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Biomedical subjects

D G Poplack

Publications and source records attributed to D G Poplack.

At least 181 records · Page 10Linked to original sources
PubMed1981

Purine pathway enzyme abnormalities in acute lymphoblastic leukemia.

The status of three purine pathway enzymes, adenosine deaminase, 5'-nucleotidase, and purine nucleoside phosphorylase, was evaluated in the leukemic cells of patients with acute lymphoblastic leukemia and correlated with routine immunological cell surface markers. A distinct pattern of enzyme activity was noted in T-lymphoblasts which have significantly higher adenosine deaminase activity (p less than 0.02) and lower 5'-nucleotidase (p less than 0.001) and purine nucleoside phosphorylase (p less than 0.01) activities than do non-T, non-B lymphoblasts. This enzyme pattern is similar to that observed in normal human thymocytes but is not shared by the mature, normal T-lymphocytes of peripheral blood, suggesting that it may reflect the differentiation status of malignant T-lymphoblasts. These findings, which confirm the biochemical heterogeneity of acute lymphoblastic leukemia, may provide an avenue for selective chemotherapy of this disease.

5'-Nucleotidase↗
PubMed1981

L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans.

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.

Animals↗
PubMed1981

Treatment of acute lymphoblastic leukemia in relapse: efficacy of a four-drug reinduction regimen.

The experience of 47 similarly-treated patients with acute lymphoblastic leukemia who developed hematologic relapse was reviewed to determine the effectiveness of reinduction therapy. The majority of patients were treated with a four-drug regimen utilizing L-asparaginase, vincristine, daunomycin, and prednisone. This regimen produced second, third, and fourth remissions in approximately 90% of patients, all of whom had experienced relapse while on chemotherapy. Eighteen percent of all patients who achieved second remissions are alive in prolonged second remissions, including four individuals who experienced relapse while receiving maintenance chemotherapy. These encouraging results underscore the efficacy of the four-drug regimen and emphasize the necessity for intensive treatment of recurrent acute lymphoblastic leukemia.

Adolescent↗
PubMed1981

Phase I study of 2'-deoxycoformycin in acute lymphoblastic leukemia.

2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2'-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2'-dCF which were not associated with limiting toxicities. These results suggest that 2'-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.

Adenosine Deaminase Inhibitors↗
PubMed1981

Levels of 2'-deoxycoformycin, adenosine, and deoxyadenosine in patients with acute lymphoblastic leukemia.

2'-Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase, has recently undergone Phase I clinical trials and has been found to be therapeutically active in acute lymphoblastic leukemia. In this report, levels of dCF in plasma, plasma concentrations of adenosine and deoxyadenosine, and urine levels of deoxyadenosine were measured in leukemic patients undergoing treatment with dCF during a Phase I clinical trial. dCF was administered i.v. at a dose of 0.25 to 1.0 mg/kg (7.5 to 30 mg/sq m) for 3 consecutive days. Plasma drug levels of 2 to 6 microM were observed following the third dose of dCF, and drug accumulation occurred only at the 1-mg/kg dosage. In this limited series of patients, the plasma concentrations of adenosine and deoxyadenosine and the urine concentrations of deoxyadenosine did not show an obvious correlation with dCF dose, therapeutic response, or toxicity.

Adenosine↗
PubMed1980

Improved treatment results in the management of single and multiple relapses of acute lymphoblastic leukemia.

One hundred twenty-five hematologic relapses of acute lymphoblastic leukemia (ALL) were treated with a four-drug reinduction regimen consisting of L-asparaginase, vincristine, daunomycin, and prednisone (Asp-VDP). Complete remission was achieved in 114 of 125 (91%) treatment courses. The regimen also proved to be highly effective in the management of multiple subsequent relapses which occurred in patients who had previously attained complete remissions with this regimen. The rates of remission induction for second and third reinduction attempts were 89% and 90%, respectively. Ten patients received this regimen for the treatment of four or more consecutive relapses and achieved complete remissions on each occasion. Toxicities related to therapy were not excessive. Although myelosuppression was the most frequently encountered toxicity, documented infection complicated only 14% of the treatment courses. These results constitute a considerable improvement in the management of recurrent ALL.

Adolescent↗
PubMed1980

Delayed allergic reactions following intramuscular L-asparaginase.

L-asparaginase, a highly effective anti-leukemic enzyme preparation is now frequently being administered intramuscularly in order to decrease the incidence of severe sensitivity reactions. Although the occurrence of immediate hypersensitivity reactions and anaphylaxis has been diminished through this technique, we report three patients who developed delayed allergic reactions occurring hours after drug administration. This suggests that patients receiving L-asparaginase intramuscularly merit prolonged observation periods beyond the usual one half to one hour.

Adolescent↗
PubMed1980

Acute tumor lysis syndrome. A review of 37 patients with Burkitt's lymphoma.

Renal and metabolic complications of tumor lysis during 46 episodes of remission induction chemotherapy were reviewed in 37 patients with American Burkitt's lymphoma. Azotemia occurred in 14 patients, preceding chemotherapy in eight. All of these patients had abdominal tumors. Pretreatment azotemia was associated with elevated lactic dehydrogenase (LDH) and uric acid levels, and sometimes extrinsic ureteral obstruction by tumor. Two patients required dialysis for uric acid nephropathy before chemotherapy was initiated. Following chemotherapy, major complications of tumor lysis (hyperuricemia, hyperkalemia and hyperphosphatemia) were associated with very large tumors, high LDH levels and inadequate urinary output. In patients undergoing diuresis and receiving allopurinol, hyperkalemia or hyperuricemia developed infrequently unless concomitant renal failure ensued. Hyperphosphatemia, which occurred only after chemotherapy, developed in 10 of 32 (31 per cent) nonazotemic and in all azotemic patients. Hemodialysis was required in three post-treatment patients for control of azotemia, hyperuricemia, hyperphosphatemia and/or hyperkalemia. Because of the potential for renal failure caused by precipitation of phosphate, severe hyperphosphatemia is an additional criterion for dialysis in patients with acute tumor lysis syndrome.

Adolescent↗
PubMed1980

Pregnancy outcome following cancer chemotherapy.

The outcome of pregnancies of patients who received aggressive chemotherapy was examined. Of 448 patients screened, 30 had 12 abortions (10 elective and two spontaneous) and 28 live births. Follow-up of off spring revealed no major malformations. In addition, growth, development and school performance were normal. These results support the contention that chemotherapy administered to women prior to gestation or after the first trimester may result in normal births in the majority of cases. Moreover, the available data suggest that chemotherapy given to men at or prior to the time of conception does not appear to result in fetal damage. These results may be of value in counseling cancer patients regarding risks to their offspring.

Abnormalities, Drug-Induced↗
PubMed1980

Purine nucleoside phosphorylase activity in acute lymphoblastic leukemia.

Purine nucleoside phosphorylase (PNP) activity has been measured in the lymphoblasts of 22 patients with acute lymphoblastic leukemia (ALL) and correlated with routine immunologic cell surface markers. Fourteen of the 22 patients were considered to have non-T, non-B-cell ALL; 8 patients had T-cell disease. The median PNP activity in 21 control samples of normal peripheral blood mononuclear cells was 83 U. The median PNP activity of the non-T, non-B lymphoblasts was 79 U. No statistical difference in PNP activity between these two groups could be discerned (p < 0.37). In contrast, T-cell lymphoblasts demonstrated diminished PNP activity with a median of 38 U. The differences in activity between T lymphoblasts and both non-T, non-B leukemic cells and normal peripheral blood mononuclear cells were significant (p < 0.001 and p < 0.003, respectively). Evaluation of PNP activity provides further evidence of biochemical heterogeneity among immunologic subclasses of ALL.

Antigens, Surface↗
PubMed1980

Fc receptors on human T lymphocytes. V: Effects of colchicine and cytochalasin B on Fc receptor expression.

Previous studies have documented that the interaction of IgG immune complexes with the FcIgG receptor (Fc-IgGR) of human T lymphocytes induces alterations both in the expression of Fc receptors and in the functional capacities of these cells. After IgG immune complex exposure, Fc-IgGR-bearing T lymphocytes lose their Fc-IgGR and generate Fc-IgMR in subsequent culture. This transition phenomenon is mediated via patching and capping of the Fc-IgGR. Since Colchicine and Cytochalasin B have been demonstrated to interfere with capping of other membrane elements by their known effects on cytoskeletal structures, we investigated the effects of these agents on the expression of Fc receptors of human T cells. Neither Colchicine nor Cytochalasin B directly affects Fc-IgGR or Fc-IgMR expression. However, both agents inhibit the loss of Fc-IgGR subsequent to IgG immune complex exposure as well as the development of Fc-IgMR in culture. Immunofluorescent studies illustrate that this inhibition is mediated in part by interference with capping of the Fc-IgGR-immune complex ligand. This study emphasizes the inverse relationship between Fc-IgGR and Fc-IgMR expression on human T lymphocytes.

Animals↗
PubMed1980

Active transport of methotrexate from cerebrospinal fluid in humans.

The cerebrospinal fluid (CSF) efflux kinetics of methotrexate (MTX) were studied in three patients with indwelling Ommaya reservoirs. A small dose of MTX was injected intraventricularly several hr after the start of a high-dose continuous i.v. infusion of MTX. In all patients, the CSF antifolate concentration returned to the preinjection level before the end of the i.v. infusion. This result indicated that the efflux of MTX from CSF in humans is independent of plasma drug concentrations. Efflux kinetics were further characterized in one patient. Serially obtained CSF samples after intraventricular injections demonstrated a biphasic disappearance curve with alpha- and beta-phase half-disappearance times of 1.7 and 6.6 hr, respectively. Prolongation of the beta-phase half-time was associated with oral acetazolamide medication and with increased intracranial pressure, indicating that inhibition of CSF production slows MTX clearance. CSF MTX concentration, however, declined more rapidly than that of simultaneously administered diethylenetriaminepentaacetic acid, an extracellular marker substance excreted by bulk flow, indicating that bulk flow excretion alone is insufficient to account for MTX efflux from human CSF. Evidence that there is an active transport component was provided by probenecid pretreatment which also prolonged the CSF MTX half-life. These findings suggest that both passive and active mechanisms govern MTX efflux from the CSF in humans and that they can be inhibited by acetazolamide and probenecid, respectively.

Acetazolamide↗
PubMed1980

Pharmacokinetics of vincristine in the cerebrospinal fluid of subhuman primates.

Adult rhesus monkeys were given 2-mg/sq m i.v. bolus injections of radiochemically pure tritiated vincristine (VCR). Simultaneous specimens of blood and cerebrospinal fluid (CSF) were sampled from 5 min to 72 hr following injection. CSF was obtained from Ommaya reservoirs which had been implanted s.c. in each monkey. VCR and its metabolic and/or decomposition products rapidly entered the CSF producing low concentrations in this fluid; 5 min following injection, the concentration of VCR was 2.3 nM, whereas approximately a 100-fold greater concentration (203.8 nM) was attained in the plasma. Throughout a 3-day period of observation, constant, low levels of VCR and its metabolic and/or decomposition products (2.3 to 5.7 nM) were maintained in the CSF. The principal form of VCR present in the CSF 1 hr or more after i.v. injection was a water-soluble metabolite and/or decomposition product(s). Although the levels achieved in the CSF are unlikely to be lethal to tumor cells, the finding of persistent low concentrations of VCR and its metabolic and/or decomposition products in the CSF indicates prolonged exposure of neural tissue which might result in neurotoxicity, particularly cumulative neurotoxicity following multiple doses of VCR.

Animals↗
PubMed1979

Adrenal suppression after short-term corticosteroid therapy.

Adrenal function was evaluated in fourteen cancer patients receiving chemotherapy which included short-term high-dose courses of prednisone. 90 min corticotropin stimulation tests were performed before therapy and 1, 2, 4, and 7 days after steroids were discontinued. Responses were evaluated by standard criteria of adrenal function and by measurement of the intergrated cortisol response to corticotropin over 90 min. Thirteen of fourteen patients had suppressed adrenal function for at least 24 h. Although in most patients adrenal function had returned to normal between day 2 and 4, in five patients it remained suppressed for 7 days or more. Suppression did not correlate with either steroid dose or duration of therapy. Four of five patients receiving only 5 days' therapy showed evidence of adrenal suppression. Although overt clinical adrenal insufficiency after steroid administration is rare, these results indicate that adrenal function is suppressed more regularly after short-term high-dose steroid therapy than has been appreciated.

Adolescent↗