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Biomedical subjects

B A Chabner

Publications and source records attributed to B A Chabner.

At least 235 records · Page 13Linked to original sources
PubMed1974

Chemotherapy of advanced ovarian carcinoma: a prospective randomized comparison of phenylalanine mustard and high dose cyclophosphamide.

Twenty-four fully staged, previously untreated patients with advanced ovarian carcinoma were prospectively randomized to either intensive intravenous cyclophosphamide or conventional oral Melphalan therapy. The median durations of initial remissions (5 and 6 mo) and the median durations of survival (15 and 14 mo) were similar for the two regimens but the toxicity of the intensive regimen was excessive. Followup indicates that long term disease free survivals are possible in those patients who achieve complete remissions on chemotherapy alone as three of the four patients achieving complete remission in the present study remain free of disease with a median survival in excess of 30 mo. High dose intensive alkylating agent therapy in the manner used in the present study fails to enhance the response to chemotherapy and produces unacceptable toxicity.

Adenocarcinoma↗
PubMed1974

Purification and properties of cytidine deaminase from normal and leukemic granulocytes.

Cytidine deaminase, an enzyme that catalyses the deamination of both cytidine and its nucleoside analogues including the antineoplastic agents cytosine arabinoside (ara-C) and 5-azacytidine (5-azaC), has been partially purified from normal and leukemic human granulocytes. The purification procedure included heat precipitation at 70 degrees C, ammonium sulfate precipitation, calcium phosphate gel ion exchange, and Sephadex G-150 gel filtration. The enzyme has mol wt 51,000, isoelectric pH of 4.8, and maximum activity over a broad pH range of 5-9.5. The enzyme is stabilized by the presence of the sulfhydryl reagent, dithiothreitol. Cytidine deaminase from normal human granulocytes has a greater affinity for its physiologic substrate cytidine (K(m) = 1.1 x 10(-5) M) than for ara-C (8.8 x 10(-5) M) or 5-azaC (4.3 x 10(-4) M). Halogenated analogues such as 5-fluorocytidine and 5-bromo-2'-deoxycytidine also exhibited substrate activity, with maximum velocities greater than that of the physiologic substrates cytidine and deoxycytidine. No activity was observed with nucleotides or deoxynucleotides. The relative maximum velocity of the enzyme for cytidine and its nucleoside analogues remained constant during purification, indicating that a single enzyme was responsible for deamination of these substrates. Tetrahydrouridine (THU) was found to be a strong competitive inhibitor of partially purified deaminase with a K(i) of 5.4 x 10(-8) M. The biochemical properties of partially purified preparations of cytidine deaminase from normal and leukemic cells were compared with respect to isoelectric pH, molecular weight, and substrate and inhibitor kinetic parameters, and no differences were observed. However, normal circulating granulocytes contained a significantly greater concentration of cytidine deaminase (3.52+/-1.86 x 10(3)/mg protein) than chronic myelocytic leukemia (CML) cells (1.40+/-0.70 x 10(3) U/mg protein) or acute myelocytic leukemia (AML) cells (0.19+/-0.17 x 10(3) U/mg protein). To explain these differences in enzyme levels in leukemic versus normal cells, the changes in cytidine deaminase levels associated with maturation of normal granulocytes were studied in normal human bone marrow. Myeloid precursors obtained from bone marrow aspirates were separated into mature and immature fractions by Ficoll density centrifugation. Deaminase activity in lysates of mature granulocytes was 3.55-14.2 times greater than the activity found in the lysates of immature cells. Decreased enzyme activity was also found in immature myeloid cells from a patient with CML as compared to mature granulocytes from the same patient. These observations support the conclusion that the greater specific activity of cytidine deaminase in normal mature granulocytes as compared to leukemic cells is related to the process of granulocyte maturation rather than a specific enzymatic defect in leukemic cells.

Adolescent↗
PubMed1973

Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues.

The suppression of DNA synthesis in host and tumor tissues by methotrexate has been monitored in mice by determining the in vivo incorporation of tritium-labeled deoxyuridine ([(3)H]UdR) into DNA. The duration of inhibition of [(3)H]UdR incorporation in normal tissues was related to the dose of methotrexate and was a direct function of plasma drug concentration. [(3)H]UdR incorporation recovered to 50% of pretreatment levels in bone marrow when plasma methotrexate concentration was 10(-8) M or less, irrespective of the dose administered, while 50% recovery of DNA synthesis in intestinal epithelium was not observed until plasma methotrexate levels were 5 x 10(-9) M or less. Ascitic L1210 leukemia cells did not fully return to pretreatment levels of [(3)H]UdR incorporation at any time, although a partial recovery of incorporation was noted at methotrexate ascitic fluid concentrations of approximately 10(-8) M. Methotrexate did not suppress the incorporation of tritium-labeled thymidine ([(3)H]TdR) into bone marrow and duodenal mucosa, confirming the specificity of its action in inhibiting thymidylate synthesis in host tissues. In the ascites tumor a gradual decline in [(3)H]TdR incorporation was seen after methotrexate, indicating that the tumor tissue depression of [(3)H]UdR incorporation is not solely due to inhibition of thymidylate synthesis. These studies indicate that host tissues are inhibited by extremely low concentrations of methotrexate, and indicate the importance of the slow final phase (t((1/2))=12 h) of drug elimination from plasma in producing a prolonged exposure of sensitive host tissues to inhibitory drug concentrations.

Animals↗