but the spectrum of defects was not very different.     

Histological effects of 6-mercaptopurine on the fetal rat central nervous system: a light-microscopic study.

Wistar rats were administered single doses of 16 or 50 mg/kg 6-mercaptopurine (6-MP) on day 12 of pregnancy. Necrosis in the fetal forebrain and spinal cord was studied by light microscope 6, 12, 14, 48, 72, and 81 h and 8 days afterward. The extent of necrosis was dose dependent. The first necroses were seen after 24 h, regardless of location (brain, spinal cord) or dose; but the extent was greatest after 48 h. All necrotic cells had a typical appearance; they were ballooned and often fragmented, their nuclei were darkly colored and frequently pyknotic, and they were often karyorhexic. Necroses appeared almost exclusively at sites of beginning cellular differentiation, i.e., in the intermediate zone. In the spinal cord the ventricular zone was also necrotic and the alar plate (dorsal horn) always affected. Phagocytizing cells (macrophages) appeared in the spinal cord after 48 h and in the brain after 72 h. After 81 h all the necrotic material had been phagocytized, at which time there was a massive congestion of the extra- and intracerebral vessels. Hemorrhages appeared in defined localizations. Eight days after exposure to 16 mg/kg 6-MP fetuses no longer showed any visible deviations. Fetuses exposed to 50 mg/kg showed deviations in the cytoarchitecture of the neopallium: an extremely broadened ventricular zone, few cells in the intermediate zone, and extensive rarefaction cells in the cortical plate with no clear layer structure. In the spinal cord, cleft formations were especially noticeable in the dorsal-horn region. All fetuses showed a hydrocephalus externus after 50 mg/kg. The mechanism leading to necrosis is discussed.     

Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress

Molecular and Cellular Biochemistry - The present study is to investigate the effect and mechanism of action of interleukin (IL)-17A and its receptor IL-17RA on non-small cell lung cancer (NSCLC)....     

Cytotoxic and apoptotic effects of menadione on rat hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common cancers, which may lead to death. Menadione shows cytotoxic activity thought affecting redox cycling in cancer cells. The aim of the present study was to investigate the effects of menadione on rat hepatocellular carcinoma (H4IIE) cell morphology, cytotoxicity, apoptosis and DNA damage or repair in vitro. Cell morphology evaluated by microscopy and cell viability was determined using the 3-[4,5-dimethylthiazol-2yl]-diphenyltetrazolium bromide test. Apoptotic cell death was assessed in H4IIE cells treated with menadione by 4′,6-diamidino-2-phenylindole staining. Quantitative real time polymerase chain reaction used to determine the expression level of poly (ADP-ribose) polymerase 1 (PARP1) gene. According to the results of this study menadione has got a cytotoxic activity (IC₅₀ 25 µM) and change the cell fate in H4IIE cells. Menadione treatments lead to PARP1 activation in a dose dependent manner and induce DNA damage and apoptosis, and this may suggest its use as a therapeutic agent in HCC treatment.     

Effect of 6-mercaptopurine on 65Zn distribution in the pregnant rat

The effect of 6-mercaptopurine (6-MP) on the distribution of gavaged 65Zn in maternal and embryonic tissues of Sprague-Dawley rats was examined 24 hr after injection of the drug on day 13 of pregnancy. 6-MP injection resulted in a significantly higher retention of counts of 65Zn in maternal liver and lower counts in maternal plasma, uterus, placenta, and embryo than in controls. Compared to controls, gel chromatography of maternal liver from 6-MP injected dams showed higher counts associated with a protein peak of molecular weight 6,000-8,000, the approximate molecular weight of the zinc-binding protein metallothionein. These results support the idea that the zinc deficiency, which is observed in day 21 fetuses from dams injected with 6-MP during midgestation, may be the result of a drug-induced sequestering of zinc into maternal liver followed by a decrease in maternal plasma zinc and subsequent reduction in fetal zinc uptake. We suggest that this 6-MP-associated redistribution of zinc into maternal liver may be due to induction of maternal metallothionein synthesis by the drug.     

Vertical development of the secondary palate in hamster embryos following exposure to 6-mercaptopurine

Cellular aspects of vertical development of the secondary palate were examined in control and 6-mercaptopurine (6MP)-treated hamster embryos. Cross-sectional area of the palatal shelf was measured and the numbers of both epithelial and mesenchymal cells counted. Also, in 6MP-treated palates the damaged mesenchymal cells, characterized by the presence of dense bodies, were counted. DNA synthesis in both control and treated fetuses was measured by 3H-thymidine incorporation. The results indicated that both the shelf area and cell numbers increased with age in control and 6MP-treated palates. However, in controls the mesenchymal cell density and DNA synthesis showed two peaks that were absent following 6MP treatment. Unlike controls, in treated embryos the damage to mesenchymal cells became increasingly pronounced between days 10:00 and 10:12 but subsided by day 11:00 of gestation. It is suggested that a major force in the development of the initial primordia and early vertical development of the palatal shelf may be provided by a spurt of DNA synthesis in the mesenchymal cells resulting in their increased number. After 6MP treatment, depression of DNA synthesis and consequent reduction in the mesenchymal cell number and density followed by cell damage lead to retardation in the vertical development of the palatal shelves.     

Effects of 6-mercaptopurine treatment on the membrane potentials of rat skeletal muscle fibers

6-Mercaptopurine (6-MP), injected daily (2 mg/kg s.c.) into Sprague-Dawley rats during the first 3 weeks of life, causes atrophy in muscles of the hindquarters beginning at 4 months of age. The extensor digitorium longus (EDL) muscles from 24 rats injected with 6-MP and 23 saline-injected controls, 6-18 months of age, were studied. Electron microscopy showed a number of abnormalities in the EDL muscle of 6-MP-treated rats, such as myocytes with atypical ultrastructure (including disorganized myofibrils) adjacent to structurally normal cells. Membrane potentials (Em) were measured in the isolated EDL and in the caudofemoralis (CF) muscle in situ. The mean Em of fibers in the EDL of 6-MP-treated rats (-61.1 +/- 0.7 (SE) mV) was lower than that of the control rats (-69.7 +/- 0.6 mV). The same was true for the fibers of the CF muscle (-64.9 +/- 1.5 mV for 6-MP-treated fibers vs. -71.6 +/- 1.3 mV for controls). The contribution of the electrogenic pump potential to Em (+/- ouabain) was similar in 6-MP-treated and control rats, and therefore could not account for the depolarization observed in 6-MP-treated rats. This depolarization was not due to a decreased intracellular K+ concentration. The Na+:K+ permeability ratio (PNa/PK) was higher in the 6-MP-treated rats and could account for the decrease in Em.(ABSTRACT TRUNCATED AT 250 WORDS)