Comparison of synthetic psoralen derivatives and 8-MOP in the inhibition of lymphocyte proliferation.
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Cell Line↗
Biomedical subjects
S Grant
Publications and source records attributed to S Grant.
Serum lactate dehydrogenase and creatine kinase during marathon training.
Serum total creatine kinase (CK) and the lactate dehydrogenase (LDH) isoenzymes were studied in 38 sedentary middle-aged men (aged 35-50 yrs) during a 30 week marathon training programme. Basal CK activity rose by 33% after 15 weeks but a significant rise (27%) in LDH activity took 30 weeks to occur. Post-exercise (maximum test on a bicycle ergometer) CK and LDH activities were higher than pre-exercise levels but the increment in enzyme activity following exercise did not change. LDH1 and LDH2 isoenzyme activity increased by 2.5% and 4% of total LDH respectively while LDH3 and LDH5 decreased by 3.9% and 2.4% respectively over 30 weeks. Post marathon total CK did not correlate with finishing time at 30 mins or 30 hrs post race. The range of CK MB isoenzyme activity at 30 mins post race was 1.8-9.8% of total CK with 11 subjects having a value above 6%. The training programme appears not to have affected muscle CK and LDH release during exercise but isoenzyme distribution changes reflect the adaptations known to occur in muscle during endurance training. Unfortunately only 16 subjects were available for all the investigations, and it is these upon whom most of the data were obtained.
Adult↗
Effects of pyrimidine antagonists on sialic acid regeneration in HL-60 cells.
Because alterations in cell membrane sialoglycoconjugates can affect the behavior of neoplastic cells, we investigated the effects of in vitro treatment with antimetabolites used in cancer therapy on the expression of membrane sialic acid in cultured HL-60 leukemic cells. In these studies, cells were incubated with Vibrio cholerae neuraminidase to remove surface sialic acid. Reappearance of membrane sialic acid during drug treatment was followed (a) by measuring changes in radioactive surface labeling of viable cells with sodium metaperiodate-sodium[3H]-borohydride, (b) by measuring the decline in accessible surface galactosyl receptor sites which occurred coincident with membrane sialic acid replacement, and (c) by measuring the incorporation of [3H]glucosamine into membrane-associated neuraminidase-labile sialic acid. We were especially interested in learning whether drugs that affect intracellular pools of cytidine triphosphate (CTP), an important nucleotide intermediate in sialylation reactions, could inhibit regeneration of membrane sialic acid. 3-Deazauridine, a competitive inhibitor of CTP synthetase, depleted CTP pools and curtailed surface membrane resialylation with little or no effect on synthesis of de novo sialic acid from precursor sugars. The addition of cytidine restored CTP pools and sialic acid regeneration. Acivicin, a glutamine antagonist, also depleted CTP pools and curtailed surface membrane resialylation. In addition, it retarded de novo synthesis of sialic acid. The addition of cytidine restored intracellular CTP pools and sialic acid regeneration. However, both cytidine and guanosine were required to restore sialic acid synthesis from precursor sugars. 1-beta-D-Arabinofuranosylcytosine, a competitive inhibitor of sialic acid synthetase and of sialyltransferase, inhibited both de novo sialic acid synthesis and membrane resialylation. Only the latter effect was reversed by the addition of exogenous cytidine. Hydroxyurea, an agent shown previously to inhibit glycoconjugate production in hamster fibroblasts, curtailed membrane resialylation and de novo synthesis of sialic acid without depleting CTP pools. Doxorubicin, at levels that caused marked arrest of cell proliferation, had no effect on sialic acid synthesis or expression on the membrane surface. These data suggest that antimetabolites, apart from their cytotoxic effects or effects on cellular growth, may directly inhibit the expression of membrane sialic acid.(ABSTRACT TRUNCATED AT 400 WORDS)
3-Deazauridine↗
Isolation and characterization of an anthracycline-resistant human leukemic cell line.
An anthracycline-resistant subline of HL-60 promyelocytic leukemia cells (HL-60/AR) has been isolated in vitro by subculturing in progressively higher concentrations of Adriamycin. The resistant cells are capable of sustaining continuous growth in 10(-6) M Adriamycin which is more than 50 times the 50% inhibitory dose for the parent line. HL-60/AR expressed variable degrees of cross-resistance to daunorubicin, dihydroxyanthracenedione, vincristine, vinblastine, and actinomycin D, but it remained sensitive to methotrexate and 1-beta-D-arabinofuranosylcytosine. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of glycoproteins of HL-60/AR revealed two prominent glycoproteins with molecular weights of 160,000 +/- 10,000 and 110,000 +/- 10,000 which were not detected in the sensitive cells. Cellular uptake and retention of daunorubicin was studied in the resistant and sensitive cells utilizing digitized video fluorescence microscopy. The sensitive cells accumulated more drug and showed at least 2-fold greater levels of brightness than the resistant cells. Studies of total intracellular accumulation, utilizing 10(-6) M [14C]-daunorubicin as a marker, showed a 1-h accumulation of 98 +/- 20 pmol/10(6) cells in HL-60/AR versus 255 +/- 25 pmol/10(6) cells in HL-60. Exposure to nontoxic concentrations of the calcium channel blocker Verapamil (10(-5) M) led to enhanced accumulation (175 +/- 8 pmol/10(6) cells) and retention of the drug in HL-60/AR, resulting in increased cytotoxicity in HL-60/AR. These anthracycline-resistant leukemic cells may serve as a valuable experimental model in studying the phenomenon of multiple drug resistance as well as strategies to circumvent it in human myeloid leukemia.
Antibiotics, Antineoplastic↗
Primary biliary cirrhosis and autoimmune disorders: a review.
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Aged↗
Posterior fluorescein streaming.
Two patients with chronic branch retinal vein occlusions and recurrent vitreous hemorrhages were evaluated with fluorescein angiography. In both patients fluorescein studies revealed a unique pattern of superior fluorescein flow. Possible mechanisms for this process are discussed.
Aged↗
Thyroglobulin may be undetectable in the serum of patients with metastatic disease secondary to differentiated thyroid carcinoma. Follow-up of differentiated thyroid carcinoma.
To assess the value of serum thyroglobulin (Tg) levels in the follow-up of differentiated thyroid carcinoma after ablative therapy simultaneous Tg estimations and radioiodine (131I) scans were performed on patients during an 18-month follow-up period. In this study, 287 scans were performed on 200 patients who were not receiving Thyroxine (T4) replacement at the time, i.e., off T4. Wherever possible, Tg was also estimated while the patient was receiving T4. All sera were screened for Tg autoantibodies which were detected on 67 occasions in 44 patients (22%). Of the 220 sera without Tg autoantibodies (156 patients), 17 were accompanied by scan evidence of functioning thyroid tissue, although Tg was undetectable (less than 5 micrograms/l) either on or off T4. Serum Tg was only detectable off T4 in a further five patients (six scans) who simultaneously had scan evidence of functioning thyroid tissue. In seven patients the finding of detectable Tg preceded scan evidence of recurrence. Thus, serum Tg is useful in the follow-up of differentiated thyroid cancer after ablative therapy. However, some patients with recurrence or metastasis will be missed if Tg alone is relied on, particularly if thyroxine treatment is continued.
Adenocarcinoma↗
Synergistic interaction between acivicin (AT-125) and 6-thioguanine in the murine leukemia L1210. Biochemical and cytokinetic considerations.
The effect of the purine antagonist acivicin (AT-125) on the metabolism and cytotoxicity of 6-thioguanine was examined in the murine leukemia L1210. Cells exposed to 5 X 10(-6) M acivicin for 18 hr followed by 10(-5) M [14C]-6-thioguanine for 2 hr accumulated 2.90 +/- 0.17 nmoles 6-thioguanine/10(6) cells compared to 0.69 +/- 0.07 nmoles 6-thioguanine/10(6) cells in untreated controls. Intracellular accumulation of 6-thioguanine monophosphate, a lethal 6-thioguanine metabolite, increased from 0.27 +/- 0.05 to 1.08 +/- 0.13 nmoles 6-thioguanine monophosphate/10(6) cells following the same acivicin exposure. A similar increment was observed for the formation of 6-thioguanine triphosphate. These alterations in 6-thioguanine metabolism were associated with an increase in the intracellular level of 5-phosphoribosyl-1-pyrophosphate, an obligatory substrate in 6-thioguanine activation (57.9 +/- 7.6 vs 13.4 +/- 2.3 ng 5-phosphoribosyl-1-pyrophosphate/10(6) cells). In contrast, there was a 50% reduction in the amount of 6-thioguanine incorporated into RNA and DNA following acivicin pretreatment. Cytofluorometric analysis revealed that an 18-hr exposure to 5 X 10(6) M acivicin increased the population 5-phase cells, which are more sensitive to the actions of 6-thioguanine, by 50% relative to untreated controls. In both suspension culture growth and soft agar studies, the sequential administration of acivicin followed by 6-thioguanine resulted in substantial growth inhibitory activity; in contrast, the effects of the reverse sequence were subadditive. Pretreatment of L1210 cells with acivicin potentiates the action of subsequently administered 6-thioguanine, and the mechanism may involve both biochemical as well as cytokinetic factors. In vivo studies involving the sequential administration of these agents appear warranted.
Animals↗
A quantitative study of enteric endocrine cells in celiac sprue.
A quantitative morphological investigation of eight endocrine cell types in mucosal biopsies from adults with untreated celiac sprue was undertaken. The quantitative data expressed as cells per millimeter of epithelium most accurately reflected the changes seen in celiac disease, as it takes into account changes in mucosal thickness due to the absence of villi in celiac biopsies. The results showed significant increases in the number of cholecystokinin and enterochromaffin cells, a significant decrease in somatostatin, gastric inhibitory polypeptide and secretin cells, and no change in the motilin, gastrin, and glicentin cells. Significant changes in cell size (cross-sectional area) were also demonstrated in the somatostatin and gastrin cells which were smaller in the celiac biopsies.
Adult↗
Isolation and characterization of a deoxycytidine kinase-deficient human promyelocytic leukemic cell line highly resistant to 1-beta-D- arabinofuranosylcytosine.
A deoxycytidine kinase-deficient variant of a human promyelocytic leukemic cell line (HL-60/ara-C) has been isolated and characterized. These cells are capable of proliferating in the presence of 10(-6) M 1-beta-D-arabinofuranosylcytosine (ara-C), a level achieved in the plasma of leukemic patients undergoing conventional-dose ara-C therapy. The cells share numerous biological and biochemical features with the parent line, including: morphology; rate of growth; cloning characteristics; karyotype; rates of DNA, RNA, and protein synthesis; and ability to undergo terminal differentiation in the presence of agents such as 12-O-tetradecanoylphorbol acetate and dimethyl sulfoxide. In contrast, these cells display a great reduction in the total intracellular accumulation of ara-C following a 4-hr exposure to 10(-6) M ara-C (2.4 versus 99.0 pmol ara-C/10(6) cells). Resistant cells exposed to 10(-6) M ara-C for 1 hr also exhibited a reduction in the generation [1.2 versus 31.9 pmol 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP)/10(6) cells] and the 4-hr retention (0.30 versus 3.87 pmol ara-CTP/10(6) cells) of ara-CTP, the lethal ara-C metabolite, in comparison to parent cells. Incorporation of ara-C into resistant HL-60 cell DNA was also profoundly decreased. These biochemical alterations were associated with a 1000-fold decrease in the sensitivity of clonogenic cells to continuously administered ara-C (ara-C 50% inhibitory concentration: 1.8 X 10(-6) M for HL-60/ara-C; 3.0 X 10(-9) M for HL-60). A variety of antagonists of de novo pyrimidine synthesis inhibited the growth of ara-C-sensitive and -resistant cells to a similar extent. When HL-60 cells were exposed to a lethal concentration of thymidine (5 X 10(-3) M), coadministration of 5 X 10(-6) M deoxycytidine restored 90 +/- 4% (S.D.) of colony-forming capacity. Normal human bone marrow progenitor cells were protected to a similar degree by 3 X 10(-3) M deoxycytidine. In contrast, deoxycytidine concentrations as high as 5 X 10(-3) M were unable to confer any protection to HL-60/ara-C cells under identical conditions. These studies suggest that an enzymatic perturbation rendering human leukemic cells highly resistant to ara-C may be exploited to achieve a selective in vitro chemotherapeutic effect.
Cell Division↗
Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis.
A uridine-cytidine kinase-deficient human promyelocytic leukemic subline (HL-60-5-aza-Cyd) has been isolated which is highly resistant to the antileukemic agent 5-azacytidine. Resistant cells exposed to 10(-5) M 5-azacytidine for 2 hr exhibit a marked reduction in both the total intracellular accumulation of 5-azacytidine (11.9 versus 156.0 pmol/10(6) cells) as well as its incorporation into RNA (3.1 versus 43.4 pmol/micrograms D-ribose) compared to the parent line. These biochemical changes are associated with nearly a 100-fold decrease in sensitivity to the growth inhibitory effects of 5-azacytidine (concentration of drug associated with a 50% reduction in cell growth, 3.5 X 10(-5) versus 5.0 X 10(-7) M). 5-Azacytidine-resistant cells exhibit cross-resistance to 3-deazauridine, 6-azauridine, and 5-fluorouridine, but not to 1-beta-D-arabinofuranosylcytosine, 2'-deoxyazacytidine, or 5-aza-1-beta-D-arabinofuranosylcytosine. Coadministration of 50 microM uridine prevented depletion of pyrimidine nucleoside triphosphates and inhibition of colony formation of HL-60 cells exposed to 3 mM N-(phosphonacetyl)-L-aspartate) or 5 X 10(-6) M pyrazofurin but was not capable of protecting HL-60-5-azacytidine under the same conditions. This uridine concentration was also able to restore control colony formation to normal human bone marrow progenitor cells (granulocyte-macrophage colony-forming units) exposed to de novo pyrimidine biosynthetic blockade. These in vitro studies suggest that 5-azacytidine resistant cells lacking the pyrimidine salvage pathway enzyme uridine-cytidine kinase may be selectively vulnerable to a regimen using pyrimidine antagonists administered in conjunction with the naturally occurring nucleoside uridine.
Azacitidine↗
[Abnormal hemoglobins, alpha thalassemia and erythrocyte G6PD deficiency in newborn infants of the negroid race].
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Black People↗
Medivac: as real as you can get.
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Alberta↗
Potentiation of 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity by 2,3-dihydro-1H-imidazolo[1,2-b]pyrazole in the human promyelocytic leukemic cell, HL-60.
The effect of IMPY (2,3-dihydro-1H-imidazolo[1,2-b]pyrazole) on the metabolism and cytotoxicity of subsequently administered 1-beta-D-arabinofuranosylcytosine (ara-C) was examined in the human promyelocytic leukemic cell line HL-60. Cells exposed to 3 mM IMPY for 12 hr followed by a 1-hr exposure to 1 microM [3H]ara-C accumulated 27.5 +/- 4.8 (S.D.) pmol ara-C/10(6) cells compared to 14.0 +/- 3.5 pmol/10(6) cells in untreated controls. Cells experienced greater than a 2-fold increment in 1-beta-D-arabinofuranosylcytosine 5'-triphosphate generation and retention following this same IMPY exposure and nearly a 4-fold increment in incorporation of ara-C into HL-60 nucleic acids. These alterations in ara-C metabolism were associated with a 36% reduction in the intracellular concentration of deoxycytidine 5'-triphosphate and reductions in deoxyadenosine 5'-triphosphate and deoxyguanosine 5'-triphosphate concentrations to undetectable levels. Coincubation of cells with IMPY along with other pyrimidine antagonists such as thymidine, N-(phosphonacetyl-L-aspartate), deoxyadenosine, and deoxyguanosine, produced up to 4-fold increments in ara-C intracellular accumulation. Pretreatment of HL-60 cells with 3 mM IMPY followed by a continuous exposure to 10 nM ara-C produced synergistic inhibitory effects on both suspension culture growth and soft agar clonogenicity. In contrast, exposure of normal human bone marrow progenitor cells (CFU-GM) to the same schedule of IMPY and ara-C produced subadditive or antagonistic effects on the growth of these cells in soft agar. These findings may have implications for the design of in vivo regimens using IMPY and ara-C.
Antineoplastic Agents↗
Differential effect of recombinant human leukocyte interferon on human leukemic and normal myeloid progenitor cells.
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Bone Marrow↗
Keratoconjunctivitis artefacta.
Six cases of keratoconjunctivitis caused by self-inflicted injury are described. The diagnosis is suggested by the combination of the characteristic sharply delineated lesions localised in the more accessible inferior and nasal quadrants of the bulbar conjunctiva and cornea, together with the unconcerned attitude of the patient and other psychological features. Secondary post-traumatic erosions, infections, and allergies may complicate the clinical appearances, and other functional eye disturbances including corneal anaesthesia may be detected. In all cases the eye condition resolved with a sympathetic but authoritative approach avoiding direct accusation. Avoidance of feelings about bereavement or sexual relationships were directly related to the onset of symptoms in 3 cases. In some patients the psychological mechanism seemed inaccessible and they continued to produce new self-inflicted diseases with considerable physical and psychological morbidity. These more intractable cases need psychiatric investigation but usually resist referral.
Adolescent↗
Dose- and schedule-dependent activation and drug synergism between thymidine and 5-aza-2'-deoxycytidine in a human promyelocytic leukemia cell line.
The ability of thymidine (dThd) to enhance the metabolism and cytotoxicity of subsequent administered 5-aza-2'-deoxycytidine (5-aza-dCyd) was studied in L1210 cells and in the human promyelocytic leukemic cell line, HL-60. Exposure of L1210 cells to 0.1 mM dThd for 5 h resulted in an increase in the total intracellular and acid-precipitable accumulation of 5-aza-dCyd. Higher dThd concentrations and longer exposure intervals resulted in smaller increments in 5-aza-dCyd accumulation. In contrast, in HL-60 cells, a 24-hr exposure in 1 mM dThd resulted in the greatest intracellular accumulation of 5-aza-dCyd, 3.3 times more accumulation than in control cells. There was also a 4-fold increase in the acid-precipitable accumulation and nearly a 3-fold increase in DNA incorporation of 5-aza-dCyd in HL-60 cells exposed to the same dThd schedule. High-pressure liquid chromatographic analysis demonstrated a greater than 3-fold increase in the intracellular amounts of 5-aza-dCyd metabolites eluting in the triphosphate region in these human cells under identical conditions. Shorter dThd incubation exposure intervals (6 hr) and lower dThd concentration (0.1 mM) produced smaller increments in these studies. Both growth and clonogenic assays of HL-60 cells demonstrated a dose- and schedule sequence-dependent synergism between dThd and 5-aza-dCyd.
Animals↗
Modulation of 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity in L1210 cells by fluoropyrimidine pretreatment.
The effect of pretreatment with the fluoropyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), and 5'-deoxy-5-fluorouridine (5'-dFUrd) on the intracellular metabolism and in vitro cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) was explored in L1210 cells. A 4-hr exposure to 100 microM FUra, FUrd, or FdUrd produced greater than 3-fold increments in the intracellular accumulation of [3H]deoxycytidine, and 2-fold increments in the intracellular accumulation of [3H]ara-C were produced over a 1-hr exposure. Intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate levels in cells exposed to these 3 agents were also increased over 2-fold. L1210 cells exposed sequentially to 1 microM FUra, FUrd, or FdUrd followed by 5 microM ara-C for 1 hr resulted in synergistic cell killing measured by soft-agar cloning. Although intracellular 2'-deoxycytidine 5'-triphosphate levels were reduced in cells treated for 4 hr with FUra and FUrd, this was not associated directly with the maximum accumulation of ara-C. FdUrd treatment was as effective as FUra and FUrd at enhancing ara-C accumulation and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate formation and producing synergistic cytotoxicity; however, the 2'-deoxycytidine 5'-triphosphate pools were minimally affected. 5'-Deoxy-5-fluorouridine did not increase intracellular ara-C accumulation, reduce intracellular 2'-deoxycytidine 5'-triphosphate levels, or enhance ara-C cytotoxicity. This sequential drug interaction is similar to that which we have observed when methotrexate precedes ara-C and provides a rational basis from which further in vivo studies can be designed.
Animals↗