Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Chlorodeoxyadenosine (CdA) is active in chronic lymphocytic leukemia, hairy-cell leukemia, and low-grade lymphomas. In part, this spectrum of activity may be attributable to the selective toxicity of CdA to nondividing lymphocytes and monocytes. However, CdA is unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. The present experiments demonstrate that the 2'-arabino-fluoro derivative of CdA, designated CAFdA, is also directly toxic to quiescent lymphocytes and macrophages. Unlike CdA, CAFdA was stable at pH 2 and resisted degradation by Escherichia coli nucleoside phosphorylase. Cell killing was preceded by the formation of DNA strand breaks and could be prevented by supplementation of the medium with deoxycytidine. The initial DNA damage initiated the pattern of oligonucleosomal DNA fragmentation characteristic of apoptosis. Mutant lymphoblasts, deficient in deoxycytidine kinase, with elevated cytoplasmic 5'-nucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotide reductase activity, were cross-resistant to both CAFdA and CdA toxicity. One-week oral treatment with CAFdA (1 mg/ml in drinking water) achieved an average plasma concentration of 0.56 microM and eliminated 90% of chronic lymphocytic leukemia cells transplanted into severe combined immunodeficiency (scid) mice. Under the same conditions, CdA was much less active. Collectively, these results suggest that CAFdA could be effective as an oral agent in indolent lymphoproliferative diseases and in autoimmune diseases where lymphocyte and monocyte depletion is desirable.
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PMID:Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine. 134 62

A murine model of severe combined immunodeficiency syndrome (scid mice) affords an opportunity to study the interaction of Candida albicans with a host lacking functional B- and T-cell mechanisms. We have previously reported no significant difference in yeast recovery after intravenous challenge of BALB/c mice and scid mice with C. albicans (S. Mahanty, R.A. Greenfield, W.A. Joyce, and P.W. Kincade, Infect. Immun. 56:3162-3166, 1988). In this study, we evaluate the course of gastrointestinal candidiasis after a single oral challenge with C. albicans. BALB/c and scid mice received H2O containing 10(6) C. albicans per ml for 16 h. Half the mice of each strain continuously received H2O containing 1 mg of tetracycline per ml. Stool samples were cultured for yeast twice weekly until they were negative three consecutive times or positive for 8 weeks. Mice were then sacrificed for quantitative cultures of liver, spleen, and kidneys. At eight weeks postinoculation, 2 of 13 BALB/c mice, 0 of 14 BALB/c mice receiving tetracycline, 6 of 12 scid mice, and 8 of 13 scid mice receiving tetracycline had positive stool cultures (P less than 0.05, likelihood ratio chi-square). Quantitative recovery of yeasts from stools was also higher in the scid mice. Cultures of liver, spleen, and kidneys wer negative in all BALB/c mice and essentially all negative in scid mice; a single colony was isolated from the kidney of one scid mouse and the liver of another scid mouse. We conclude that B cells and/or T cells and their products are important in gastrointestinal colonization with C. albicans but that even in their absence, dissemination of infection from the gastrointestinal tract does not consistently occur. Thus, other aspects of host defense must be critical in containing gastrointestinal Candida colonization.
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PMID:Gastrointestinal candidiasis in a murine model of severe combined immunodeficiency syndrome. 203 73

Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + IG-->A) in the 5' splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme-associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in alpha helix 4 and beta strand 4 of the alpha/beta barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.
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PMID:Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site. 759 35

The lack of a safe, economical murine lentivirus model for human immunodeficiency virus type 1 (HIV-1) infection of humans has hampered the preclinical evaluation of potential antiviral compounds, vaccines, and biological response modifiers. A small animal model that does not employ HIV-1 is needed to minimize risk of accidental human exposure, enhance efficient use of scarce experimental compounds, and reduce laboratory space necessary to conduct statistically significant in vivo trials. Feline immunodeficiency virus (FIV), an immunosuppressive lentivirus of domestic cats, has been used extensively as an animal model for the pathogenesis and therapy of human HIV-1 infection. Cats, however, are not amenable to large-scale efficacy trials because of their relatively large size, high cost, and limited degree of physiologic characterization, particularly with regard to drug metabolism. To adapt the feline immune system to a small laboratory animal host, severe combined immunodeficient mice (SCID mice) were engrafted with feline lymphoid tissues (forming the SCID-fe mouse) and inoculated with FIV. Two quantitative parameters, the incidence of provirus detection in feline tissue grafts and the level of feline IgG in plasma, were used to demonstrate the antiviral efficacy of 3'-azido-3'-deoxythymidine (AZT, azidothymidine, Retrovir, zidovudine) in the SCID-fe system. Of 17 SCID-fe mice inoculated with 7 x 10(6) peripheral blood mononuclear cells (PBMC) from an FIV-infected cat, eight had detectable FIV provirus in both the feline thymus and feline lymph node implants, as measured by polymerase chain reaction (PCR)/Southern blot analysis. Treatment of these mice with AZT at a dose of 125 mg kg-1 day-1 in drinking water beginning 1 day prior to FIV inoculation and continuing throughout the study interval prevented the dual detection of provirus in feline lymph node and thymus grafts of all mice tested. In a separate experiment, the level of spontaneous feline IgG production was quantified by ELISA 2 weeks after FIV inoculation with and without AZT treatment. Mean plasma feline IgG level of five SCID-fe mice inoculated with 10(3) TCID50 cell-free FIV was 2.23 mg ml-1. Mean feline IgG level of five mice inoculated with the same quantity of FIV and treated with AZT beginning 1 day prior to virus inoculation and continuing for 2 weeks thereafter was 14.98 mg ml-1. AZT significantly (P < 0.05) enhanced feline humoral immune function at a virus inoculum titer of 10(3) TCID50.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reduced provirus burden and enhanced humoral immune function in AZT-treated SCID-feline mice inoculated with feline immunodeficiency virus. 761 56

A paired feeding experiment was conducted to investigate if reduced food intake is a reason for the body weight loss previously observed in severe combined immunodeficient beige (SCID bg) mice infected with Mycobacterium paratuberculosis. Mice were paired on the basis of age, litter and sex. One of each pair was injected intraperitoneally with 10(5) viable M. paratuberculosis organisms. The remainder served as uninfected pairfed mates. Each uninfected mouse was restricted to the amount of food (per gram body weight) that its infected paired mate ate in the previous 24 hour period starting at four weeks postinfection until 12 weeks postinfection when the mice were necropsied. The mean body weights of the two groups were not significantly different (p < 0.05) at the start of the experiment (infected 27.6 +/- 2.1 g, pairfed 27.3 +/- 3.4 g) but the pairfed group weighed less after 12 weeks of restricted food intake. Mycobacterium paratuberculosis was isolated from the spleen, liver, gut and fecal pellets of the infected but not the uninfected mice. Acid-fast bacilli were seen histologically in the liver, spleen and intestines of the infected mice only. Analysis of carcass compositions indicated that both infected and pairfed mice lost dry matter. Despite the loss in dry matter, the infected mice appeared to have maintained their body weights due to an increased retention of body water (presumably due to edema of inflammation). These results suggest that infection of SCID bg mice with M. paratuberculosis causes a reduction in their food intake (presumably due to reduced appetite) which, in turn, contributes to a loss in dry matter. We suggest that this loss in dry matter is one of the initial events that eventually lead to cachexia, and that it precedes the body weight loss that inevitably occurs in SCID bg mice chronically affected with M. paratuberculosis.
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PMID:The role of restricted food intake in the pathogenesis of cachexia in severe combined immunodeficient beige mice infected with Mycobacterium paratuberculosis. 770 41

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.
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PMID:In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells. 774 43

Malignant cells possess a high degree of proteolytic activity in which the plasminogen activator system plays an important role. An increased expression of urokinase type plasminogen activator (uPA) is of significance for degradation of the extracellular tumor matrix, facilitating invasiveness and growth. Inhibition of the active site of uPA makes it possible to evaluate the significance of uPA in tumor growth. We report here experiments on a uPA-producing human prostate xenograft (DU 145) using a competitive inhibitor of uPA, p-aminobenzamidine. In vitro experiments with DU 145 cells showed that p-aminobenzamidine caused a dose-dependent inhibition of uPA activity. DU 145 cells were inoculated s.c. in SCID mice and, once tumors were established, treatment with p-aminobenzamidine added to drinking water was started and lasted for 23 days. Mice receiving 250 mg/kg/day of p-aminobenzamidine showed a clear decrease in tumor-growth rate compared to the non-treated mice, resulting in 64% lower final tumor weight. In addition, uPA-antigen levels in the membrane fractions of DU 145 tumors from p-aminobenzamidine-treated mice were found to be decreased by 59%. We also show that p-aminobenzamidine has an anti-proliferative effect in cell culture at low cell number, correlating with a dose-dependent decrease in uPA production. In conclusion, we show that a low-molecular-weight uPA-inhibitor, p-aminobenzamidine, has a growth-inhibitory effect on a solid uPA-producing tumor.
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PMID:The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice. 775 60

A model for the in vivo evaluation of antipneumocystis drugs has been developed in SCID mice infected intratracheally with cryopreserved mouse-derived Pneumocystis carinii. The development of a highly reproducible fatal P. carinii pneumonia occurred within 10 weeks (mean survival time +/- SEM = 72.2 +/- 1.2 days). Continuous administration of dexamethasone (2 mg/liter in the drinking water) exacerbated the rate of onset of severe P. carinii pneumonia (mean survival time +/- SEM = 63 +/- 1.3 days) in SCID mice. The number of cysts per g of lung homogenate (homogenate counts) were maximal with an inoculum of 20,000 cysts at 6 weeks post infection. Homogenate counts correlated with infection scores (graded assessments of immunofluorescent cysts on lung impression smears) suggesting that infection scoring accurately and rapidly reflects the severity of P. carinii pneumonia in SCID mice. These studies led to the development of a drug screening protocol in which Pneumocystis-free female SCID mice (20-25 g) were started on dexamethasone 7 days prior to IT inoculation with a single dose of 20,000 cysts. Drugs were evaluated either for: a) prophylaxis (continuously from day 1 post infection) or b) treatment (from day 21 post infection) until day 42 post infection, when all mice were killed and infection scores determined. Co-trimoxazole (at 250 mg sulfamethoxazole + 50 mg trimethoprim/kg/day) given in the drinking water was found to be highly effective in both the prophylaxis and treatment of mouse P. carinii pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Artificial infections of Pneumocystis carinii in the SCID mouse and their use in the in vivo evaluation of antipneumocystis drugs. 786 80

The use of polymers for delivering peptide and protein drugs is described. Soluble-polymer technology attempts to bind a polymer to all sites on therapeutic protein molecules that cause the body to recognize the molecules as foreign. Goals include a stable linkage, water solubility, low immunogenicity, prolonged half-life, and intact biological activity. Polyethylene glycol (PEG)-adenosine deaminase (ADA), or pegademase bovine, has FDA-approved labeling as replacement therapy for ADA deficiency in patients with severe combined immunodeficiency disease who are not suitable candidates for bone marrow transplantation. Pegademase bovine reverses the toxic accumulation of adenosine and deoxyadenosine in adenosine deaminase-deficient cells, restoring the immune system. PEG-asparaginase (pegaspargase) has shown promise in patients with acute lymphocytic leukemia; allergic reactions have been minimal. Animal studies suggest that superoxide dismutase has potential use in conditions in which the body's ability to remove oxygen free radicals is reduced, such as burns and myocardial infarction; coupling with PEG may greatly increase the protein's half-life. Other PEG-conjugated proteins under investigation include PEG-catalase, PEG-uricase, PEG-honeybee venom, PEG-hemoglobin, and PEG-modified ragweed pollen extract. Dextran, albumin, DL-amino acids, and polyvinyl pyrrolidone have also been studied as protein carriers; most of the products created thus far have not shown much promise. The coupling of polymers to proteins has yielded protein drugs with intact biological activity and reduced immunogenicity, but much remains to be learned about this technology.
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PMID:Polymers for delivering peptides and proteins. 816 Jun 72

We report an unusual case of disseminated dermatitis, osteomyelitis, and bacteremia in an immunocompromised host. An infant presented with a pustular skin rash resembling chicken pox, but culture of a skin lesion yielded Mycobacterium marinum. Upon further evaluation, severe combined immunodeficiency was diagnosed. Radiographs of the hands and feet showed evidence of osteomyelitis. M. marinum was isolated from blood and synovial fluid. We recommend a high level of suspicion for this organism in immunocompromised hosts who have been exposed to fresh water or salt water, particularly those of aquaria. Drug susceptibility testing of serial clinical isolates from our patient revealed development of high-level resistance to isoniazid and rifampin during therapy. We believe that treatment of disseminated M. marinum infections should include combinations of antimycobacterial agents chosen on the basis of results of susceptibility testing done by an experienced laboratory, thereby limiting the emergence of drug resistance.
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PMID:Disseminated Mycobacterium marinum infection and bacteremia in a child with severe combined immunodeficiency. 858 69


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