Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procarbazine hydrochloride (PCZ), a chemotherapeutic agent used extensively to treat Hodgkins disease and other tumors, induces leukemia, lymphoma, mammary gland and other solid tumors in rodents and non-human primates and is strongly implicated as a leukemogen in humans. Lipotrope (choline and methionine) deficiency is a powerful potentiator of chemical carcinogenesis in liver and, under some conditions, in other tissues in rodents. Methotrexate (MTX), another commonly used chemotherapeutic agent, interferes with one-carbon metabolism and limits availability of lipotropes. Studies of PCZ carcinogenesis in lipotrope-deficient or MTX-treated male rats are reported, showing that both deficiency and MTX increased PCZ carcinogenicity in the mammary gland. In addition, PCZ was found to induce abnormalities of hepatic choline metabolism. Weanling male Sprague-Dawley rats were fed control (C) or lipotrope-deficient (D) diet. After 3 weeks, C and D rats were given PCZ, MTX, the two drugs together or 0.9% saline by i.p. injection. Doses were 0.2 or 0.5 mg MTX/kg or 25 mg PCZ/kg, given 2 or 3 days per week for 5 or 14 weeks. After 5 weeks of drug treatment livers were assayed for choline, phosphatidylcholine, phosphocholine (PCho), glycerophosphocholine and betaine. PCZ perturbed choline metabolism, increasing hepatic choline and PCho in deficient or MTX-treated rats and, to a smaller extent, in rats fed control diet. MTX markedly enhanced the effect of PCZ on choline metabolism. PCZ-induced mammary tumor incidence was increased 50-70% by lipotrope deficiency or by MTX. In PCZ-treated rats, cumulative probability of bearing a mammary tumor was significantly increased by lipotrope deficiency (P = 0.05), and was increased similarly but not significantly by MTX (P = 0.1). Cumulative tumor numbers per group in PCZ-treated rats were significantly greater in both deficient and MTX-treated rats compared to rats fed control diet (P less than 0.005). Incidences of leukemia, lymphoma and Zymbal's gland tumors induced by PCZ were not significantly altered by diet or MTX.
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PMID:Procarbazine carcinogenicity in methotrexate-treated or lipotrope-deficient male rats. 240 Oct 40

PCBs are industrial chemicals that continue to contaminate our environment. They cause various toxic effects in animals and in exposed human populations. The mechanisms of toxicity, however, are not completely understood. PCBs are metabolized by cytochromes P450 to mono- and dihydroxylated compounds. Dihydroxy-PCBs can potentially be oxidized to the corresponding quinones. We hypothesized that reactive oxygen species (ROS) are produced by redox reactions of PCB metabolites. We tested several synthetic dihydroxy- and quinoid-PCBs with 1-3 chlorines for their potential to produce ROS in vitro and in HL-60 human leukemia cells, and DNA strand breaks in vitro. All dihydroxy-PCBs tested produced superoxide. The quinones generated superoxide only in the presence of GSH, probably during the autoxidation of the glutathione conjugates. We observed increased superoxide production with decreasing halogenation. Incubation of dihydroxy-PCBs or PCB quinones + GSH with plasmid DNA resulted in DNA strand break induction in the presence of Cu(II). Tests with various ROS scavengers indicated that hydroxyl radicals and singlet oxygen are likely involved in this strand break induction. Finally, dihydroxy- and quinoid PCBs also produced ROS in HL-60 cells in a dose- and time-dependent manner. We conclude that dihydroxylated PCBs, and PCB quinones after reaction with GSH, produce superoxide and other ROS both in vitro and in HL-60 cells, and oxidative DNA damage in the form of DNA strand breaks in vitro. The reactions seen in vitro and in cells may well be a predictor of the toxicity of PCBs in animals.
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PMID:Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites. 1122 76

This study concerned a group of ex-workers (372 males and 99 females) from a firm situated in Bergamo (Italy) that ceased its activity at the beginning of the Nineties. From an introductory analysis of the results, we found out that there isn't excess in the death-rate for liver and bile ducts cancers among the males of this group. Among them, for what concerns the other tumoral pathologies, such as leukaemia and stomach tumors, the information allowed to verify an excess of mortality. However, this increase hasn't result statistically significant. On the contrary, it came out that there is an excess of risk for intestine tumors: standardized death-rate of 2.58. In accordance with the information collected, for the future it will be necessary to carefully examine the research in order to verify the existence of a direct connection to the exposure at PCB and study the incidence (not only for mortality) of these neoplasms.
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PMID:[Introductional results of a mortality study in 471 ex-exposed workers to PCBs]. 1624 May 73

PCB19, a 2,2',6-trichlorinated biphenyl, is one of many non-dioxin-like polychlorinated biphenyls (NDL-PCBs), which are ubiquitous pollutants. NDL-PCBs affect cytosolic Ca2+ signaling by promoting Ca2+ release from ryanodine receptor-sensitive Ca2+ pools and inhibiting store-operated Ca2+ entry (SOCE) from the extracellular space. However, NDL-PCB-mediated SOCE inhibition has only been demonstrated in PC12 cells, in which SOCE is thought to be mainly mediated by TRPC family channels. Here, we investigated the effect of PCB19 on SOCE using human embryonic kidney 293 (HEK293) cells, human leukemia T cell line Jurkat-T cells and human promyelocytoma HL-60 cells which are the cell lines that are previously demonstrated to mediate the most common form of SOCE solely by the intrinsic Orai channels. PCB19 reduced thapsigargin-induced Ca2+ influx after Ca2+ pool depletion in HEK293 cells. SOCEs in HEK293, Jurkat T, HL-60 and PC12 cells showed distinct sensitivities to SOCE inhibitors such as Gd3+ and ML-9; however, PCB19 also showed a common effect of inhibiting SOCEs in all cell lines. PCB19-mediated SOCE inhibition was confirmed by demonstrating the ability of PCB19 to inhibit the SOCE current but not the TRPM7 current. These results imply that PCB19 inhibits not only TRPC-mediated SOCE as in PC12 cells but also Orai-mediated SOCE as in many other cells including HEK293, Jurkat T and HL-60 cells.
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PMID:Polychlorinated biphenyl 19 blocks the most common form of store-operated Ca2+ entry through Orai. 2886 55

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with poor long-term survival often owing to relapse. Current treatments for AML are associated with considerable toxicity and are frequently not effective after relapse. Thus, it is important to develop novel therapeutic strategies. Short interfering RNA (siRNA)-based therapeutics targeting key oncogenes have been proposed as treatments for AML. We recently developed novel siRNA delivery polycations (PCX) based on AMD3100 (plerixafor), an FDA-approved inhibitor of the CXC chemokine receptor 4 (CXCR4). Inhibitors of CXCR4 have been shown to sensitize leukemia cells to chemotherapy. Therefore, PCX has the potential to target leukemia cells via two mechanisms: inhibition of CXCR4 and delivery of siRNAs against critical genes. In this report, we show that PCX exerts a cytotoxic effect on leukemia cells more effectively than other CXCR4 inhibitors, including AMD3100. In addition, we show that PCX can deliver siRNAs against the transcription factor RUNX1 to mouse and human leukemia cells. Overall, our study provides the first evidence that dual-function PCX/siRNA nanoparticles can simultaneously inhibit CXCR4 and deliver siRNAs, targeting key oncogenes in leukemia cells and that PCX/siRNA has clinical potential for the treatment of AML.
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PMID:Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia. 3102 89