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Biomedical subjects

H D Preisler

Publications and source records attributed to H D Preisler.

At least 181 records · Page 10Linked to original sources
PubMed1984

Inhibition of DNA synthesis by cytosine arabinoside: relation to response of acute non-lymphocytic leukemia to remission induction therapy and to stage of the disease.

The sensitivity of leukemic marrow cell DNA synthesis to cytosine arabinoside (araC) exposure in vitro was studied in specimens obtained from patients with acute non-lymphocytic leukemia. Cells from patients who had been treated with araC in the past were more likely to be resistant to the effect of araC on DNA synthesis than cells obtained from patients who had not been so-treated previously. Resistance to the effects of araC on DNA synthesis was associated with the failure of high-dose araC therapy to induce remissions in relapsed patients, whereas remission induction failure in previously untreated patients was not associated with araC resistance.

Acute Disease↗
PubMed1984

Ph1-positive acute leukemia.

Twenty-five cases of Ph1-positive acute leukemia (AL) are described, 13 presenting an acute lymphocytic leukemia (ALL) and 12 an acute non-lymphocytic leukemia (ANLL). In 12 cases coarse, pink, peroxidase-negative cytoplasmic granules were found in the leukemic cells. These granules have not been described in Ph1-negative AL and their presence appears to be pathognomonic of Ph1-positive acute leukemia. The leukemias of three patients consisted of both lymphoid and myeloid clones while the cells of two patients had lymphoid and myeloid markers simultaneously present in the same cells. Cytogenetic studies were useful for monitoring response and some patients clearly acquired a Ph1-negative status during clinical remission. The disease appears to be more resistant to chemotherapy than Ph1-negative acute leukemia. While similar to chronic myelocytic leukemia (CML) in the Ph1 translocation, Ph1 AL differed from it both in age at presentation and response to therapy.

Adolescent↗
PubMed1984

Relationship between the per cent of marrow cells in S phase and the outcome of remission-induction therapy for acute nonlymphocytic leukaemia.

The relationship between the pretherapy cell cycle characteristics of leukaemic marrow cells and the outcome of remission-induction therapy for acute nonlymphocytic leukaemia was studied in newly diagnosed and relapsed patients who were then treated with either combination chemotherapy consisting of cytosine arabinoside/anthracycline antibiotic +/- 6 thioguanine or with single agent high-dose cytosine arabinoside therapy. The outcome of high-dose cytosine arabinoside therapy was highly dependent upon the per cent of pretherapy cells in S phase with no remissions occurring in patients in whom the 3H-TdR labelling index was less than 6%. In contrast, the outcome of cytosine arabinoside/anthracycline antibiotic therapy was independent of the pretherapy cell cycle characteristics of the leukaemic cells.

Acute Disease↗
PubMed1984

Prediction of response of acute nonlymphocytic leukaemia to therapy with 'high dose' cytosine arabinoside.

The Leukemia Intergroup Study has treated 110 patients with acute nonlymphocytic leukaemia with 'high dose' cytosine arabinoside remission induction therapy and studied the factors which were related to the outcome of therapy. With respect to death during remission induction therapy, only patient age was of prognostic significance. Treatment failure due to resistant leukaemia was associated with a high pretherapy leukaemic cell mass, the presence of few cells in S phase, and insensitivity of DNA synthesis to cytosine arabinoside. If, after 6 d of therapy, more than 40% of the marrow cells were leukaemic, the patient almost invariably failed to enter complete remission because of persistent leukaemia. Simultaneous consideration of the pretherapy labelling index and the per cent abnormal cells in the day 6 marrow permitted a distinction to be made between almost all patients who would enter remission or fail therapy because of persistent leukaemia.

Age Factors↗
PubMed1984

Assessment of the drug sensitivity of acute nonlymphocytic leukaemia using the in vitro clonogenic assay.

The ability of an in vitro clonogenic drug sensitivity assay to predict the outcome of therapy for acute nonlymphocytic leukaemia was evaluated using marrow cells obtained from previously untreated or first relapsed patients treated with either cytosine arabinoside/anthracycline antibiotic or high dose cytosine arabinoside remission induction therapy. While the per cent of leukaemic cells killed in vitro was correlated with the outcome of therapy, this drug sensitivity assay provided little or no clinically useful information.

Acute Disease↗
PubMed1984

Different sensitivities of granulocyte-macrophage and erythroid progenitor cells of normal human bone marrow to S-phase-specific agents.

The extraordinary sensitivity of early erythroid progenitor cells (BFU-e) of normal human bone marrow to tritiated thymidine ([3H]TdR) was studied. While exposure of bone-marrow cells to [3H]TdR for 1 hr resulted in the death of only 40% of the granulocyte-macrophage progenitor cells (CFU-c), 90% of BFU-e were killed. Experiments in which normal bone-marrow cells were mixed with bone-marrow cells which had been exposed to [3H]TdR demonstrated that the excessive killing of BFU-e by [3H]TdR reflected carry-over of the [3H]TdR by the exposed cells. A carry-over effect was not observed for CFU-c, suggesting the presence of a fundamental difference in the metabolism of TdR between CFU-c and BFU-e. There was a suggestion of a carry-over effect regarding two other S-phase-specific agents, hydroxyurea and 1-beta-D-arabinofuranosylcytosine.

Bone Marrow Cells↗
PubMed1984

Protection of normal hematopoietic stem cells from the toxicity of purine base analogs: in vivo application.

Normal murine bone marrow cells were incubated with adenosine (100 microM) for 2 hrs followed by the addition of 6-thioguanine (6-TG) (0.3 and 1.0 microgram/ml) for 1, 24, and 48 hrs, and the survival of the committed stem cells (CFUc) and pluripotential stem cells (CFUs) was compared to the survival of CFUc and CFUs which were similarly incubated without adenosine. When 0.3 microgram/ml of 6-TG was used, preincubation with adenosine increased the survival of CFUc from 25% to 80% and from 14% to 36% for 24- and 48-hr incubations, respectively (P less than or equal to 0.005). For 1 microgram/ml of 6-TG, pretreatment with adenosine increased survival from from 11% to 69% and from 5% to 24%, respectively, for 24- and 48-hr incubations (P less than or equal to 0.0005). Adenosine had a similar effect on CFUs (P less than or equal to 0.03). This effect was not seen when equimolar concentrations of hypoxanthine, inosine, or adenine were substituted for adenosine. Inoculation of adenosine into mice (500 mg/kg of body weight) 1 hr prior to injection of lethal doses of 6-TG (50 mg/kg) increased the survival of the mice from 10% to 100% and from 20% to 80%, respectively, using two administration schedules. This effect of adenosine, which, as has been previously shown, is the result of the depletion of cellular phosphoribosyl pyrophosphate pools, is potentially useful for the selective protection of normal hematopoietic cells from the toxicity of purine analogs which require activation via a phosphoribosyl pyrophosphate-dependent reaction, while therapeutic effects are produced against malignant tissue.

Adenosine↗
PubMed1984

Treatment of myeloid blastic crisis of chronic myelogenous leukemia.

Patients with myeloid blastic crisis of chronic myelogenous leukemia were treated by chemotherapy or by autologous hematopoietic reconstitution after aggressive chemotherapy. Chemotherapy alone failed to produce a second chronic phase. Autologous transplantation resulted in the establishment of a second chronic phase in two of ten patients treated with a four-drug regimen, while treatment with high-dose cytarabine with or without busulfan resulted in the establishment of a second chronic phase in three of six patients and the return of normal hematopoiesis in a fourth. Consolidation chemotherapy appeared to be beneficial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Comparison of in vitro assays for detecting subpopulations of P388 leukemic cells resistant to AraC.

The kinetics of cytosine arabinoside (AraC) were studied in vitro using P388 murine leukemia lines sensitive (P388-S) and resistant (P388-R) to the drug. Using P388-S cells, the 3H-thymidine index (L.I.) was paralleled by the 3H-AraC index, i.e. any cell in the S-phase of the cycle also incorporated the 3H-AraC into DNA. With the resistant line, the 3H-AraC index was zero in spite of high L.I. This discrepancy between the L.I. and 3H-AraC index could be used to predict the percentage of resistant cells when known mixtures of sensitive and resistant populations were used. The reason for lack of incorporation into DNA by the resistant cells was shown to be the presence of very low levels of the enzyme deoxycytidine kinase in P388-R cells resulting in an inability to phosphorylate AraC to its active form AraCTP. Immediate inhibition of DNA synthesis caused by AraC was directly proportional to the number of sensitive cells present in the population, but was not as accurate a predictor of sensitivity as the 3H-AraC index. Cloning in methylcellulose was found to be the least sensitive predictor of the percentage of sensitive and resistant cells, most likely related to the difference in cloning efficiency of the sensitive and resistant lines.

Animals↗
PubMed1984

Chemotherapy in AML.

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Antineoplastic Agents↗
PubMed1984

Relationship of the growth of leukemic cells in vitro to the outcome of therapy for acute nonlymphocytic leukemia.

Bone marrow cells obtained from 166 patients with acute nonlymphocytic leukemia were cloned in vitro. The number and size of clones produced differed among patients and was unrelated to French-American-British type of leukemia, to patient age, to whether the patient was studied at the time of initial diagnosis or at relapse, or to the cytogenetic (normal or abnormal metaphases) or cell cycle characteristics of the leukemic bone marrow cells. The ability of leukemic cells to clone in vitro was associated with poor response to therapy in vivo, with the remission rate being inversely related to cloning efficiency of the leukemic cells, and with remission durations being inversely correlated with the size of the cluster/colonies formed in vitro. Only an occasional patient whose marrow cells produced clonal growth in vitro and in whom cytogenetic abnormalities were detected entered complete remission with conventional remission induction therapy. Measurement of the clonogenic potential in vitro of leukemic marrow cells together with their cytogenetic type may help to distinguish between patients who should and should not receive cytosine arabinoside/anthracycline antibiotic remission induction therapy and patients who do and do not require intensive remission consolidation chemotherapy.

Antineoplastic Agents↗
PubMed1983

Treatment of erythroleukemia with anthracycline antibiotics and cytosine arabinoside.

The introduction of the anthracycline antibiotics and cytosine arabinoside have significantly improved the remission induction rate for patients with acute nonlymphocytic leukemia. Erythroleukemia (M6 by French-American-British classification) has long been considered to be resistant to chemotherapy. Since 1973 we have treated 14 patients with erythroleukemia with daunorubicin 45 mg/m2 or doxorubicin 30 mg/m2 for three days and cytosine arabinoside 100 mg/m2 by continuous infusion for 7 to 10 days. Six complete remissions (43%) were obtained with remission durations of 3+, 4+, 9, 13, 29+, and 35 months. While this remission rate is somewhat lower than that obtained with other types of acute nonlymphocytic leukemia, the combination of anthracycline antibiotics and cytosine arabinoside is clearly effective against erythroleukemia. Five patients treated before mid 1976 died soon after remission induction therapy was started. Four of these five patients were treated for 6 to 9 months with prednisone, halotestin, and/or splenectomy before remission induction chemotherapy was started and three of these patients died of systemic fungal infection, suggesting that these modalities of treatment may interfere with patient tolerance to remission induction therapy. It is suggested that erythroleukemia should be treated with intensive chemotherapy soon after the diagnosis is made.

Adolescent↗
PubMed1983

The clonogenic assay as a reproducible in vitro system to study predictive parameters of treatment outcome in acute nonlymphoblastic leukemia.

Seven institutions studied the cloning pattern of leukemic cells from pretherapy bone marrows of 273 patients with newly presenting and relapsed acute nonlymphoblastic leukemia. The cloning assay was done in all centers using an identical double-layer agar method with a common source of colony-stimulating factor. Cells were incubated for seven days, and clones were identified visually with an inverted microscope. All centers were able to obtain clonal growth in a substantial proportion of patients. Differences in growth pattern were observed between the major contributing center and the pooled results for all other centers. However, an analysis of clinical results suggested that in vitro differences were more likely related to differences in the patient populations than to variability in laboratory technique. The proportion of marrows in which leukemic cells formed colonies (greater than 40 cells) and large clusters (20-40 cells) was greater in relapsed patients than in newly presenting patients (P less than .06). A progressive improvement in induction treatment outcome was seen with decreasing clonal growth. Patients whose marrows did not produce clones had a complete remission (CR) rate of 83% versus 50% for those patients whose marrow leukemic cells formed colonies and/or large clusters (P = .05). In vitro drug sensitivity studies with cytosine arabinoside and adriamycin were performed on bone marrow cells of patients treated with this combination clinically. The percent killing of clonogenic cells in this assay correlated with remission induction outcome. Complete remission was obtained in 73% of 15 patients whose bone marrow leukemic cells showed greater than 30% killing by in vitro drug exposure, and CR was obtained in only 30% of 23 patients whose marrows showed less than 30% killing (P less than .01). The results indicate that the clonogenic assay correlates with treatment outcome and can be used for drug sensitivity testing in patients with acute nonlymphoblastic leukemia. The limitations of the assay are discussed.

Acute Disease↗
PubMed1983

A non-clonogenic assay for the determination of the sensitivity of leukemic cells to chemotherapeutic agents.

A new method for measuring the effects of chemotherapeutic agents on leukemic cells has been developed. In this method tritiated thymidine [( 3H]-TdR) is used to determine the surviving proportion of leukemic cells which are stimulated to proliferate by colony-stimulating factor (CSF). The effects of four antileukemia drugs on bone marrow cells from 20 AML patients were studied using this method and the results correlated well with the effects of the drugs on the CFUc, which were studied simultaneously. Using the liquid culture method drug effects were measured on five bone marrow specimens which failed to clone in the CFUc assay as well as on three specimens which produced too few colonies/clusters to allow estimation of drug effects.

Aclarubicin↗
PubMed1983

Adverse effects of aneuploidy on the outcome of remission induction therapy for acute nonlymphocytic leukaemia: analysis of types of treatment failure.

Cytogenetic studies were carried out on bone marrow specimens obtained from 98 patients with acute nonlymphocytic leukaemia. Patients were treated with cytosine arabinoside and an anthracycline antibiotic. The remission rate for patients in whom only normal metaphases were detected (NN patients) was 69% while the remission rates were 50% and 40% respectively for patients in whom both normal and abnormal metaphases were seen (NA patients) and for those in whom only abnormal metaphases were noted (AA patients). Analysis of remission induction failure types suggests that the differences in outcome were related to a tendency for patients with aneuploid leukaemia to be more likely to have drug resistant disease and to the lesser ability of NA and AA patients to survive and receive a second course of therapy if the first course failed to induce a complete remission.

Acute Disease↗