Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of highly active antiretroviral therapy (HAART) has had a dramatic impact on the morbidity and mortality of individuals living with human immunodeficiency virus (HIV). In addition to contributing to dramatic declines in the incidence of several opportunistic infections, HAART is affecting the incidences of several acquired immunodeficiency syndrome (AIDS)-defining malignancies. The incidence of Kaposi's sarcoma (KS) and primary central nervous system lymphoma (PCNSL) has dropped precipitously since the introduction of HAART in 1995. Systemic non-Hodgkin's lymphoma (NHL) appears to be declining in incidence as well, but to a lesser degree than KS and PCNSL. On the contrary, the incidence of invasive cervical carcinoma has not significantly changed in the HAART era. The impact of HAART on the epidemiology of other HIV-associated malignancies, including Hodgkin's disease and anal carcinoma, remains unclear. Data regarding the impact of HAART on the natural history and treatment outcomes of HIV-associated malignancies are limited. The possibility of direct and indirect roles of HIV in HIV-related carcinogenesis suggests that antiretroviral therapy may be an important component of the treatment strategy for several HIV-related malignancies. Patients with HIV-NHL treated with HAART in addition to chemotherapy experience fewer intercurrent opportunistic infections. Furthermore, the simultaneous administration of HAART and chemotherapy does not appear to significantly increase toxicity. Whether the combination of HAART and standard therapy results in improved survival remains uncertain. This two-part article, which began in the April 2002 issue, analyzes the impact of HAART on the incidence, clinical course, and outcomes of each of the AIDS-related malignancies.
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PMID:AIDS malignancies in the era of highly active antiretroviral therapy. 1210 91

Inadequate attention has been paid to the frequent and often extensive cancer-associated DNA hypomethylation. This hypomethylation usually includes undermethylation of certain DNA repeats in constitutive heterochromatin, although it is not limited to such sequences. Many cancers display an overall deficiency in the levels of genomic 5-methylcytosine compared to a variety of normal postnatal somatic tissues. The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome, a rare recessive DNA methyltransferase deficiency disease, results in a small decrease in the extent of global genomic methylation. In ICF, DNA hypomethylation is targeted to the satellite DNA in juxtacentromeric (centromere-adjacent) heterochromatin of chromosomes 1 and 16 (1qh and 16qh), which are prone to rearrangements in ICF lymphoid cells. Also, 1qh and 16qh DNA sequences frequently are hypomethylated in human cancers and rearrangements in their vicinity are overrepresented in cancers. These often lead to chromosome arm imbalances and gene dosage imbalances that could participate in carcinogenesis. Studies of ICF cells suggest that hypomethylation in the normally highly methylated 1qh and 16qh regions predisposes to heterochromatin decondensation in these regions, which in turn leads to elevated levels of rearrangements. Studies of ICF cells also suggest that some of these rearrangements, namely multiradial chromosomes with multiple arms joined in the pericentromeric region, may be unstable intermediates in formation of more stable pericentromeric rearrangements in cancer. Microarray gene expression analysis on ICF and normal lymphoblastoid cell lines suggests that this hypomethylation also may affect gene expression elsewhere in the genome.
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PMID:DNA hypomethylation, cancer, the immunodeficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements. 1216 5

Mother-to-child transmission of the human immunodeficiency virus is substantially reduced by prenatal and postnatal treatment with anti-retroviral nucleoside analogues; however, the long-term consequences of these drug interventions are not known. The nucleoside analogue zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) is carcinogenic in mice when administered transplacentally or neonatally, and this may be due to a genotoxic mechanism. Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine (3'-thia-2',3'-dideoxycytidine; 3TC), or a combination of the two drugs. B6C3F(1)/Tk+/- mice were treated daily from days 1-8 of age with 200 mg AZT/kg/day, 200 mg 3TC/kg/day, or a mixture of 200 mg AZT + 200 mg 3TC/kg/day (AZT/3TC). One and 2 days after the last dose, bone marrow was collected to assess the induction of micronuclei in polychromatic erythrocytes; 3 weeks following treatment, the induction of mutants was determined in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) and thymidine kinase (Tk) genes of spleen lymphocytes. AZT and AZT/3TC, but not 3TC, caused a significant increase in micronuclei, with the response being greatest one day after the last dose. None of the drugs induced mutations in the Hprt gene, while AZT and AZT/3TC, but not 3TC, caused a significant increase in the Tk mutant frequency. The increase in Tk mutants by AZT and AZT/3TC was associated with loss of the wild-type (Tk+) allele (loss of heterozygosity). These data suggest that AZT, but not 3TC, is genotoxic in neonatal mice, and that 3TC does not alter significantly the responses observed with AZT alone.
Carcinogenesis 2002 Sep
PMID:Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine. 1218 83

The deamination of cytosines in DNA to uracil, thought to be initiated by free water within the cells, is a well studied pathway by which C to T mutations occur. Until recently, this conversion was frequently referred to as being spontaneous because of the involvement of cellular water. The recent discovery of a family of enzymes in mammalian cells that catalyze this reaction was unexpected and has created excitement in at least two areas of biology, immunology and virology. One of these enzymes, activation-induced cytidine deaminase (AID), is required for the final steps in the maturation of antibodies. The key features of this process include the introduction of a wide variety of base substitutions in the immunoglobulin genes and the creation of region-specific double-strand breaks. Another member of this family, Apobec3G, is involved in the mutational inactivation and degradation of the human immunodeficiency virus (HIV-1). Among the many intriguing features of these processes is the likely involvement of the enzyme that is thought to "protect" cellular DNA against the accumulation of uracils, uracil-DNA glycosylase (UDG). It appears that in certain situations, the newly discovered DNA-cytosine deaminases can team up with UDG to extensively mutate and degrade DNA. This article discusses the many questions raised regarding the role of these enzymes in protecting cells against infections, and about their possible roles in genome evolution and carcinogenesis.
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PMID:DNA-cytosine deaminases: from antibody maturation to antiviral defense. 1517 77

Some hemophilic patients in Japan suffer from infections with both human immunodeficiency virus (HIV) and hepatitis virus because they received contaminated nonheated blood products. Coinfection with HIV appears to accelerate the course of chronic hepatitis. Although powerful antiviral therapy was introduced as HIV treatment and the prognosis of HIV patients was dramatically improved, the risk of rapid progression of hepatitis and carcinogenesis remains for the patients. Recently, we performed surgery for hepatocellular carcinoma (HCC) in two hemophilic patients with HIV and hepatitis C virus (HCV) coinfection. Case 1 was a 52-years-old man who suffered from liver cirrhosis, hypersplenism, and hyperammonemia due to portosystemic shunt. A recent abdominal computed tomography (CT) scan had revealed a low-density area in segment VI of the liver. Splenectomy and partial resection of the liver were performed. Case 2 was a 66-year-old man who had been diagnosed with chronic hepatitis at age 50, and HIV infection at age 52 years. When his serum alpha-fetoprotein level was increased, CT scan of the liver revealed a mass in segment VIII. Subsegmentectmy of the liver was performed. Although the CD4 value in each patient was lower than 200 micro l, the operations were safely carried out and no major complication occurred. Because the chance of encountering HCC patients infected with HIV and HCV is increasing in Japan, we should consider the perioperative care of these patients, as well as the protection of medical workers against HIV infection.
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PMID:Operated hepatocellular carcinoma in two HIV- and HCV-positive hemophilic patients. 1523 96

Dextran sulfate sodium (DSS) is a strong negatively charged heparin-like polysaccharide and has anti-immunodeficiency virus, anti-carcinogenesis, or occasionally tumor-promotion effects. The biological metabolism of DSS, however, remains unclear. In a previous study, we reported a novel method for the separation and quantification of DSS, using fluorometric labeling with 2-aminopyridine and a combination of size-exclusion and reverse phase high-performance liquid chromatography. In the present study, we have applied this method for analyses of in vitro chemical or enzymatic depolymerization of pyridylamino-DSS (PA-DSS). PA-DSS was depolymerized by specific enzymes such as alpha-amylase and alpha-glycosidase, but not by dextranase or heparinase. Unknown enzymes derived from cultured intestinal cells also strongly depolymerized PA-DSS as did alkaline substances. On the other hand, we have established a novel detection system using a post-column reaction. This method utilizes the spectrophotometrically metachromatic reaction of toluidine blue solution with DSS. This novel detection system may be specific and may potentially provide useful information in the analyses of sulfated polysaccharides, which are present in environmental and biological materials.
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PMID:The analysis of pyridylamino-dextran sulfate oligomers by high-performance liquid chromatography and a novel detection system for sulfated polysaccharides. 1525 3

Ataxia telangiectasia (AT) is a hereditary human disorder resulting in a wide variety of clinical manifestations, including progressive neurodegeneration, immunodeficiency, and high incidence of lymphoid tumors. Cells from patients with AT show genetic instability, hypersensitivity to radiation, and a continuous state of oxidative stress. Oxidative stress and genetic instability, including DNA deletions, are involved in carcinogenesis. We examined the effect of dietary supplementation with the thiol-containing antioxidant N-acetyl-l-cysteine (NAC) on levels of oxidative DNA damage and the frequency of DNA deletions in Atm-deficient (AT-mutated) mice. We confirmed that Atm-deficient mice display an increased frequency of DNA deletions (Bishop et al., Cancer Res 2000;60:395). Furthermore, we found that Atm-deficient mice have significantly increased levels of 8-OH deoxyguanosine, an indication of oxidative DNA damage. Dietary supplementation with NAC significantly reduced 8-OH deoxyguanosine level and the frequency of DNA deletions in Atm-deficient mice. These levels were similar to the levels in wild-type mice. Our findings demonstrate that NAC counteracts genetic instability and suggest that genetic instability may be a consequence of oxidative stress in Atm-deficient mice.
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PMID:Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice. 1528 18

The protease inhibitor ritonavir is an integral part of current antiretroviral therapy targeting human immunodeficiency virus. Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor-kappaB and is an inhibitor of interleukin-1beta and tumor necrosis factor-alpha production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1.
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PMID:The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells. 1550 50

The impact of highly active antiretroviral therapy (HAART) on the incidence of non-Hodgkin's lymphoma was less obvious initially, although primary central nervous system lymphoma (PCNSL) has dropped precipitously since the introduction of HAART. The pathogenesis of acquired immunodeficiency syndrome-related lymphoma is multifactorial. Epstein-Barr virus plays a significant role in these diseases, especially Burkitt lymphoma and PCNSL. Data regarding the effect of HAART on the natural history and treatment outcomes of these malignancies are emerging. The possibility of direct and indirect roles of human immunodeficiency virus in the carcinogenesis suggests that antiretroviral therapy may be an important component of the treatment for these malignancies. The simultaneous administration of HAART and chemotherapy does not appear to significantly alter the toxicity profile, although the information with respect to the interaction of HAART and chemotherapy is limited. The use of biological agents, for example, monoclonal antibody against CD-20, is being explored to improve the clinical outcome of this disease.
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PMID:AIDS-related cancer in the era of highly active antiretroviral therapy (HAART): a model of the interplay of the immune system, virus, and cancer. "On the offensive--the Trojan Horse is being destroyed"--Part B: Malignant lymphoma. 1558 Oct 59

Advances made in the field of chemotherapy and radiotherapy have considerably increased the survival of patients with Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), and chronic lymphocytic leukemia (CLL). Unfortunately, these antiblastic therapies have also increased the risk of late complications such as second tumors, especially second lung cancers. Although the role of ionizing radiations in carcinogenesis is now clear, less is known about the damage caused by chemotherapy, immunodeficiency induced by drugs or hematological pathologies, and cigarette smoking. In HD, the relative risk (RR) of second lung cancer increases considerably in relation to the dose of ionizing radiation given to the patient, with an RR of 9.6 when more than 9 Gy are administered. Some studies have reported a significantly higher risk of second lung cancers in smokers compared with nonsmokers ( p = .03). The role of chemotherapy in the development of second lung cancers has yet to be determined. Although some authors correlate a greater risk with an increased number of chemotherapy cycles, others maintain that chemotherapy increases the risk of second lung cancer only if associated with cigarette smoking. Even less is known about the correlation between NHL and second lung cancer. Although the RR is higher in long-term NHL survivors than in healthy individuals (RR = 1.36), the heterogeneity of histotype and treatment does not permit us to confirm a correlation with chemotherapy and smoking. Conversely, in CLL, the development of second lung cancer appears to be linked to the immunodeficiency that accompanies this hematological malignancy. This is confirmed by the identical RR (1.66) for CLL patients subjected to chemotherapy and for those who have only follow-up.
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PMID:Secondary lung tumors in hematological patients. 1626 3


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