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Biomedical subjects

L G Israels

Publications and source records attributed to L G Israels.

At least 55 records · Page 3Linked to original sources
PubMed1986

Biochemical changes induced in hairy-cell leukemia following treatment with the adenosine deaminase inhibitor 2'-deoxycoformycin.

The adenosine deaminase inhibitor 2'-deoxycoformycin and interferon are highly effective in the treatment of hairy-cell leukemia. In this study, a patient with type 2 hairy-cell leukemia was treated with one cycle of 2'-deoxycoformycin (4 mg/m2, i.v. weekly for 3 weeks), which was repeated at 9 wk. No toxicity was observed, and the hairy cell count fell from 72,000/mm3 to 5,000/mm3 in 3 mo, with a concomitant 50% decrease in the spleen size. The erythrocyte deoxyadenosine triphosphate content increased to 13.6 pmol/10(6) cells following the initial three weekly treatments, but there was no decrease in the adenosine triphosphate pool size and no evidence of hemolysis. The hairy cell adenosine deaminase activity was inhibited by greater than 95% 24 h following the first 2'-deoxycoformycin injection and returned to the pretreatment value at Day 8, although there was a linear decline in peripheral hairy cell count (50%) during this period. No ultrastructural changes were observed in the hairy cells following 2'-deoxycoformycin to suggest lymphocytotoxicity or cellular differentiation. The antitumor activity of 2'-deoxycoformycin could not be attributed to alterations in the hairy cell deoxyadenosine triphosphate/adenosine triphosphate levels or to the induction of DNA strand breaks. Additionally, the plasma levels of interferon did not change during therapy, making it unlikely that 2'-deoxycoformycin exerts its activity by inducing endogenous interferon synthesis.

Adenosine↗
PubMed1985

Vitamin K1 as a modulator of benzo(a)pyrene metabolism as measured by in vitro metabolite formation and in vivo DNA-adduct formation.

Vitamin K1 (2-methyl-3-phytyl-1,4-napthoquinone) increases the microsomal metabolism of benzo(a)pyrene in rat liver microsomes in vitro. The increase is most marked in the 9,10 diol, 4,5 diol and 3-OH metabolites. The effect is seen at an in vitro concentration of 25 microM and disappears at higher concentrations of K1. The production of BP metabolite-DNA adducts in liver in vivo in ICR/Ha mice is reduced in dietary induced vitamin K deficient mice and this effect is reversed by vitamin K1. These findings indicate a role for vitamin K1 in the regulation of the microsomal mixed function oxidase system and suggest a reason for the low intracellular content and minimal body stores of this vitamin.

Animals↗
PubMed1985

A permeabilized cell system for studying regulation of aryl hydrocarbon hydroxylase: NADPH as rate limiting factor in benzo(a)pyrene metabolism.

The disadvantage of a whole cell system for studying the metabolism of xenobiotics is that some substrates and regulatory molecules do not readily cross the cell membrane. The present study describes a technique to permeabilize H-4-II-E rat hepatoma cells for the study of benzo(a)pyrene metabolism. NADPH is an essential cofactor in the in vitro microsomal metabolism of benzo(a)pyrene and has been shown by indirect measurement to be a rate limiting factor in mixed function oxidase activity in whole liver perfusion systems. The role of NADPH has not been directly demonstrated in an intact cell system. Using this permeabilized whole cell system it is possible to directly demonstrate that NADPH is rate limiting in the mixed function oxidation of benzo(a)pyrene.

Animals↗
PubMed1983

Vitamin K as a regulator of benzo(a)pyrene metabolism, mutagenesis, and carcinogenesis. Studies with rat microsomes and tumorigenesis in mice.

Vitamin K3 inhibits the conversion of benzo(a)pyrene to its more polar metabolites in an in vitro rat liver microsomal system. Vitamin K3 also inhibits benzo(a)pyrene metabolism in rat liver fragments and reduces its mutagenicity in the Ames test. Higher concentrations of vitamin K3 are required to comparably reduce benzo(a)pyrene metabolism when the microsomal system has been induced with 3-methylcholanthrene. High pressure liquid chromatography analysis of the products of benzo(a)pyrene metabolism shows a uniform reduction of all the metabolic products. When tumors were induced in ICR/Ha female mice by the intraperitoneal injection of benzo(a)pyrene, those mice given vitamin K3 before or both before and after benzo(a)pyrene had a slower rate of tumor appearance and tumor death rate as compared with those receiving benzo(a)pyrene alone. However, vitamin K1 increased the rate of tumor death while vitamin K deprivation and warfarin decreased the rate of tumor appearance and death in benzo(a)pyrene-injected mice. These studies indicate that vitamin K3 is an inhibitor of aryl hydrocarbon hydroxylase and reduces the carcinogenic and mutagenic metabolites in vitro, and inhibits benzo(a)pyrene tumorigenesis in vivo. That vitamin K1 enhances the benzo(a)pyrene effect while warfarin and vitamin K deficiency inhibit benzo(a)pyrene tumorigenesis indicates that vitamin K1, vitamin K deprivation, or possibly blockade of its metabolic cycle also modulates benzo(a)pyrene metabolism in vivo but by a mechanism or at a site different from the vitamin K3 effect. The vitamin K series should be considered as capable of serving a regulatory function in the metabolism of benzo(a)pyrene and possibly other compounds metabolized through the mixed function oxidase system.

Aflatoxin B1↗
PubMed1982

Treatment of advanced plasma cell myeloma with weekly cyclophosphamide and alternate-day prednisone.

Three of five patients with refractory myeloma were successfully palliated using a simple and relatively nontoxic regimen consisting of weekly cyclophosphamide in combination with alternate-day oral prednisone. Control of advanced disease in some patients may be associated with more frequent scheduling of known active drugs, even though these drugs, either alone or in combination, may not be effective when given at standard intervals of 4--6 weeks.

Aged↗
PubMed1982

Tumour cell-antibody interactions. II. In vitro studies.

The interaction of L5178Y thymic lymphoma cells syngeneic to DBA/2 mice and of normal thymocytes with goat IgG antibodies was studied in vitro. Viable tumour and normal cells exerted a rapid, continuous and temperature-dependent destruction of antibody activity. Fractionation studies of culture supernatants from antibody-coated cells revealed that a significant portion of the antibody was completely degraded to amino acids. Tumour cells digested antibody more effectively than did normal lymphocytes. This observed degradation of antibody was most extensive at 37 degrees, significantly less at room temperature (23 degrees) and not detectable at 0 degrees. Undegraded antibody released from antibody-coated cells had also lost its antibody activity to a considerable extent. This was due to the formation of soluble antigen-antibody complexes, which was observed even at 0 degrees. Cells fixed with 10% formalin bound maximum amounts of antibody were incapable of digesting antibody even at 37 degrees and did not release immune complexes. These findings are of relevance to cancer immunodiagnosis and immunotherapy.

Animals↗
PubMed1982

Tumour cell-antibody interactions. I. In vivo experiments.

Goats were immunized with membrane fractions of the L5178Y tumour syngenic to DBA/2 mice. IgG fractions of this antiserum were made tumour specific by repeated in vitro and in vivo absorptions with normal cells and concentrated by adsorption to and elution from tumour cells. In vivo studies indicated that the accumulation of 125I-labelled antibody in tumour tissue could not be improved by extensive purification and concentration. The observed clearance rates of radioactivity from tumours and whole animals showed that the metabolism of antibodies was significantly accelerated in the presence of target cells. It is suggested that a rapid neutralization and degradation of antibody by the target tissue prevents its accumulation in tumour nodules.

Animals↗
PubMed1979

Prevention by menadione of the hepatotoxic effects in chickens fed rapeseed meal. Observations on coagulation factors and cytochrome P-450.

Rapeseed meal, the residue after oil extraction, is an animal feed of great commercial interest. Some genetic strains of rapeseed yield a meal which when fed in high concentration produces hemorrhagic lesions in the liver of chickens. These lesions are reduced in incidence by the simultaneous feeding of menadione. This hepatotoxicity is accompanied by elevated levels of cytochrome P-450, delta-aminolevulinic acid synthetase, and the clotting factors V and X. The hemorrhagic lesions were associated with hepatic necrosis, and menadione was protective by mechanisms other than its effect on blood coagulation.

5-Aminolevulinate Synthetase↗
PubMed1978

Effects of conjugated and nonconjugated antithymocyte globulin and trenimon on T lymphocytes and skin graft rejection.

These studies were undertaken to investigate the use of a technique for "homing" of an alkylating agent to lymphocytes as an immunosuppressive approach to inhibit allograft rejection. Trenimon (Tr) was bound covalently to antithymocyte globulin (ATG) and the effects of the complex on peripheral blood cells, thymus cells, spleen cells, and on foreign skin graft rejection assessed. When rabbit ATG was bound covalently to Tr, an alkylating agent, the conjugate (ATG-Tr) retained both complement-dependent antithymus cell acitivity and alkylating activity in vitro, but these activities were reduced. In vivo ATG decreased lymphocytes and increased neutrophils in the blood. ATG-Tr reduced circulating lymphocytes to lower levels and partially attenuated the rise in neutrophils. The in vivo effects of ATG, Tr, ATG-Tr, and ATG mixed with Tr (ATG + Tr) on thymus cells, spleen cells, T lymphocytes in the spleen, and rejection of a foreign skin graft were compared. Tr decreased all cell types, especially thymocytes, but did not delay graft rejection. ATG and ATG-Tr decreased thymocytes, eradicated T cells from the spleen, and delayed graft rejection 3-fold. ATG + Tr decreased thymocytes as Tr had done, eradicated T cells from the spleen, and delayed graft rejection 5-fold. It was concluded that ATG-Tr possessed antithymocyte antibody activity and Tr alkylating activity, but did not confer an immunological advantage over ATG alone, and that ATG and Tr mixed together unbound acted synergistically to delay graft rejection.

Animals↗
PubMed1976

Human spleen heme oxygenase in normal, hemolytic and other pathological states.

Heme oxygenase (HO), the primary enzyme responsible for heme catabolism, was measured in spleens from 10 normal subjects, 14 patients with chronic hemolytic anemia (HA), 12 with idiopathic thrombocytopenic purpura (ITP), and 10 with various lymphoproliferative disorders (LD) to determine the splenic enzymatic capacity for heme catabolism and the response of splenic HO to hemolysis. Splenic NADPH-cytochrome c reductase activity and cytochrome P-450 levels were also measured. Splenic HO specific activity in normal spleens was 0.235 +/- 0.106 (SE) nmoles bilirubin/mg protein/min; in HA, 0.276 +/- 0.050; in ITP, 0.228 +/- 0.036; and in LD, 0.420 +/- 0.105. However, the total HO activity per spleen was significantly greater in HA (742.9 +/- 137.4 (SE) nmoles/min, p less than 0.001) and LD (681.9 +/- 180.3, p less than 0.005) than in normal spleens (137.1 +/- 55.0), but was not significantly increased in ITP (269.5 +/- 121.5). In normal spleens cytochrome P-450 was 0.052 +/- 0.006 (SE) nmoles/mg and NADPH-cytochrome c reductase activity was 8.3 +/- 2.2 (SE) nmoles/mg/min; neither of these specific activities was significantly altered in HA, ITP, or LD. Again, total activity was significantly increased in HA and LD associated with increased splenic size. Although total HO activity is greater in the larger spleens, HO activity does not increase per unit weight of tissue. In normal spleen the calculated capacity for bilirubin production by HO was 115 mg per day. This accounts for only 50% of normal daily production from erythroid sources and suggests that other sites are of major importance for hemoglobin degradation.

Anemia, Hemolytic↗