Biomedical subjects

A Mazumder

Publications and source records attributed to A Mazumder.

At least 109 records · Page 6Linked to original sources

PubMed1993

Peripheral blood stem cells harvested during marrow recovery from disease-specific chemotherapy shorten duration of neutropenia in patients undergoing autologous bone marrow transplantation.

A total of 41 patients who underwent autologous bone marrow transplantation without the use of granulocyte-macrophage colony-stimulating factor were retrospectively evaluated to determine whether the infusion of peripheral blood stem cells collected during the period of recovery of bone marrow from previous disease-specific chemotherapy could shorten the time to bone marrow engraftment after transplantation. Of the 41 patients, 24 patients received bone marrow only (group 1), 8 patients received bone marrow plus steady-state peripheral blood stem cells (group 2) and 9 patients received bone marrow plus rebound peripheral blood stem cells collected during the period of recovery from disease-specific chemotherapy (group 3). Infusion of rebound peripheral blood stem cells (group 3) accelerated recovery of white blood cells and neutrophils and resulted in a white blood cell count of > 10(9)/L by day 15 compared with day 25 in group 1 (P < 0.001), and a neutrophil count of > 0.5 x 10(9)/L by day 16 versus day 26 in group 1 (P = 0.0034). Addition of steady-state peripheral blood stem cells (group 2) did not hasten myeloid engraftment, and recovery of platelets was not improved in either group given peripheral blood stem cells. Compared with patients in group 1, patients in group 3 required 7 fewer days of parenteral antibiotics (25 days versus 18 days, respectively; P = 0.0072) and were discharged about 3 weeks earlier than patients in group 1 (day + 41 verus day +21; P = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1992

Antitumor effect of interferon plus cyclosporine A following chemotherapy for disseminated melanoma.

Interferon (IFN) increases the expression of major histocompatibility (MHC) antigens on the surface of tumor cells. Cyclosporine A (CsA) administration following myeloablative therapy and syngeneic bone marrow transplantation results in the generation of cells with autoreactive and antitumor effects that are related to the expression of MHC antigens. We used these two agents following conventional chemotherapy in a non-bone marrow transplantation setting for a melanoma in a murine model. Treatment with IFN alone or CsA alone was ineffective in controlling the dissemination of melanoma. A combination therapy with both these agents resulted in a significant control in the dissemination of the tumor, prolonged the survival of the tumor-bearing mice over that with chemotherapy alone, and generated cells with potent MHC-unrestricted cytotoxic potential in vitro. Adoptive transfer of these cells to secondary tumor bearers treated with chemotherapy showed potent antitumor effect; in the absence of chemotherapy, these cells had no antitumor effect in the secondary recipients. The antitumor effect of cells generated by IFN plus CsA therapy following chemotherapy could be blocked by normal spleen cells. These data suggest that treatment with IFN plus CsA following nonmyeloablative chemotherapy generates cells with MHC-unrestricted cytotoxicity; this effect may be related to abolition of suppressor influences by the chemotherapy.

Animals↗

PubMed1992

1,10-Phenanthroline-copper, a footprinting reagent for single-stranded regions of RNAs.

The 1,10-phenanthroline-cuprous complex (OP-Cu) with hydrogen peroxide as a coreactant nicks the single-stranded loops and bulges of RNA stem-loop structures more rapidly than the double-stranded stems. This chemical nuclease is therefore a useful footprinting reagent for these regions and can be used to monitor both intramolecular and intermolecular hybridization of single-stranded domains. The formation of A-form structures characteristic of either RNA-RNA or RNA-DNA duplexes inhibits scission because it blocks the binding site of the coordination complex in single-stranded loops and not because the oxidatively sensitive hydrogens of the ribose moiety are blocked. The C-4' and C-1' hydrogens are accessible to solvent in A-structures.

Base Sequence↗

PubMed1992

Synergism of interleukin-2 and cyclosporine A in induction of a graft-versus-tumor effect without graft-versus-host disease after syngeneic bone marrow transplantation.

Interleukin-2 (IL-2) therapy generates killer cells with major histocompatibility complex (MHC)-unrestricted cytotoxicity against most tumors but not normal tissues. Cyclosporine A (CsA) has been reported to break tolerance to self and to induce killer cells with specificity against class II MHC (Ia) antigens both on the host and the tumor cells, resulting in a mild graft-versus-host disease (GVHD) in an autologous bone marrow transplantation (BMT) setting in the rat. We used these two agents in a syngeneic BMT model in a strain of mice that does not develop GVHD with CsA. Therapy with either agent alone was ineffective, whereas a combination of CsA plus IL-2 after BMT induced a potent graft-versus-tumor (GVT) effect against a melanoma and an acute myeloid leukemia. The antitumor effect could be adoptively transferred by infusing spleen cells harvested from mice treated with CsA plus IL-2 into secondary recipients that received chemoradiotherapy. The cytotoxicity of these cells was not influenced by treatment of tumor cells with gamma-interferon or Ia antibody. The cytotoxic effect was mediated by Thy 1+ and asialo GM 1+ cells. There was no GVHD either in the primary recipients of CsA and IL-2 or in those receiving the adoptively transferred spleen cells. Our findings show that combination therapy with CsA and IL-2 after syngeneic BMT induces a potent GVT effect in a non-MHC-restricted manner, and point to the existence of differences between the mechanisms of GVT and GVHD.

Animals↗

PubMed1992

Differential lysis of tumor target cells displayed by lymphokine activated killer (LAK) cell clones.

Lymphokine-activated killer (LAK) cells exhibit major histocompatibility complex (MHC) unrestricted cytolysis against a wide variety of fresh and cultured tumor cells. Because previous work from our laboratory suggested that trypsin treatment of unseparated populations of LAK cells had a differential effect on lysis of different tumors, in this report we analyzed the lytic specificity of LAK cell clones against a panel of three different targets: MCA, B16 and YAC-1. We found that 21 out of the 24 analyzed murine spleen and bone marrow clones killed a combination of two, but not all three, of these tumor cells. Determinations of the phenotype of 10 LAK cell clones showed six with rearrangements for the T cell receptor (TCR) beta chain gene, suggesting a T cell origin, and four with germ line configurations for the TCR beta and delta chain genes, a result consistent with a non-T cell lineage. This cloning procedure provided an experimental tool to develop new procedures of adaptive immunotherapy.

Animals↗

PubMed1992

Recognition of heterogeneous lymphokine-activated killer (LAK) receptors on Kaposi's sarcoma cells, endothelial cells, and monocytes/macrophages: evidence of distinct LAK-cell antigen on Kaposi's sarcoma cells--potential for use of LAK cells for immunotherapy.

The purpose of this study was to determine the potential use of lymphokine-activated killer (LAK) cells against Kaposi's sarcoma (KS) cells. We used chromium release cold-target inhibition assay for understanding the expression of heterogeneous LAK-cell antigens (Ags) on KS cells, endothelial cells (ECs), and monocytes/macrophages (M phi) which could allow for the utilization of LAK-cell immunotherapy in KS without side effects. Our data show that (i) all three cell types express the CD18 Ag of LFA-1 or Leu-CAM, (ii) rare KS cells from eyes cannot cold target-inhibit ECs, (iii) KS cells express a distinct LAK-cell Ag, which we have called LAK-KS Ag, and (iv) LAK-KS Ag allows for cold-target inhibition between different KS cells. The identification of LAK-KS Ag and a monoclonal antibody capable of inhibiting lysis of ECs and M phi without obstructing LAK-KS Ag would be important.

Antigens, CD↗

PubMed1992

Resistance of different tumor cells to lysis by lymphokine activated killer cells can be mediated by distinct mechanisms.

Lymphokine activated killer (LAK) cells have been shown to exert a potent cytotoxic effect on many histologically different tumors and virally infected targets. Most normal cells but very few tumors have proven resistant to LAK lysis. The availability of two LAK resistant tumors, P815r, a murine mastocytoma, and SNUC-1, a human colon carcinoma, allowed us to study the phenomenon of LAK lysis. We examined the role of surface molecules on targets, which mediate binding to LAK cells, by cold target competition experiments and lectin dependent cellular cytotoxicity assays. The results showed that in the murine system, P815r cells do not compete for lysis of the LAK sensitive target B16 whereas other LAK sensitive murine targets compete. Alternatively, in the human system, SNUC-1 cells compete for lysis of the LAK sensitive target SNUC-4 as do other LAK sensitive human tumor cells. Furthermore, inducing binding of target and effector cells with lectin reverted the resistance of P815r but not SNUC-1 targets to lysis by LAK cells. These results imply that distinct stages of the lytic pathway might be involved in the resistance of different tumors to killing by LAK cells. The murine cell line is resistant to lysis because it cannot bind LAK cells. The human target, which does bind LAK, was insensitive to the effects of tumor necrosis factor alpha (TNF-alpha), a lymphokine released by LAK effectors and possibly involved in their lysis. Resistance to TNF-alpha was not mediated by the presence of endogenous short-lived proteins in the SNUC-1 targets. The elucidation of mechanisms of resistance may provide a tool to improve current protocols of adoptive immunotherapy as well as insights as to how tumor cells are or are not killed by LAK effectors.

Animals↗

PubMed1992

Lymphokine-activated killer cells in autologous bone marrow transplantation. Evidence against inhibition of engraftment in vivo.

Lymphokine activated killer cells have potent antitumor effect both in vitro and in vivo. They have been reported to suppress bone marrow (BM) progenitor cell activity (PCA) in vitro, thus raising concern about the feasibility of their use after autologous bone marrow transplantation. The present study was carried out to evaluate the effect of LAK cells on BM engraftment in a syngeneic BMT setting in mice. LAK cells supplemented with or without exogenous interleukin-2 therapy did not impair the hematopoietic reconstitution or survival of mice undergoing BMT. LAK cells also did not reduce the PCA of the engrafted BM. LAK cell therapy did not cause graft-versus-host disease. Finally, LAK cells supplemented with IL-2 therapy improved the graft-versus-leukemia effect. These findings suggest that LAK cells plus IL-2 therapy after BMT does not impede hematopoiesis and should be evaluated as an adjuvant therapy with the aim of eradication of minimal residual disease after autologous BMT.

Animals↗

PubMed1992

Interleukin-2 in bone marrow transplantation: preclinical studies.

Interleukin-2 (IL-2) promotes the generation and proliferation of killer cells in the peripheral blood and bone marrow (BM) both in vitro and in vivo. When employed in a syngeneic bone marrow transplantation (BMT) setting and followed by IL-2 therapy, murine BM cells activated with IL-2 in vitro (ABM) demonstrate potent graft-versus-leukemia (GVL) and anticytomegalovirus effects. ABM cells retain the capacity to reconstitute the hemopoietic system both in normal and leukemic mice. This therapy does not cause graft-versus-host disease (GVHD). Human ABM cells carry out purging of leukemia without loss of progenitor cell activity in vitro. The purging ability of ABM can be augmented by interleukin-1, interferon, and tumor necrosis factor. IL-2 therapy stimulates the veto suppressor cell activity of T cell-depleted BM, and has reduced GVHD and permitted engraftment of mismatched allogeneic BM in murine models. Future studies should determine the optimum treatment schedules with IL-2 for improving the GVL effect in autologous BMT, and for abolishing GVHD in allogeneic BMT settings.

Animals↗

PubMed1992

The acute phase response in autologous bone marrow transplantation.

Due to the stress imposed by the process of bone marrow transplantation (BMT), we hypothesized that individuals receiving such a transplant underwent an acute phase response (APR). Circulating levels of C-reactive protein (CRP), haptoglobin (HAP), alpha-1 acid glycoprotein (AAG), ceruloplasmin (CER), zinc (Zn), copper (Cu), interleukin-6 (IL-6), albumin (ALB), and thyroxine-binding prealbumin (TBPA), were measured at baseline (Day -7), Day -4, Day 0 (Transplant Day), Day +2, +7, and weekly until day 28 in 14 adults receiving an autologous bone marrow transplant as Phase 1 treatment for various hematologic or solid tumor malignancies. Ten of 14 recipients survived, 9 of which had a significant increase in CRP (p = 0.012), HAP (p = 0.011), AAG (p = 0.002), and decrease in ALB (p = 0.002) and TBPA (p = 0.004) on Day +7, but not Day 0, after bone marrow reinfusion. These findings document the presence of an APR and suggest that the bone marrow transplant process (post reinfusion) initiates a stress response in the recipient.

Acute-Phase Reaction↗

PubMed1992

Interleukin-2 increases the antibody response in patients receiving autologous intralymphatic tumor cell vaccine immunotherapy.

The production of tumor-binding antibodies was studied in a group of cancer patients undergoing active specific immunotherapy with irradiated, cholesterol-treated, cell culture-derived autologous tumor cells injected by the intralymphatic route. Fifteen patients were analyzed: nine patients (four melanoma, one breast, one sarcoma, one colon, and one undifferentiated cancer) received three injections of 10 to 15 x 10(6) tumor cells, spaced 2 weeks apart, and six patients (two melanoma, two renal, one breast, and one colon cancer) received tumor cells admixed with 3 x 10(6) U recombinant interleukin-2 (IL-2) (Proleukin, Cetus, Emeryville, CA, USA) plus a 10-day intravenous infusion of 15 x 10(6) U/kg/day IL-2 after each immunization. Serum antibody binding to autologous tumor cells was measured at 2 and 4 weeks after initiation of therapy using an enzyme-linked immunosorbent assay with patient serum being added to adherent tumor cells bound to 96-well microtiter plates. After 4 weeks, we found a significant difference (0.02 less than P less than 0.04) in serum titer in the group receiving IL-2 (33% mean increase) compared with the non-IL-2 group (8% mean increase). Although neither group showed clinical improvement in response to the therapy, the results clearly demonstrated the efficacy of IL-2 in augmenting patient antibody response to autologous intralymphatic tumor cell immunization.

Antibodies, Neoplasm↗

PubMed1992

Interleukin-2 (IL-2) and IL-2-activated bone marrow in transplantation: evaluation from a clinical perspective.

Incubation of bone marrow (BM) with interleukin-2 (IL-2) in vitro results in generation of killer cells providing a tool for enhancing the graft-versus-tumor effect in transplantation. We have evaluated the influence of IL-2 on the progenitor cell activity (PCA), homing pattern of BM and hemopoiesis in a syngeneic bone marrow transplantation (BMT) model in mice. The PCA index and homing pattern of BM activated with IL-2 in vitro for 24 h (ABM) were similar to those of fresh bone marrow (FBM). In vitro culture of BM for more than 1 day resulted in progressive decline in its PCA index; this was not related to the presence or absence of IL-2 in the culture medium. Toxicity of IL-2 was related to the dose and not the time of institution of IL-2 therapy after BMT. Maximum tolerated dose of IL-2 instituted immediately after BMT was 10 times higher than the dose in a non-BMT setting. The pattern of marrow reconstitution following BMT with ABM was comparable to that with FBM. This study shows that BMT with BM activated with IL-2 for 24 h results in normal hemopoiesis, and IL-2 therapy instituted immediately after BMT with ABM does not cause additional toxicity.

Animals↗

PubMed1991

Characterization of conformational features of DNA heteroduplexes containing aldehydic abasic sites.

The DNA duplexes shown below, with D indicating deoxyribose aldehyde absic sites and numbering from 5' to 3', have been investigated by NMR. The 31P and 31P-1H correlation data indicate [formula: see text] that the backbones of these duplex DNAs are regular. One- and two-dimensional 1H NMR data indicate that the duplexes are right-handed and B-form. Conformational changes due to the presence of the abasic site extend to the two base pairs adjacent to the lesion site with the local conformation of the DNA being dependent on whether the abasic site is in the alpha or beta configuration. The aromatic base of residue A17 in the position opposite the abasic site is predominantly stacked in the helix as is G17 in the analogous sample. Imino lifetimes of the AT base pairs are much longer in samples with an abasic site than in those containing a Watson-Crick base pair. The conformational and dynamical properties of the duplex DNAs containing the naturally occurring aldehyde abasic site are different from those of duplex DNAs containing a variety of analogues of the abasic site.

Aldehydes↗

PubMed1991

Adoptive transfer of anti-cytomegalovirus effect of interleukin-2-activated bone marrow: potential application in transplantation.

This work is a continuation of our studies that showed that interleukin-2 (IL-2)-activated murine bone marrow (ABM) cells have potent cytotoxic potential against murine cytomegalovirus (MCMV)-infected targets in vitro, without loss of reconstitutive ability in vivo. Our data show that ABM cells lyse the MCMV-infected cells in vitro, at both acute and chronic stages of infection; this lysis is specific for the MCMV-infected cells. ABM cells supplemented with IL-2 therapy virtually eradicated the viral infection and prolonged the survival of MCMV-infected Balb/c mice, whether or not they were immunocompromised by irradiation (P less than .001 in both situations). Efficacy of ABM cells alone or IL-2 alone was less than the combination of ABM cells and IL-2. The efficacy of combination treatment with ABM cells and IL-2 in improving the survival of MCMV-infected mice was comparable, whether used in a preventive or a therapeutic setting. Therapy with ABM plus IL-2 also prevented the reactivation of chronic MCMV infection after irradiation. Preliminary findings indicate that Thy-1+ and asialo GM1+ cells limited the MCMV proliferation by approximately 30% and 80%, respectively, while BM macrophages limited the proliferation of MCMV by 100%. These results suggest that BM transplantation (BMT) with ABM cells followed by IL-2 therapy may constitute a novel strategy to improve the host resistance against cytomegalovirus infection after BMT.

Animals↗

PubMed1991

Enhanced tumor uptake of macromolecules induced by a novel vasoactive interleukin 2 immunoconjugate.

Low uptake of monoclonal antibodies (MAbs) in cancer lesions is a significant problem in cancer therapy. Recent studies have shown that antibody uptake in tumor is controlled in large part by the tumor blood flow and the vascular permeability of the tumor endothelium. We have hypothesized that these physiological properties of tumor vessels may be altered by pretreatment with vasoactive drugs or peptides linked to tumor-specific MAbs. To test this hypothesis, two MAbs, Lym-1 directed against human malignant lymphomas and B72.3 reactive with the TAG-72 antigen expressed in solid tumors, were chemically conjugated with human recombinant interleukin 2 (IL-2). IL-2 has been used in humans to activate lymphokine-activated killer cells for the treatment of cancer but is also known to produce a generalized vascular permeability by an unknown mechanism when used systemically. Chemical conjugation of IL-2 to MAbs appears to destroy its cytokine function as shown by T-cell proliferation studies in vitro. Despite this finding, MAb/IL-2 immunoconjugates retain their ability to produce an enhanced vascular permeability when injected i.v. into nude mice bearing relevant tumor models only. Biodistribution studies using 125I-labeled tracer Lym-1 have demonstrated that the Lym-1/IL-2 immunoconjugate can increase antibody uptake in tumor by a factor of 4 in a time (2.5-h pretreatment)- and dose (30 micrograms/mouse)-dependent manner. In contrast, treatment of mice with free IL-2 and antibody showed this effect in all organs of the mouse including the tumor. Bidirectional crossover imaging studies in individual tumor-bearing nude mice showed improved uptake and decreased blood pool when the MAb/IL-2 immunoconjugates were used compared to controls. Finally, tumor blood flow and vascular permeability studies demonstrate that the physiological effect of the MAb/IL-2 is due to a reversible and specific vascular leakage at the tumor site. These studies indicate that pretreatment with this novel immunoconjugate may enhance the diagnostic and therapeutic potential of MAbs, drugs, and other macromolecules for the treatment of cancer.

Animals↗

PubMed1991

Induction of graft versus leukemia effect in bone marrow transplantation: dosage and time schedule dependency of interleukin 2 therapy.

The present work is a continuation of our studies to improve the graft versus leukemia (GVL) effect in autologous bone marrow transplantation. We have recently shown that the GVL effect of bone marrow transplantation (BMT) with interleukin 2 (IL-2)-activated bone marrow (ABM) followed by IL-2 therapy immediately after BMT is superior to the GVL effect of BMT with fresh, syngeneic bone marrow, with or without IL-2 therapy, in mice with acute myeloid leukemia. The present studies show that institution of IL-2 treatment 1, 2, or 3 weeks after BMT with ABM resulted in shortening of survival and fall in cure rate as compared to IL-2 therapy instituted immediately after BMT with ABM. Increasing the dose of IL-2 did not improve results. However, reducing the frequency of IL-2 administration to once a day instead of twice a day affected the results adversely. Commencing IL-2 therapy 1, 2, or 3 weeks after BMT with fresh, syngeneic bone marrow did not improve the GVL effect as compared to IL-2 therapy started immediately after BMT with fresh, syngeneic bone marrow. Cryopreserved bone marrow was effectively activated with IL-2 and used successfully for BMT after thawing. The animals cured of leukemia by BMT with ABM and and IL-2 therapy were not resistant to leukemia and died when reinfused with leukemic cells. Our findings suggest that for optimum GVL effect, activation of bone marrow is necessary and IL-2 therapy should be started immediately after BMT with ABM.

Acute Disease↗

PubMed1991

Stereochemical studies of the beta-elimination reactions at aldehydic abasic sites in DNA: endonuclease III from Escherichia coli, sodium hydroxide, and Lys-Trp-Lys.

The DNA strand cleavage reaction catalyzed by endonuclease III from Escherichia coli (endo III) on the 3'-side of aldehyde abasic sites proceeds by a syn beta-elimination involving abstraction of the 2'-pro-S proton and formation of a trans alpha,beta-unsaturated aldose product; we previously reported the same stereochemical course for the reaction catalyzed by UV endonuclease V from bacteriophage T4 (UV endo V) [Mazumder, A., Gerlt, J. A., Rabow, L., Absalon, M. J., Stubbe, J., & Bolton, P. H. (1989) J. Am. Chem. Soc. 111, 8029-8030]. Since the UV endo V does not contain an 4Fe-4S center, the 4Fe-4S center present in endo III need not be assigned a unique role in the beta-elimination reaction. The beta-elimination reactions that occur under alkaline conditions (0.1 N NaOH) and in the presence of the tripeptide Lys-Trp-Lys proceed by anti beta-elimination mechanisms involving abstraction of the 2'-pro-R proton and formation of a trans alpha,beta-unsaturated aldose product. The different stereochemical outcomes of the enzymatic and nonenzymatic beta-elimination reactions support the hypothesis that the enzyme-catalyzed reactions may involve general-base-catalyzed abstraction of the 2'-pro-S proton by the internucleotidic phosphodiester leaving group.

Aldehydes↗

PubMed1991

Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia.

Fourteen patients with sexually transmitted human immunodeficiency virus (HIV)-related immune thrombocytopenia were treated with intravenous gammaglobulin (IVIG). The patients were treated with a uniform program consisting of 1 g/kg of IVIG on day 1 and day 2, followed by 1 g/kg on day 15. Most patients had pretreatment bleeding symptoms, which included petechiae, spontaneous and traumatic ecchymoses, gum bleeding, and epistaxis. Median baseline platelet count was 17,000/mm3 (range 3-61,000/mm3). After the infusion of the IGIV, all patients had a resolution of their bleeding by day 8. The median maximum platelet count achieved with the IGIV was 220,000/mm3 (range 76-426,000/mm3). No patient achieved either a sustained complete or partial remission after the conclusion of the IVIG therapy. Toxicities were minimal with the majority being headache and nausea. In conclusion, patients with sexually transmitted HIV infection and immune thrombocytopenia respond favorably to IVIG. This treatment should be considered as first-line therapy for patients with HIV-related immune thrombocytopenia who require immediate but temporary increase in their platelet count, attributable to symptoms or signs of clinical bleeding or because of the need for an invasive procedure.

Adult↗