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Biomedical subjects

B Mookerjee

Publications and source records attributed to B Mookerjee.

16 recordsLinked to original sources
PubMed2004

Activity of single-agent melphalan 220-300 mg/m2 with amifostine cytoprotection and autologous hematopoietic stem cell support in non-Hodgkin and Hodgkin lymphoma.

High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220-300 mg/m(2) plus amifostine (AF) cytoprotection and AHSCT as part of a phase I-II trial. Median age was 51 years (range 24-62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, 'first-line' AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D +100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL+AF+AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median follow-up in these latter patients of D +1163 (range D +824 to D +1630); one of these patients had a nonmyeloablative allograft as consolidation on D +106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure. Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL+AF+AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens.

Adult↗
PubMed2002

Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy.

Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.

Adult↗
PubMed2001

Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB.

TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IkappaBalpha or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-kappaB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-kappaB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-kappaB by blocking activation of the IkappaB kinase complex reduces Bcl-x L expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-kappaB as a mediator or inhibitor of cell death during immune and stress responses.

Animals↗
PubMed2000

Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.

The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.

Adenocarcinoma↗
PubMed1999

Salvage therapy for refractory chronic graft-versus-host disease with mycophenolate mofetil and tacrolimus.

Chronic graft-versus-host disease (GVHD) is a common late complication of allogeneic bone marrow transplantation (BMT) and is the principal cause of morbidity and non-relapse mortality. The improved management of acute GVHD has not translated into lower rates of chronic GVHD as older patients undergo allogeneic BMT, more patients receive unrelated or related mismatched allogeneic BMT, and donor lymphocyte infusion is increasingly used for treatment of post-BMT relapses. Patients with high risk chronic GVHD or those who fail on standard therapy have a bad prognosis. Salvage therapies have produced disappointing results. Here, we present a retrospective analysis of 26 patients where a steroid sparing synergistic combination of mycophenolate mofetil (MMF) and tacrolimus was used in refractory chronic GVHD. 46% patients showed an objective response, 11.5% had stable disease, 34.6% had progression and 7.7% were not evaluable. The combination was well tolerated. This promising preliminary result has prompted a trial to assess the safety and efficacy of this regimen in patients with chronic GVHD who have failed prior therapy and to determine if it would improve survival as well as quality of life in such patients.

Adult↗
PubMed1998

p53-mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300.

The p53 tumor suppressor gene plays an instrumental role in transcriptional regulation of target genes involved in cellular stress responses. p53-dependent transactivation and transrepression require its interaction with p300/CBP, a coactivator that also interacts with the RelA subunit of nuclear factor-kappaB. We find that p53 inhibits RelA-dependent transactivation without altering RelA expression or inducible kappaB-DNA binding. p53-mediated repression of RelA is relieved by p300 overexpression and the increased RelA activity conferred by p53-deficiency is counteracted by either transactivation domain-deficient p300 fragments that bind RelA or a transdominant mutant of IkappaB alpha. Our results suggest that p53 can regulate diverse kappaB-dependent cellular responses.

CREB-Binding Protein↗
PubMed1998

Biological significance and molecular mechanisms of p53-induced apoptosis.

The recognition that the p53 tumour suppressor gene is frequently inactivated in human cancers has galvanized an intense pursuit of the fundamental mechanisms by which the encoded protein halts malignant transformation and tumour progression. It is now evident that p53 is a multifunctional transcription factor that is intimately involved in the cellular response to stressful stimuli such as DNA damage and hypoxia. In addition to its role in the surveillance mechanisms that arrest cell cycle progression, p53 can also trigger apoptosis in response to DNA damage or oncogenic aberrations that induce aberrant cell cycle progression. Since p53 is a critical component for DNA damage-induced apoptosis, the frequent occurrence of p53 mutations in human neoplasia provides a genetic basis for their poor response to genotoxic anticancer agents. Two recent studies offer key insights into the molecular mechanisms employed by p53 to induce cell death. One model indicates that p53 induces redox-related genes that generate reactive oxygen species and promote the oxidative degradation of mitochondrial components. The other demonstrates p53-mediated induction of DR5, a death receptor of the tumour necrosis factor receptor family, that induces death by caspase-mediated proteolysis. These insights provide an exhilarating array of possible therapeutic interventions against p53-deficient human cancers that may pay enormous dividends in the not-too-distant future.

Journal Article↗
PubMed1994

Regulation of phosphoprotein p18 in leukemic cells. Cell cycle regulated phosphorylation by p34cdc2 kinase.

p18 is a phosphoprotein that is expressed at very high levels in leukemic cells, at moderately high levels in proliferating normal lymphocytes, and at low levels in quiescent lymphocytes. Induction of terminal differentiation of leukemic cells in culture results in a decrease in cellular proliferation. These phenotypic changes are associated with rapid phosphorylation of p18, followed by a more gradual decrease in the level of its mRNA expression. More than 12 different phosphorylation products of p18 have been identified in different cells by high resolution two-dimensional polyacrylamide gel electrophoresis. Previous studies have suggested that p18 may be a substrate for protein kinase C in some cellular processes and protein kinase A in others. In this report, we show that the phosphorylation of p18 increases as cells progress toward the G2-M phases of the cell cycle in proliferating leukemic cells. We have examined the hypothesis that the putative role of p18 in cellular proliferation may be mediated by its involvement in the p34cdc2 kinase signal transduction pathway. We have produced recombinant p18 in bacterial cells and shown that it can be phosphorylated in vitro by purified p34cdc2 kinase with a stoichiometry of 0.86 mol of PO4/mol of substrate. We have used site-directed mutagenesis to demonstrate that the site of p34cdc2 phosphorylation is the serine at position 38. This same site has previously been shown to be phosphorylated in vivo in bovine brain along with another serine at position 25. The observation that p18 gets phosphorylated in the G2-M phases of the cell cycle and the demonstration that p18 is phosphorylated efficiently by p34cdc2 kinase in vitro at a residue that is also phosphorylated in vivo support the hypothesis that p18 may be a physiologic substrate for p34cdc2 kinase in vivo. We have also examined the effect of inhibiting the expression of p18 on cell cycle progression. These experiments demonstrated that antisense inhibition of the expression of p18 in K562 erythroleukemia cells is associated with a decrease in cellular proliferation and accumulation of cells in the G2-M phases of the cycle. The implications of these findings to the proposed role of p18 in the regulation of cellular proliferation are discussed.

Base Sequence↗
PubMed1992

Spontaneous delta- to beta-globin switching in K562 human leukemia cells.

Previous analysis of the hemoglobin phenotype of the K562 human erythroleukemia cell line showed regulated expression of the epsilon-, zeta-, gamma-, alpha-, and delta-globin genes. Expression of the beta-globin genes has not been previously detected in this cell line. In this report, we describe the isolation of a variant of the K562 cell line that actively expresses beta-globin messenger RNA (mRNA) and polypeptide and shows greatly reduced expression of the delta-globin genes. This phenotype developed spontaneously in culture while two other K562 isolates grown under the same culture conditions have not undergone the same delta- to beta-globin switch. Analysis of this unique K562 variant shows that a construct containing a beta-globin promoter is quite active upon transient transfection into these cells. This finding suggests that the activation of the endogenous beta-globin genes results from changes in the trans-acting environment of these cells. The regulation of the beta-globin genes in this variant is characterized by a paradoxical decrease in the level of beta-globin mRNA after exposure to hemin. Other globin genes of this variant are appropriately regulated and show increased expression after hemin induction. Further study of this variant may shed light on mechanisms of gene regulation that are involved in hemoglobin switching.

Gene Expression Regulation↗
PubMed1976

Choline loss during hemodialysis: homeostatic control of plasma choline concentrations.

Endogenous concentrations of free choline in plasma were measured in azotemic subjects receiving repetitive hemodialysis and excretion of free choline into the dialysate was determined. Chemical choline in plasma and dialysate was measured by adding choline kinase and measuring the production of radiolabelled phosphorycholine in the presence of radiolabelled adenosine triphosphate (ATP). Mean free choline concentration in plasma of azotemic subjects receiving hemodialysis was found to be 37 muM, which is about twice that of normal persons. The total excretion of choline into the dialysate during 360 min averaged 730 mumoles +/- 69 (SEM). Levels of free choline in plasma fell during hemodialysis at two hours but recovered toward predialysis values at six hours. The return of plasma choline concentrations toward control values during dialysis suggests that a feedback mechanism exists which was activated rapidly to produce homeostasis of plasma choline concentrations. In these patients, the degree of peripheral neuropathy as judged by measurement of nerve conduction velocities showed a significant inverse correlation with levels of free choline in plasma.

Blood Flow Velocity↗
PubMedDate not supplied

Role of endogenous prostaglandins in volume expansion and during furosemide infusion in conscious dogs.

The renal effects of two structurally dissimilar inhibitors of prostaglandin synthesis (Meclofenamate and RO-20-5720) were studied in conscious, chronically instrumented dogs during mild volume expansion and during a constant infusion of furosemide. When either inhibitor was administered following volume expansion, urinary excretion of PGE2 and urine flow rate were reduced by more than 50%. In contrast, renal plasma flow fell by less than 10% while glomerular filtration rate, sodium excretion, and plasma renin activity (PRA) were unchanged. In separate studies, infusion of furosemide increased renal plasma flow, urine flow rate, sodium excretion, PRA, and urinary excretion of PGE2, while glomerular filtration rate decreased. Administration of inhibitors of prostaglandin synthesis during constant infusion of furosemide reduced the urinary excretion of PGE2 to control levels, as renal plasma flow and glomerular filtration rate fell below control level. Despite these hemodynamic alterations, the furosemide-induced diuresis and increase in PRA were only partly attenuated by prostaglandin inhibition. It is concluded that in conscious dogs, intrarenal prostaglandins modulate urine flow rate during mild volume expansion and play a major role in mediating the renal hemodynamic effects of furosemide.

Animals↗
PubMedDate not supplied

Allopurinol in prevention of reperfusion injury of hypoxically stored rat hearts.

We have studied the effect of the xanthine-oxidase inhibitor allopurinol on the performance of hypoxically stored rat hearts to evaluate the drugs' potential value in heart transplantation. Hearts were stored for 2 hours at 15 degrees C after potassium chloride cardioplegia. Hemodynamics were measured before hypoxia and after reperfusion. Hearts were treated with allopurinol in the cardioplegia, at the time of reperfusion, or with superoxide dismutase (SOD) and catalase (CAT) and compared with control hearts that received no treatment. Hemodynamic performance after hypoxia was significantly improved in the SOD/CAT group compared with the control group. Allopurinol-treated hearts were also significantly improved, especially when the drug was given in the reperfusion phase. Our results demonstrate the importance of free radicals during reperfusion of hypoxically stored hearts. Allopurinol and SOD/CAT may be of value in reducing such damage after heart transplantation.

Allopurinol↗