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Z Arlin

Publications and source records attributed to Z Arlin.

At least 55 records · Page 3Linked to original sources
PubMed1987

Humoral-dependent hemopoiesis and flow cytometric analysis of chronic myelogenous leukemia in erythroblastic transformation.

Bone marrow and peripheral blood cells from a patient with chronic myelogenous leukemia in erythroblastic transformation were studied by flow cytometry and for hemopoietic colony growth. Results demonstrated that this disorder had greatly expanded bone marrow erythroid colony (CFU-E) and myeloid colony (CFU-GM) progenitor compartments that were totally dependent upon erythropoietin and colony-stimulating factor. DNA, RNA and cell cycle analysis revealed that the bone marrow cells were diploid, had a high percentage of S phase cells (17%), and a unique bimodal RNA index of 5 and 13.8. Results are discussed and contrasted with other myeloproliferative disorders.

Adult↗
PubMed1987

Effect of deoxycytidine on the metabolism and cytotoxicity of 5-aza-2'-deoxycytidine and arabinosyl 5-azacytosine in normal and leukemic human myeloid progenitor cells.

The effect of deoxycytidine (dCyd) on the inhibitory effects of two antileukemic nucleoside analogs, 5-aza-2'-deoxycytidine and ara-5-aza-Cyd, toward the clonogenic growth of normal human bone marrow progenitors (CFU-GM) and leukemic blast progenitors (L-CFU) was examined. Continuous exposure of cells to 10(-6)-10(-5) M 5-aza-deoxycytidine or 10(-5)-5 x 10(-5) M ara-5-aza-Cyd in conjunction with a 10- 100-fold excess of dCyd resulted in significantly greater restoration of CFU-GM growth than L-CFU colony formation at each dose relationship. Normal bone marrow mononuclear cells exposed to 10(-3) M dCyd for 4 hr (along with 5-aza-dCyd or ara-5-aza-Cyd) exhibited intracellular deoxycytidine triphosphate (dCTP) pools 20-fold higher than their leukemic counterparts. However, this finding was not associated with enhanced analog incorporation into leukemic cell DNA. These results suggest that high concentrations of dCyd preferentially protect normal versus leukemic progenitor cells from the inhibitory actions of 5-aza-dCyd and ara-5-aza-Cyd. They also raise the possibility that this in vitro selectivity may be related to enhanced expansion of dCTP pools in normal bone marrow elements and involves factors other than differential short-term analog incorporation into DNA.

Acute Disease↗
PubMed1987

CML patients in blast crisis have breakpoints localized to a specific region of the BCR.

Chronic myelogenous leukemia (CML) is associated with the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between chromosomes 9 and 22. This activates the abl oncogene by moving it from chromosome 9 and combining it with sequence located on chromosome 22. The new fusion gene, with chromosome 22 sequence at its 5' end and chromosome 9-abl sequence at its 3' end, generates a new messenger RNA (mRNA) and protein that are implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 are concentrated within a 6 kilobase (kb) region termed the breakpoint cluster region (bcr). This study was designed to determine whether chronic-phase and blast crisis patients had identifiable differences in the structure of their Ph chromosomes. Restriction mapping of the chromosome 22 translocation breakpoints performed for 26 patients showed that the breakpoints of eight of the nine patients in blast crisis were in the 3' portion of the bcr, whereas the breakpoints in the 17 patients in the chronic phase were clustered in the 5' portion of the bcr. This suggests a strong correlation between a 3' bcr breakpoint and blast crisis in CML.

Blast Crisis↗
PubMed1987

Cellular interactions in hemopoiesis.

The role of immunocompetent cells in hemopoiesis remains controversial. We used an autologous system in which activated peripheral blood mononuclear cells (LAK) and interleukin-2 (IL-2) are administered to patients with cancer. We found little change in the numbers of circulating erythroid progenitors. Cocultures of these progenitors with LAK or supernatants lead to a decrease in the numbers of detectable burst forming units-erythroid (BFU-E) in culture. However, using an assay for burst promoting activity (BPA) we noted production of this hemopoietin by these LAK cells. We could not detect circulating levels of gamma interferon (IF). Variable levels were found in the LAK supernatants. We could not detect circulating eosinophil progenitors (CFU-Eo), but we did find evidence of production of a colony stimulating factor (CSF), which gave rise to a high number of eosinophil colonies in cultures of bone marrow. These results suggest that administration of LAK/IL-2 has potent effects on hemopoiesis and that these effects may emphasize the anemia and eosinophilia seen in patients receiving this therapy.

Anemia↗
PubMed1987

High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia.

In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

Adolescent↗
PubMed1987

High-dose cytosine arabinoside in combination with mitoxantrone for the treatment of refractory acute myeloid and lymphoblastic leukemia.

In the present study 55 patients with refractory acute myeloid leukemia (AML) (n = 44) and acute lymphoblastic leukemia (ALL) (n = 11) were treated with high-dose cytosine arabinoside (HD-ara-C) and mitoxantrone (HAM) to assess the toxicity and antileukemic activity of the two-drug combination. All patients had received a standardized first-line therapy according to the corresponding multicenter trials of the German AML and ALL cooperative groups and were considered refractory to conventional treatment. Therapy consisted of HD-ara-C 3 g/m2 every 12 hours on days 1 to 4; mitoxantrone was started at 12 mg/m2/d on days 3, 4, and 5 and was escalated to four and five doses of 10 mg/m2/d on days 2 to 5 and 2 to 6. From the 44 patients with AML, 24 (54%) achieved a complete remission, two a partial remission, and five were nonresponders. Thirteen patients died of infections (n = 11), pericardiac effusion, or acute cardiomyopathy. In refractory ALL, seven of 11 patients (64%) went into a complete remission, one patient was resistant, and three patients were early deaths. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. More severe CNS symptoms were encountered during five treatment courses. The median time to complete remission was 36 days. Excluding five patients who underwent bone marrow transplantations, the median remission duration was 4.5 months in AML and 2.3 months in ALL. The median survival time was three months for all patients and nine months for responders only. These data emphasize a high antileukemic activity of HAM in refractory AML and ALL and support the incorporation of the HAM regimen into first-line treatment.

Adolescent↗
PubMed1987

Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity.

We examined the ability of high concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) to reverse the cytotoxicity of high (eg, greater than or equal to 10(-5) mol/L) concentrations of 1-B-D arabinofuranosylcytosine (Ara-C) toward normal (CFU-GM) and leukemic myeloid progenitor cells (L-CFU). Leukemic myeloblasts from patients with acute nonlymphocytic leukemia (ANLL) and normal human bone marrow mononuclear cells were cultured in soft agar in the continuous presence of 10(-5) to 5 X 10(-5) mol/L of Ara-C together with dCyd (10(-4) to 5 X 10(-3) mol/L). Administration of 10(-5) mol/L of Ara-C alone eradicated colony formation in all samples tested. Coadministration of 10(-3) mol/L of dCyd restored 72.2% of control colony formation for CFU-GM, but only 10.9% for L-CFU. When higher concentrations of Ara-C (eg, 5 X 10(-5) mol/L) were administered, dCyd-mediated protection toward CFU-GM decreased, but remained significantly greater than that observed for L-CFU. Incubation with 10(-3) mol/L of dCyd reduced the 4-hour intracellular accumulation of the triphosphate derivative of Ara-C (Ara-CTP) in both normal and leukemic cells by greater than 98%; under identical conditions, a significant expansion of the intracellular of the triphosphate derivative of dCyd (dCTP) pools was observed in normal bone marrow mononuclear cells but not in leukemic blasts. This finding was associated with a greater reduction in Ara-C DNA incorporation in normal elements. These in vitro studies suggest that dCyd may preferentially protect normal v leukemic myeloid progenitor cells from the lethal actions of high-dose Ara-C.

Antineoplastic Agents↗
PubMed1986

Suppression of lymphocyte activation and functions by a leukemia cell-derived inhibitor.

An inhibitor isolated from the serum-free culture medium of human myeloid leukemic HL-60 cells was able to suppress mitogen- and alloantigen-stimulated proliferative responses of normal lymphocytes in a dose-dependent manner. In vitro production, concentration, and purification by column chromatography and electrophoresis revealed that the inhibitor was produced constitutively, required RNA synthesis, and had a molecular weight in the range of 40,000-60,000. The inhibitor was also produced in vitro by myeloid leukemia cells isolated from patients with acute myelogenous leukemia. In a similar manner, the inhibitory material suppressed proliferative responses of allogeneic and autologous lymphocytes. Suppression was accompanied by drastically reduced production of interleukin 2 and lymphokines, which regulate differentiation of myeloid leukemia cells, and suppression was reversed by addition of exogenous interleukin 2. The inhibitor did not suppress clonogenic proliferation of normal granulocytes and macrophages suggesting that inhibition of production or interference with interleukin 2 activity as a possible mechanism. These interactions between leukemia cells and lymphocytes have shed new light on the immunosuppression and growth advantage of leukemia cells. Inhibitory activity of HL-60 cells was diminished after they were induced to differentiate, indicating that differentiation induced by lymphokines may be an effective means of controlling leukemia.

Cell Differentiation↗
PubMed1986

High-dose cytosine-arabinoside and mitoxantrone in refractory acute myeloid leukemia: a clinical phase I/II-study.

In a multi-institutional study 26 patients with refractory acute myeloid leukemia were entered into a phase I/II study of HD-ara-C and mitox. HD-ara-C 3 g/m2 q 12h was given by 3h infusion on days 1-4. Mitox was started at 12 mg/m2/d on days 3, 4 and 5, and escalated to 4 and 5 doses of 10 mg/m2/d on days 2-5 and 2-6, respectively. From 24 patients presently evaluable for response, 12 achieved a CR and 2 a PR. 7 patients died of infectious complications within the first 4 weeks of treatment while persistent AML was found in 3 cases. Except for one death, possibly related to acute cardiomyopathy, toxicity was mild to moderate consisting of nausea and vomiting, mucositis and diarrhea. These data indicate a high anti-leukemic activity of HD-ara-C/mitox in AML refractory against conventional chemotherapy.

Anthraquinones↗
PubMed1986

Lymphoblastic lymphoma in adults.

Fifty-one patients with lymphoblastic lymphoma (LBL) treated with one of five successive intensive chemotherapy protocols for acute lymphoblastic leukemia (ALL) since 1971 were reviewed. The patients were divided into leukemic and nonleukemic groups, and their clinical and laboratory parameters compared. The projected 5-year survival rate for all patients treated with the L10/17 protocols was 45% for both leukemic and nonleukemic LBL. The response to treatment was compared with that of 111 patients with ALL and was nearly identical. Poor prognostic factors were age beyond 30, WBC greater than 50,000/microL, failure to achieve a complete response (CR), and a late CR during induction. Leukemia at presentation, T cell surface markers, and the presence of a mediastinal mass did not adversely affect survival. The use of intensive chemotherapy protocols has proven to be a significant advance in the treatment of LBL.

Adolescent↗
PubMed1986

Prognostic significance of terminal deoxynucleotidyl transferase activity in acute nonlymphoblastic leukemia.

Bone marrow and/or peripheral blood samples from 133 (75%) of a total of 177 consecutive previously untreated protocol patients with acute nonlymphoblastic leukemia (ANLL) were analyzed for terminal deoxynucleotidyl transferase (TdT) activity at the time of presentation. Twenty-nine (22%) were found to exhibit TdT activity (greater than or equal to 0.10 U/10(8) cells, TdT+) as measured in a biochemical microassay. There were no differences between TdT+ as compared with TdT-negative (TdT-) patients with respect to age, sex, French-American-British (FAB) classification, or the presence of Auer's rods. Remission induction rates were higher for the TdT- patients, with 68% v 48% for the TdT+ patients (P = .05). TdT- patients also experienced longer remissions (P = .003) than TdT+ patients, especially in the Auer's rod-positive subgroup (P = .002). None of five patients with TdT+ ANLL treated with vincristine and prednisone as initial therapy achieved complete remission; all required induction regimens containing daunorubicin or amsacrine in combination with cytosine arabinoside and 6-thioguanine. It is concluded that TdT activity in ANLL indicates biphenotypia or lineage infidelity and is associated with a poor prognosis on chemotherapy protocols currently used for the treatment of ANLL.

Bone Marrow↗
PubMed1986

Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1.

We have examined the effect of supraphysiologic concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) on the in vitro growth of normal (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. Bone marrow samples obtained from 34 consecutive patients undergoing routine diagnostic bone marrow aspirations for nonmalignant hematologic disorders exhibited nearly a twofold increment in CFU-GM when continuously cultured in the presence of 10(-4) mol/L dCyd. Higher dCyd concentrations were associated with a smaller degree of enhancement of colony formation. In contrast, the growth of leukemic blast progenitors obtained from patients with acute nonlymphocytic leukemia were not enhanced by any of the dCyd concentrations tested. Coadministration of 10(-3) mol/L tetrahydrouridine (THU), a cytidine deaminase inhibitor, failed to alter the relative inability of dCyd to enhance L-CFU colony growth. The stimulatory effect of dCyd on normal CFU-GM was not mediated by the adherent mononuclear cell population of the marrow, nor was it restricted to the subpopulation of CFU-GM in S phase at the time of initial exposure. Moreover, treatment of normal bone marrow cells with dCyd at concentrations ranging from 10(-6) to 5 X 10(-3) mol/L for 24 hours had only a minor effect on the fraction of CFU-GM in S phase. Coadministration of 10(-4) mol/L dCyd was able to reverse the inhibitory effects of several putative regulators of normal myelopoiesis, including leukemia inhibitory activity (LIA), acidic isoferritins (AIF), and prostaglandin E1 (PGE1). Leukemic myeloblasts exposed to 10(-4) mol/L dCyd exhibited substantial expansion of intracellular pools of dCyd triphosphate (dCTP), demonstrating that inability to metabolize dCyd could not be solely responsible for the absence of growth potentiation in these cells. These studies suggest that supraphysiologic concentrations of dCyd may confer a selective in vitro growth advantage upon normal v leukemic myeloid progenitor cells, and may free the former from the inhibitory effects of several potential negative regulators of myelopoiesis.

Alprostadil↗
PubMed1985

Relationship of Auer rods and chromosome findings to outcome in eighty-nine adults with acute nonlymphoblastic leukemia.

We performed cytogenetic analyses using banding techniques on 89 adults with acute nonlymphoblastic leukemia prior to receiving protocol chemotherapy. The relationships of cytogenetic findings both to outcome and to other pretreatment variables (particularly the presence or absence of Auer rods) were analyzed. Patients were followed up to 90+ months. When patients were grouped according to cytogenetic findings (NN: all normal metaphases; AA: all abnormal metaphases; AN: both normal and abnormal metaphases; F: no evaluable metaphases; I: insufficient (less than three) metaphases) no significant differences were noted with regard to age, sex, terminal transferase positivity, complete remission rate, remission duration or survival. The marrow aspirates of patients with only normal (69%) metaphases or no evaluable metaphases (64%) were more likely to display Auer rods than specimens from individuals with only abnormal (26%) or a mixture of normal and abnormal (42%) metaphases (p = 0.03). The presence of Auer rods in the pretreatment marrow aspirate was associated with an increased complete remission rate (71% vs 41%, p = 0.004), median remission duration (12 months vs 9 months, p = 0.02), and median survival (13 months vs 4 months, p = 0.01). Using multivariable analyses, the presence or absence of Auer rods was the pretreatment factor that most significantly predicted response and survival in this group of patients. The presence of a normal karyotype in the initial cytogenetic preparation is associated with the presence of Auer rods. The finding of Auer rods in the initial bone marrow predicts greater response and longer survival in acute nonlymphoblastic leukemia.

Acute Disease↗
PubMed1985

Elaboration of granulocyte-macrophage colony-stimulating factor by human tumor cell lines and normal urothelium.

A total of 72 cell conditioned media (CCM) were screened for their ability to stimulate colony formation by human granulopoietic progenitor cells. Granulocyte-macrophage (GM) colony-stimulating factor(s) (CSF) were found in CCM of nine tumor cell lines, two primary urinary bladder tumors, and three epithelial cell cultures of normal urinary tract. The most active medium came from urinary bladder carcinoma cell line 5637. CSF released by the 5637 cell line induced dose-dependent GM colony formation from human fetal, normal adult, and CML bone marrow (BM) and from mouse BM. Human fetal and normal adult BM formed more colonies when stimulated with 5637 CCM than with peripheral blood leukocyte (PBL) feeder layers, while CML BM produced more colonies with PBL feeder layers. CCM from 5637 was more active in stimulating GM colony formation than human placenta conditioned medium (PCM) and PHA-LCM. 5637 CCM produced in serum-free hormone-supplemented medium was nearly equipotent and can serve as suitable starting material for purification.

Animals↗
PubMed1984

Male reproductive capacity may recover following drug treatment with the L-10 protocol for acute lymphocytic leukemia.

Six men with acute lymphocytic leukemia (ALL) were studied prospectively to assess the effect of treatment with the L-10 protocol on reproductive capacity. Before therapy three men had fathered children (two, two children; one, three children); the others were sexually mature although no fertility studies had been done prior to or during their treatment. Each patient had a minimum of 3 1/2 years of continuous chemotherapy as part of this study. Semen analysis was done 10 to 52 months (median, 31.5 months) after completion of therapy. One patient had lower than normal sperm concentration but near normal total sperm count and normal motility; the others had a normal sperm concentration and motility. Sperm nuclei were isolated from each sample and analyzed by flow cytometry for resistance to DNA denaturation in situ; all samples had relatively high resistance to denaturation, consistent with a normal, fertile reproductive status. After completion of therapy, one patient fathered a normal child, and a second patient fathered one child with multiple congenital malformations followed by a second child who was normal.

Adult↗
PubMed1984

Oral trimethoprim/sulfamethoxazole in attempt to prevent infection after induction chemotherapy for acute leukemia.

The efficacy of orally administered trimethoprim/sulfamethoxazole for infection prevention following induction chemotherapy was evaluated in 43 patients with acute leukemia. Twenty patients were randomly assigned to treatment with trimethoprim/sulfamethoxazole during 20 episodes of profound granulocytopenia; 23 patients in the control group were followed through 25 granulocytopenic episodes. The incidences of superficial skin and overall infections were significantly lower in those patients with multiple relapses who received trimethoprim/sulfamethoxazole (p = 0.008); however, there was no difference between the groups in regard to days of fever, days of antibiotic administration, days of hospitalization, or gram-negative rod bacteremia. As a result of this study, this regimen cannot be unequivocally recommended for infection prevention in neutropenic patients with acute leukemia undergoing induction or reinduction chemotherapy.

Acute Disease↗