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Biomedical subjects

J Blatt

Publications and source records attributed to J Blatt.

At least 91 records · Page 5Linked to original sources
PubMed1982

Cerebrospinal fluid levels of 2'-deoxycoformycin after systemic administration in monkeys.

2'-Deoxycoformycin (DCF) is an inhibitor of the enzyme adenosine deaminase (ADA) and has shown promise as an antileukemia agent. For the assessment of the extent to which systemically administered DCF crosses into the central nervous system (CNS), rhesus monkeys were given iv boluses of DCF. Simultaneous blood and cerebrospinal fluid (CSF) samples were assayed for DCF levels at times ranging from 10 minutes to 6 hours after the drug was given. Average peak CSF drug levels of 5.5 X 10(-8) M and 3 X 10(-7) M were reached 1 1/2 - 2 hours following injections of 0.25 and 1.0 mg DCF/kg, respectively. The ratio of peak CSF to simultaneous plasma levels was 1 to 10. Data obtained from a patient who had acute lymphocytic leukemia and who was given iv DCF were comparable. Drug levels achieved within the CSF following iv administration of 0.25 mg DCF/kg are similar to those previously demonstrated to inhibit ADA. These results may be important both for understanding DCF-related CNS toxicity and for designing combination chemotherapy with DCF.

Animals↗
PubMed1982

Lactate dehydrogenase isoenzymes in normal and malignant human lymphoid cells.

Intracellular lactate dehydrogenase (LD) isoenzyme patterns were studied in the malignant cells of patients with a variety of lymphoid malignancies. These were compared with intracellular LD isoenzyme patterns of normal lymphoid cells and were also correlated with immunologic cell surface marker characteristics. Results showed that, in general, the malignant B cells of Burkitt's lymphoma and the lymphoblasts of T-cell acute lymphoblastic leukemia had isoenzyme patterns similar to those of normal B and T cells, respectively. The isoenzyme patterns of malignant lymphoid cells from patients with non-T, and non-B acute lymphoblastic leukemia, cutaneous T-cell lymphoma, and chronic lymphocytic leukemia were more heterogeneous. These data, although based on small numbers of patients, are consistent with the hypothesis that LD isoenzymes may reflect differences in the maturational status of cells within a single diagnostic category.

B-Lymphocytes↗
PubMed1982

Clinical pharmacology of 9-beta-D-arabinofuranosyladenine in combination with 2'-deoxycoformycin.

It has been suggested that, by inhibiting the adenosine deaminase (ADA)-mediated catabolism of 9-beta-D-arabinofuranosyladenine (ara-A), 2'-deoxycoformycin (DCF) would increase the half-life (t1/2) of ara-A, a compound with known antileukemic activity. To test this hypothesis, we collected serial plasma samples from five patients with refractory acute lymphoblastic leukemia who participated in a Phase I trial of i.v. DCF 915 mg/sq m) in combination with i.v. single-dose ara-A (120-250 mg/sq m). In four of these patients, of whom three were known to have achieved greater than 98% ADA inhibition, a mean ara-A t1/2 of 227 min was achieved. Extrapolated peak levels (i.e., following infusion of ara-A) ranged from 1.5 to 7.4 micrograms/ml (mean, 4.2 micrograms/ml). Elimination of drug appeared to follow a single-compartment model. In two patients who received ara-A without prior DCF and in a third patient who had significant residual ADA activity despite DCF, ara-A was unmeasurable within 5 min of the end of infusion. These data confirm that the kinetics of ara-A catabolism can be altered by inhibition of ADA and suggest that more than one dose of DCF may be necessary for complete inhibition of the enzyme and optimal pharmacological modulation of ara-A.

Adolescent↗
PubMed1981

Testicular function in boys after chemotherapy for acute lymphoblastic leukemia.

Fourteen boys with acute lymphoblastic leukemia who had been treated with combination chemotherapy (prednisone, vincristine, methotrexate, and 6-mercaptopurine) were followed prospectively to assess the effect of this regimen on gonadal function. At the start of therapy, nine patients were prepubertal, four were intrapubertal, and one was sexually mature. The interval between discontinuation of chemotherapy and the most recent endocrine evaluation ranged from two months to 8 1/2 years (median, 5 1/2 years). Throughout the follow-up period, all patients had normal testicular function as determined by Tanner staging at physical examination and by serum gonadotropin and testosterone levels. Semen samples from six patients were unremarkable except for one sperm count that fell in the low-normal range. These results indicate that the administration of antileukemic chemotherapy can be compatible with normal gonadal development.

Adolescent↗
PubMed1981

Lymphoblast purine pathway enzymes in B-cell acute lymphoblastic leukemia.

Activities of enzymes of the purine metabolic pathway, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'-nucleotidase (5'-N), were investigated in the lymphoblasts of a patient with B-cell acute lymphoblastic leukemia. These lymphoblasts exhibited increased ADA activity and diminished activities of both PNP and 5'N' as compared to normal lymphocytes as well as non-T, non-B leukemia cells. This enzymatic pattern is identical to that which has been described in T-cell leukemic lymphoblasts and differs from that which has been observed in the malignant cells of undifferentiated B-cell lymphomas. These data suggest that there is biochemical heterogeneity within the spectrum of B-cell malignancies. Furthermore, inhibitors of ADA may be of use in those B-cell lymphoid neoplasms that exhibit increased ADA activity.

Acute Disease↗
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

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

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

Microanalysis and X-ray fluorescence spectrometry of platelets in diseases with elevated muscle calcium.

Electron microscopic X-ray microanalysis and X-ray fluorescence spectrometry were done on platelets from patients with Duchenne muscular dystrophy and idiopathic scoliosis (both these conditions are known to be associated with increased intramyofibre calcium). A significant increase in calcium and phosphorus concentrations was found in the dense granules and whole cells of both conditions. The findings suggest that idiopathic scoliosis like Duchenne muscular dystrophy is a multisystem disease with detectable changes in platelets.

Adolescent↗
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↗