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Biomedical subjects

B A Chabner

Publications and source records attributed to B A Chabner.

At least 217 records · Page 12Linked to original sources
PubMed1975

Non-Hodgkin's lymphoma: patterns of relapse from complete remission after combination chemotherapy.

An analysis of patterns of relapse from complete remission in patients with non-Hodgkin's lymphoma treated with combination chemotherapy has demonstrated differences between histologic subgroups. Patients with diffuse histiocytic lymphoma who achieved a histologically proven complete remission after 6 months of treatment without maintenance have remained disease-free whereas those with nodular poorly differentiated lymphocytic and diffuse well-differentiated lymphocytic lymphomas have demonstrated a pattern of continuous late recurrence. The initial sites of relapse from complete remission in lymphocytic lymphoma were lymph nodes and bone marrow which were involved prior to treatment. Aggressive attempts at remission induction appear warranted in patients with diffuse histiocytic lymphoma because of the potential for extended disease-free survival. Patients with nodular poorly differentiated lymphocytic lymphoma may benefit from the use of maintenance chemotherapy, or radiotherapy to regions of previously known involvement after initiation of remission with chemotherapy.

Antineoplastic Agents↗
PubMed1975

Competitive protein binding assay for methotrexate.

A competitive protein binding assay has been developed for methotrexate based on the tight binding of this drug to Lactobacillus casei dihydrofolate reductase (= tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase; EC 1.5.1.3). Free drug may be separated from that bound to reductase by adsorption with dextran--albumin coated charcoal. Scatchard plot analysis of the enzyme--drug interaction confirmed the presence of a single homogeneous class of binding sites with an association constant Ka of 2.1 X 10(8) M-1. This high affinity binding permits detection of methotrexate in the range of 0.3--30 pmol with a coefficient of variation of 15% or less. The predominant circulating folate, 5-methyl tetrahydrofolate, and the clinically useful rescue agent leucovorin (5-formyl tetrahydropteroyl-glutamic acid) do not interfere with the assay, nor does the methotrexate metabolite 4-amino-4-deoxy-10-methylpteroic acid. Assay of clinical samples, including plasma and cerebrospinal fluid, showed close agreement between the previously described enzyme inhibition assay and the more rapid competitive binding method.

Binding Sites↗
PubMed1975

Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion.

5-Fluorodeoxyuridine monophosphate (FdUMP), the active metabolite of 5-fluorouracil (5-FU), is a tight-binding inhibitor of thymidylate synthetase, the enzyme which converts dUMP to TMP. Newly developed assays for FdUMP and dUMP were utilized to assess the competitive roles played by these nucleotides in determining the inhibition of TMP synthesis in mice bearing the P1534 ascites tumor. After 5-FU administration, levels of FdUMP reached a dose-dependent peak within 6 h in the ascites tumor and in bone marrow, and declined thereafter in a biphasic manner with an initial t 1/2 of 6 h and a final t 1/2 of 7-9 days. In duodenal mucosa, FdUMP levels were 1.8-2-fold higher than in the other tissues, but elimination was much more rapid. Simultaneous with the fall in FdUMP a progressive accumulation of the competitive substrate dUMP was observed in each tissue after 5-FU; and peak dUMP levels coincided with recovery of thymidylate synthesis, as determined by the incorporation of [3H]deoxyuridine into DNA. In vitro experiments with partially purifed thymidylate synthetase revealed and initial competitive interaction of dUMP and FdUMP, which, at high concentrations of dUMP was capable of markedly slowing the rate of irreversible inactivation of enzyme by FdUMP. These studies were found to be quantitatively consistent with a two-phase model of enzyme inactivation involving an initial competition between dUMP and FdUMP, with subsequent irreversible inactivation of enzyme by covalent linkage to the inhibitor. Recovery of thymidylate synthesis after 5-FU appears to result from both a fall in intracellular levels of inhibitor and a progressive accumulation of the competitive substrate dUMP.

Animals↗
PubMed1975

Results of combination chemotherapy of non-Hodgkin's lymphoma.

The analysis of the results of CVP and MOPP chemotherapy in 80 patients with advanced stages of non-Hodgkin's lymphoma shows that 36 achieved a complete remission. Twenty-five percent of all patients remain free of disease for periods ranging from 4 months to over 7 years, with a projected median duration of complete remissions of 3 1/2 years. Well differentiated and nodular histology were positive determinants for survival, confirming the overall clinical validity of the Rappaport classification system for the non-Hodgkin's lymphomata. However, it has been demonstrated that it is possible to achieve a complete remission using combination chemotherapy even in the most clinically aggressive histological subgroups, and that these responses can be correlated with an extended survival. An analysis of patterns of relapse from complete remission in patients with non-Hodgkin's lymphoma treated with combination chemotherapy has demonstrated differences between histological subgroups. Patients with diffuse histiocytic lymphoma who achieved a complete remission after 6 months of treatment without maintenance have remained disease-free, whereas those with nodular poorly differentiated lymphocytic and diffuse well differentiated lymphocytic lymphomata demonstrate a pattern of continuous late recurrence. The initial sites of relapse from complete remission in lymphocytic lymphoma were lymph nodes and bone marrow which were involved before treatment.

Antineoplastic Agents↗
PubMed1975

Therapy of advanced lymphocytic lymphoma a preliminary report of a randomized trial between combination chemotherapy (CVP) and intensive radiotherapy.

The initial results of a randomized clinical trial comparing intensive cyclical combination chemotherapy (CVP) and total body radiation therapy in the treatment of advanced (Stage III and IV) lymphocytic lymphoma is presented. Sixty-five patients have been entered and randomized according to stage. Of the chemotherapy treated patients, (22/27 (81%) achieved a response with 55% complete responders. The radiation group or those treated with radiation 27/32 (84%) responded with 56% in complete response. There is no significant difference in overall survival between the two groups. Nodular lymphoma (44 patients) responds more often and has s significantly longer survival than diffuse lymphoma (21 patients). Approximately 50% of the complete remitters have relapsed but reinduction of disease control was possible in almost all cases.

Adult↗
PubMed1975

Percutaneous liver biopsy, peritoneoscopy and laparotomy: an assessment of relative merits in the lymphomata.

The relative merits of percutaneous liver biopsy, peritoneoscopy directed liver biopsy and wedge liver biopsy during laparotomy were examined in a series of 100 consecutive untreated patients with non-Hodgkin's lymphoma. Sixteen of 77 patients had positive findings on percutaneous liver biopsy specimens, with the best yield in patients with nodular (21%) and diffuse (33%) poorly differentiated lymphocytic lymphoma. Forty-nine of the 61 patients having negative percutaneous biopsies were subjected to peritoneoscopy and 9 additional positive biopsies were obtained. Thirty-two of the 40 patients having negative percutaneous and peritoneoscopy findings underwent laparotomy and wedge biopsy of the liver, and 8 specimens (25%) were positive for liver involvement; all but one of these were in patients with nodular or diffuse poorly differentiated lymphocytic lymphoma. This study indicates that over two-thirds of untreated patients with non-Hodgkin's lymphoma can be shown to have Stage IV disease without undergoing laparotomy, and that in the remaining patients, laparotomy proved of consistent value only in patients with poorly differentiated lymphocytic lymphoma.

Biopsy↗
PubMed1975

Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes.

Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara-CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine-cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.

Azacitidine↗
PubMed1975

Preliminary Results of trials of chemotherapy in advanced ovarian carcinoma.

A search for improved forms of systemic chemotherapy in advanced ovarian carcinoma has resulted in two prospective trials at the Medicine Branch National Cancer Institute. The first trial compared high-dose, split-course intravenous cyclophosphamide with conventional treatment with an oral alkylating agent, melphalan [also called L-phenylalanine mustard (PAM)]. While both regimens were essentially equal in therapeutic efficacy, the former was considerably more toxic and the latter was therefore preferred. The second trial employed a 4-drug combination (5-fluorouracil, methotrexate, cyclophosphamide, and hexamethylmelamine); the results indicated a higher overall response rate (85%) and a higher complete remission rate (31%) with the combination therapy than with the PAM therapy, although the study is short and the observations are preliminary.

Altretamine↗
PubMed1974

Cyclical combination chemotherapy for advanced breast carcinoma.

Twenty-five patients with advanced metastatic breast cancer were treated with the combination of methotrexate 60 mg/M(2) and 5-fluorouracil 700 mg/M(2) intravenously on the first and eighth days, and cyclophosphamide 100 mg/M(2) and prednisone 40 mg/M(2) by mouth daily for the first 14 days of a 28-day cycle. The patients had had no previous chemotherapy or extensive radiotherapy and all but two had not responded to hormonal therapy or endocrine ablation. The major metastatic lesions were: lung (12 patients), liver (four patients), bone (four patients), soft tissue (three patients), nodes (two patients). Seventeen of the 25 patients (68%) responded to treatment with seven complete remissions; these included patients suffering metastatic lesions in the lung, nodes, and soft tissue. The overall median duration of response was nine months (range 6-26 months). Toxicity was primarily haematological, but the group received an average of at least 75% of their calculated dose for each monthly cycle. Haematological toxicity was most pronounced in patients with liver dysfunction and bone marrow involvement. Out of eight nonresponders seven died, with a median survival of six months. Only six of 17 responders died, and the median survival in this group will exceed thirteen months. There was no correlation between the length of the metastasis-free interval after previous treatment and subsequent response to chemotherapy.

Adrenalectomy↗