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Biomedical subjects

E Berman

Publications and source records attributed to E Berman.

At least 37 records · Page 2Linked to original sources
PubMed1996

Granulocyte colony-stimulating factor following chemotherapy in elderly patients with newly diagnosed acute myelogenous leukemia.

Given the high treatment-related mortality in elderly patients with acute myelogenous leukemia (AML), we undertook a study using granulocyte colony-stimulating factor (G-CSF) following chemotherapy in an effort to ameliorate toxicity. Patients ( > 60 years) received induction with idarubicin 12 mg/m2/day x 3 and cytosine arabinoside (Ara-C) 200 mg/m2/day x 5. A second course of chemotherapy consisting of mitoxantrone 12mg/m2/day x 3, etoposide (VP-16) 150 mg/m2/day x 3 and Ara-C 200 mg/m2/day x 4 was given approximately 1 month after achieving a complete remission (CR) or immediately if patients failed the first induction. Twenty-four hours following completion of the chemotherapy, G-CSF (10 micrograms/kg/day continuous i.v. infusion) was started. A historical control group of 28 patients treated without G-CSF was used for comparison. Twenty-six patients were evaluable for response. Following induction, the recovery of neutrophils to greater than 500/microliters and 1000/microliters was more raped in the responders who received G-CSF compared to historical controls (median 13 vs 17 days, P = 0.008; 14 vs 19 days, P = 0.005). The toxic death rate of 8% in the study group was significantly lower than the 32% mortality observed in the historical controls (P = 0.04). There was no difference in supportive care requirements or infectious complications. The complete remission (CR) rate was 58% in the entire study group with 71% of de novo AML patients achieving CR. Disease-free survival and overall survival were comparable between the study and historical control groups. These results indicate that G-CSF benefits elderly patients after intensive chemotherapy for AML by decreasing the duration of neutropenia. The reduced neutropenic period may have contributed to the small number of early toxic deaths.

Aged↗
PubMed1996

c-kit ligand stimulates tyrosine phosphorylation of a similar pattern of phosphotyrosyl proteins in primary primitive normal hematopoietic progenitors that are constitutively phosphorylated in comparable primitive progenitors in chronic phase chronic myelogenous leukemia.

Characteristic of Philadelphia (Ph)+ chronic myelogenous leukemia (CML) is the presence of the chimeric BCR/ABL (p210) protein possessing elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Our previous studies demonstrated subtle differences in the growth, phenotypic and morphologic characteristics of the most primitive subpopulations of primary lin-Ph+ chronic phase CML blasts and comparable primary lin- normal blasts. Recently, in comparing proteins phosphorylated on tyrosine in these cell populations, we reported a prominent 62 kDa phosphotyrosyl (P-tyr) protein constitutively present in primary primitive lin- CML chronic phase blasts which was virtually undetectable in primary primitive lin- normal blasts. In the present studies, we demonstrate that this P-tyr p62 from primary primitive lin- chronic phase CML blasts co-immunoprecipitates with ras-GAP. Furthermore, in addition to the p210 protein, we show in whole cell lysates the presence of other clearly consistent but less prominent P-tyr proteins with molecular weights of approximately 155, 140, 110, 55 and 45 kDa as well as more minor P-tyr proteins of approximately 190, 85, 52, 42 and 39 kDa constitutively present in primary primitive lin- chronic phase CML blasts. In analyzing proteins tyrosine phosphorylated in primary primitive lin- normal blasts in response to various hematopoietic growth factors, we found a striking similarity in the phosphorylation of four major (approximately 140, 110, 62 and 56 kDa) and three minor (approximately 51, 45 and 42 kDa) P-tyr proteins after stimulation with c-kit ligand and the P-tyr proteins constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other growth factors tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand and EPO) were much less active or stimulated phosphorylation of other proteins. It is provocative that at least seven proteins rapidly and transiently phosphorylated on tyrosine in the c-kit ligand signal transduction pathway in lin- normal blasts may be constitutive substrates for the p210 activated tyrosine kinase in comparable lin- chronic phase CML blasts. In addition, it is intriguing that some of the biological effects on hematopoietic progenitors attributed to the c-kit ligand may be similar to some of the observed biological consequences of the p210 protein, including survival and expansion of a more mature stem cell population, probably at the time of lineage commitment rather than at the level of the earliest self-renewing stem cell.

Cell Lineage↗
PubMed1995

An early transient increase of intracellular Na+ may be one of the first components of the mitogenic signal. Direct detection by 23Na-NMR spectroscopy in quiescent 3T3 mouse fibroblasts stimulated by growth factors.

23Na-NMR spectroscopy was designed to allow for continuous recording of intracellular Na+ in 3T3 fibroblasts stimulated by serum growth-factors in the presence of ion transport inhibitors. The metabolic state of cells at rest and following stimulation was monitored by 31P-NMR spectra of ATP and related high-energy phosphates. The study demonstrates that early activation of ion transporters by addition of serum is marked by the appearance of transient increase of the intracellular Na+, beginning 3 min after addition of serum to quiescent culture and lasting approx. 20 min. The initial rise in cellular Na+ results from an increased activity of the bumetanide-sensitive Na+/K+/Cl- cotransport and of the amiloride-sensitive Na+/H+ antiport. It is suppressed by any one of these inhibitors. Subsequent activation of the ouabain-sensitive Na+/K(+)-ATPase results in an increased Na+ efflux, leading to a return of intracellular Na+ to its initial baseline. Previous work had shown that the early activation of bumetanide-sensitive and amiloride sensitive ion-transporters by growth-factors was essential for induction of cell division, at least in some cell types. Preventing ion activation by adding ion-transport inhibitors lead to the inhibition of DNA synthesis 18 h later. This process was reversible upon elimination of these inhibitors. Even though alternative non-specific effects of these inhibitors cannot be ruled out, the observed transient peak in intracellular Na+ may be one of the earliest components of the mitogenic signal. On the basis of previous works, its effect seems to be related to the activation of Ca(2+)-dependent and cyclic AMP second messenger pathways. The different mechanisms whereby the activated Na+/K+/Cl- cotransport and the Na+/H+ antiport contribute to this signal need to be further investigated.

3T3 Cells↗
PubMed1995

Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations.

Although dihydrofolate reductase (DHFR) gene amplification is a common mechanism of resistance to methotrexate (MTX) in tumor cell lines, with the exception of a few case reports, the incidence of this phenomenon as a mechanism of MTX resistance in the clinic has not been reported. We studied 38 untreated patients and 29 patients in relapse with acute lymphoblastic leukemia (ALL) for gene amplification and p53 gene mutations. Three patients were studied both at diagnosis and at each of two relapses after treatment with MTX. Nine of 29 relapsed patients (31%) had low-level DHFR gene amplification (two to four gene copies) associated with increased levels of DHFR mRNA and enzyme activity. Of significance was a correlation of gene amplification with p53 mutations in seven of nine relapsed patients (P < .001). Low-level DHFR gene amplification may be an important cause of MTX resistance in ALL and strengthens the concept that mutations in the p53 gene may lead to gene amplification as a consequence of defective cell cycle control.

Adolescent↗
PubMed1995

Assessment of proton magnetic resonance spectroscopy of blood serum as a diagnostic tool in bone marrow transplantation.

The use of proton high-resolution magnetic resonance spectroscopy (MRS) allows the rapid detection and quantitation of modification in the blood serum metabolic profiles in haematooncological patients. This study examines the feasibility of using proton MRS as a diagnostic tool in predicting the outcome of bone marrow transplantation (BMT) at the earliest possible date. Proton spectra of serum samples from 18 BMT patients (11 autologous-BMT and seven allogeneic-BMT), six hematooncological patients that did not undergo BMT and six normal individuals were recorded at 400 MHz. A longitudinal MRS study was carried for these groups and the data were evaluated for statistical significance. It was determined that the MRS results, taken at different time points before and after the BMT treatment, are statistically significant. However, no significant difference was observed in the MRS parameters between the transplanted patients and the control patients. We could not obtain significant correlation between the MRS results and the immunoglobulin level, engraftment parameters or the age, sex, stage of basic disease, conditioning protocols, transplant type, post transplant complications (including death) and outcome.

Adolescent↗
PubMed1995

A multidisciplinary approach to toxicological screening: I. Systemic toxicity.

The toxicity of 10 chemicals, including pesticides (carbaryl, chlordane, heptachlor, and triadimefon), solvents (carbon tetrachloride, dichloromethane, tetrachloroethylene, and trichloroethylene), and industrial chemicals [diethylhexylphthalate (DEHP) and phenol] was examined in the liver, kidneys, spleen, thymus, and adrenals of female F344 rats after 1 or 14 d of oral dosing. For each chemical, 4 doses were based on fractions of the acute LD50, which was estimated using an abbreviated (up-and-down) method. A multivariate analysis (MANOVA) was conducted for each organ using selected measures of toxicity. A post hoc contrast analysis was also conducted for significant MANOVA results in order to determine effective and ineffective doses. A single dose of heptachlor resulted in necrotic lymphocytes in the spleen and thymus at doses > or = 23 mg/kg. Triadimefon altered liver and spleen weights; this effect has not been described previously. Dichloromethane (> or = 337 mg/kg/d for 14 d) increased the incidence of necrosis of individual centrilobular hepatocytes. Trichloroethylene-induced hepatotoxicity was obtained at doses an order of magnitude lower than those reported in the literature. Acute DEHP (150 mg/kg) increased mitotic figures in hepatocytes, which were replaced by hepatocellular cytomegaly after 14 d of dosing at the same level. Following phenol exposure, there was an increased incidence in hepatocellular necrosis at 1 d, and an increased incidence of kidney lesions at 1 and 14 d; these findings were considered to be the result of vascular stasis. Overall, the algorithm used to select doses was effective for both 1- or 14-d dosing regimens. For all chemicals except carbon tetrachloride, the lowest effective dose for systemic toxicity was within the range of 3-56% of the LD50 for acute dosing, and 1-30% of the LD50 for repeated administration.

Administration, Oral↗
PubMed1995

A multidisciplinary approach to toxicological screening: IV. Comparison of results.

Toxicity data collected under standardized test conditions may be of the utmost importance in health risk assessment, in which human exposure limits are often derived from laboratory experiments. A standardized approach to data collection is also important for evaluating the sensitivity and specificity of test methods used to determine toxic potential. Several experiments were undertaken to determine the effects of chemical exposures using a multidisciplinary screening battery, which included tests for systemic, neurological and developmental toxicity. The effects of 1- and 14-d exposures to 10 chemicals on systemic and neurological indices of toxicity were determined in female F344 rats using standardized test batteries. Parallel experiments determined chemical effects on prenatal and postnatal development following exposure of the dams for 14 d. The chemicals included four pesticides (carbaryl, triadimefon, chlordane, and heptachlor), four solvents (trichloroethylene, tetrachloroethylene, carbon tetrachloride, and dichloromethane), and two industrial compounds (phenol and diethylhexyl phthalate). The results showed that the chemicals produced markedly different qualitative patterns of effect on systemic, neurological, and developmental indices of toxicity. Differences in the pattern of systemic and neurological effects were also obtained that depended on dosing duration. Quantitative analyses indicated that the highest ineffective dose as well as the lowest effective dose could vary by as much as two orders of magnitude across the different indices of toxicity. These results clearly show that a test battery focused on a single endpoint of toxicity cannot be used to accurately predict either qualitatively or quantitatively a chemical's systemic, neurological, and developmental toxicity profile.

Analysis of Variance↗
PubMed1995

Evaluation of the nephrotoxicity of complex mixtures containing organics and metals: advantages and disadvantages of the use of real-world complex mixtures.

As part of a multidisciplinary health effects study, the nephrotoxicity of complex industrial waste mixtures was assessed. Adult, male Fischer 344 rats were gavaged with samples of complex industrial waste and nephrotoxicity evaluated 24 hr later. Of the 10 tested samples, 4 produced increased absolute or relative kidney weight, or both, coupled with a statistically significant alteration in at least one of the measured serum parameters (urea nitrogen (BUN), creatinine (CREAT), and BUN/CREAT ratio). Although the waste samples had been analyzed for a number of organic chemicals and 7 of the 10 samples were analyzed also for 12 elemental metals and metalloids, their nephrotoxicity was not readily predicted from the partial chemical characterization data. Because the chemical form or speciation of the metals was unknown, it was not possible to estimate their contribution to the observed biological response. Various experimental approaches, including use of real-world complex mixtures, chemically defined synthetic mixtures, and simple mixtures, will be necessary to adequately determine the potential human health risk from exposure to complex chemical mixtures.

Animals↗
PubMed1995

A phase II study of continuous infusion of trimetrexate in patients with refractory acute leukemia.

Trimetrexate, a second-generation folate antagonist, is a potent inhibitor of dihydrofolate reductase with a broader spectrum of activity and different mechanism of entry and intracellular accumulation than methotrexate. Six patients with refractory or relapsed acute leukemia were treated with a 5-day continuous infusion of trimetrexate of 8 mg/m2/day after an initial loading dose of 4 mg/m2 to achieve a target plasma concentration of 0.2-0.5 microM. In 4 patients with peripheral blasts at study entry, transient decrease or disappearance of blasts was observed, although no decrease of bone marrow blasts occurred. Mucositis was dose-limiting and severe in 4 patients. Neutrophil and platelet nadirs occurred on day 5-12 postinfusion. Because of dose-limiting mucositis, this dose schedule of trimetrexate is not recommended for further studies in refractory acute leukemia. However, other dose schedules (24- to 72-hr infusions) and its use as a modulating agent with thiopurines or leucovorin in patients that are resistant to methotrexate should be explored.

Adult↗
PubMed1995

Myocardial protection by warm blood cardioplegia. A 31P nuclear magnetic resonance spectroscopy study of an isolated perfused rat heart.

OBJECTIVE: A study of the protective efficiency imparted by intermittent warm blood cardioplegia (WBCP) using perfused rat heart model. METHODS: Hemodynamic parameters were monitored simultaneously with metabolic changes in high-energy phosphates using 31P-NMR spectroscopy. Following 30 min perfusion with Krebs-Henseleit (KH) buffer, all hearts were arrested for one hour (G1 and G2) and than reperfused with KH for 30 minutes. A warm oxygenated crystalloid cardioplegia (WCCP, modified St Thomas' hospital solution) was used for the control group (G1). The second group of hearts (G2) were arrested with oxygenated WBCP (K+ = 15 mM; Hct = 15-20%) and the third group (G3), was subjected to a protocol consisting of 4 periods (10 min each) of WBCP interspersed by 10 min of global ischaemia. RESULTS: The post-arrest percentage recoveries of LVDP, +dP/dt and HR were respectively: 88, 93 and 90 for G1 (n = 8); 97, 100 and 98 for G2 (n = 10); 76, 79 and 91 for G3 (n = 12). The corresponding metabolic recoveries of ATP and PCr were respectively, 85 and 90 for G1; 91 and 98 for G2 and 73 and 85 for G3. The PCr level declined during the arrest period in G1 contrasting with elevated PCr level (> 140%) during the WBCP arrest in G2. After an initial rise to approximately 140%, PCr level gradually decreased during the intermittent WBCP interval (G3). CONCLUSIONS: At normothermia, with equal CF rates, continuous WBCP provides better myocardial protection, through an effective oxygen supply, compared with WCCP. During the intermittent periods of ischaemia, certain metabolic and hemodynamic dysfunction occurs.

Animals↗
PubMed1995

Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia.

Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.

Adult↗
PubMed1995

Familial acute myeloid leukemia and DiGuglielmo syndrome.

A family is described in which two sisters developed acute myeloblastic leukemia (AML FAB M2) and erythroleukemia (FAB M6) at ages 60 and 53, 15 years apart. Their father was diagnosed as having chronic erythremic myelosis (DiGuglielmo syndrome) 24 years earlier at age 56. Cytogenetic analysis of bone marrow blasts in the patient with AML M2 revealed a complex hyperdiploid karyotype with clonal abnormalities -3, -5, del(5)(q13q23), -8, +i(8)(q10), -11, add(11) (q23), add(12)(p13), -13, +3mar. No environmental risk factors could be identified. Hematologic and cytogenetic analysis of all living first degree relatives of the affected persons revealed hematological abnormalities, but normal constitutional karyotypes of peripheral blood lymphocytes and no induction of cytogenetic abnormalities in folate deficient medium.

Aged↗
PubMed1994

All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study.

OBJECTIVE: To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia. DESIGN: Phase II evaluation and comparison with historical control patients. SETTING: Tertiary care cancer referral center. PATIENTS: Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again. RESULTS: 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior. CONCLUSIONS: All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Adolescent↗
PubMed1994

Comparative activity of tamoxifen and N-desmethyltamoxifen in human multidrug resistant leukemia cell lines.

Tamoxifen (Tmx) is one of a number of agents that can reverse the multidrug resistant (MDR) phenotype in vitro; it is unique, however, in that both the parent compound and the main metabolite, N-desmethyltamoxifen (NDMTmx), have long plasma half-lives, 7 and 14 days, respectively. To determine whether NDMTmx was as active as the parent compound in restoring sensitivity to daunorubicin (DNR) in vitro, we performed uptake and retention studies in the MDR-positive human leukemia cell lines CEM-VLB and HL-60/RV+ using laser flow cytometry to quantitate intracellular DNR concentration. Cells incubated with DNR and NDMTmx 10 microM demonstrated increased intracellular DNR levels that were very similar to those obtained with DNR and Tmx 10 microM. Cellular retention of DNR was also measured after incubation with Tmx 10 microM or NDMTmx 10 microM and resuspension in fresh medium containing Tmx or NDMTmx in order to stimulate in vivo conditions. Washout curves in both cell lines were similar with both Tmx and NDMTmx. Finally, clonogenic experiments were performed to determine whether Tmx and NDMTmx demonstrated the same degree of cytotoxicity. The combination of Tmx 10 microM plus DNR and that of NDMTmx 10 microM plus DNR each resulted in > 80% growth inhibition. These results suggest that NDMTmx is as active as Tmx in restoring sensitivity to DNR in vitro, a finding which may have important implications in clinical trials that assess the ability of Tmx to reverse the MDR phenotype.

Daunorubicin↗
PubMed1994

Concomitant administration of chlorambucil limits dose intensity of fludarabine in previously treated patients with chronic lymphocytic leukemia.

Fifteen patients with chronic lymphocytic leukemia (CLL) were treated in a phase I-II study of chlorambucil with an escalating dose of fludarabine. The study was designed to identify a maximum tolerated dose (MTD) of fludarabine given in conjunction with a constant dose of chlorambucil. Patients were eligible for study if they had Rai intermediate or high-risk disease which had relapsed from or was refractory to conventional treatment. The initial cohort of patients received fludarabine 10 mg/m2/d days 1-5 and chlorambucil 20 mg/m2 days 1 and 15. Cycles were repeated every 28 days. Unacceptable toxicity was encountered in this cohort. The protocol was then modified to give chlorambucil 20 mg/m2 on day 1 (only). At this chlorambucil dose, cohorts of three patients were treated with fludarabine 10, 15, and 20 mg/m2/d x 5 days. The predominant toxicity was thrombocytopenia with 73% experiencing grade > or = 3 toxicity. The dose-limiting non-hematologic toxicity was infection. We identified an MTD of fludarabine of 15 mg/m2/d x 5 days when given with chlorambucil 20 mg/m2 for this group of patients. One patient achieved a CR and three patients achieved a PR for a total response rate of 27%. We conclude that concomitant administration of chlorambucil limits the dose intensity of fludarabine which can be administered to previously treated patients with CLL.

Aged↗