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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BALL-1, a human B leukemia/lymphoma cell line, was transplanted into nude and SCID mice under various conditions. The transplantation was substantially improved by preadaptation of BALL-1 by serial passages in newborn and young nude mice. We were able to establish the desirable conditions where 100% of SCID and nude mice that were inoculated i.p. with various doses of the adapted BALL-1 (termed BALL-1a) developed tumors. Tumors in SCID mice were disseminated to various tissues in a manner analogous to tumors in patients with B leukemia/lymphoma, whereas tumors in nude mice were not as widely disseminated and grew mainly as ascites. Flow cytometric analyses showed that all of the 11 tested cell surface markers of the parental BALL-1 were well maintained on the tumor cells recovered from the SCID and nude mice. The utility of the developed tumor models for the therapeutic studies was investigated by i.p. or i.v. administration of an anti-B leukemia/lymphoma monoclonal antibody, termed SN7 (IgG1 kappa), and SN7 immunotoxin (IT) that was prepared by conjugating SN7 to ricin A chain (RA) or deglycosylated RA (dgRA). In the nude mouse model study, SN7-RA that had been administered i.p. suppressed the tumor growth completely in all of the treated mice (n = 5) without any sign of tumor or undesirable side effects for as long as followed (i.e., 350 days), whereas unconjugated SN7 showed only a slight therapeutic effect. A control RA conjugate was not effective. In the SCID mouse model studies, several sets of experiments were carried out by i.p. or i.v. administration of IT, monoclonal antibody, or control IT. In the first three sets of experiments, SCID mice inoculated with 1.1 x 10(6) BALL-1a cells received an i.p. administration of phosphate-buffered saline or three different doses (i.e., 4 x 10 micrograms, 4 x 20 micrograms, and 4 x 30 micrograms) of therapeutic agents (SN7-RA and SN7). Virtually an identical result was obtained from the three experiments. All of the phosphate-buffered saline control group mice (n = 15) died within 35 days post tumor inoculation. In contrast, all of the mice that were treated with SN7-RA (n = 19) or with SN7 (n = 15) survived for as long as followed (i.e., 250 days). However, the unconjugated SN7 was less effective than SN7 IT for tumor suppression in SCID mice that were inoculated with a larger tumor burden (i.e., 4 x 10(7) BALL-1a cells).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Establishment of new SCID and nude mouse models of human B leukemia/lymphoma and effective therapy of the tumors with immunotoxin and monoclonal antibody: marked difference between the SCID and nude mouse models in the antitumor efficacy of monoclonal antibody. 816 98

Protein G-purified goat anti-ricin IgG, previously demonstrated to protect against ricin toxicity in vitro and in vivo, was used to raise BALB/c mouse and New Zealand White rabbit polyclonal anti-idiotypic antibodies. The generated anti-idiotypic sera were repeatedly absorbed over agarose conjugated to normal goat immunoglobulins, and purified by protein A-agarose affinity chromatography. Immunization of BALB/c mice with BALB/c anti-idiotypes did not result in a significant anti-ricin antibody response. However, injection of BALB/c mice with BALB/c anti-idiotypes conjugated to keyhole limpet haemocyanin (KLH) or with unconjugated rabbit anti-idiotypes resulted in specific and anti-ricin immune responses. The anti-idiotype-induced anti-ricin antibody responses protected against the in vitro cytotoxicity of ricin, a potent plant-derived protein synthesis inhibitor, as assessed by the murine EL-4 leukaemia cell assays. Thus, anti-idiotype-based vaccines may represent an alternative, safe and effective means of inducing protective immunity against toxins such as ricin, whose extreme in vivo toxicity render them unsafe as immunogens.
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PMID:Polyclonal anti-idiotypes induce antibody responses protective against ricin cytotoxicity. 840 96

In this study, the systemically administered anti-human T-leukemia immunotoxins (ITs) are shown to be effective for tumor suppression in Ichikawa T-leukemia-bearing nude mice. In addition, their antitumor efficacy was markedly potentiated by recombinant human IFN-alpha. The combination of ITs and IFN-alpha effectively killed the tumor in the majority of the treated mice; 9 of the 12 treated mice survived tumor-free for as long as they were followed, i.e. for 140 days. Two different ITs, SN1-ricin A chain (RA) and SN2-RA, were used together to minimize the problem of tumor heterogeneity; monoclonal antibodies SN1 and SN2 are directed toward two different human T-leukemia associated cell surface antigens. In the biodistribution experiments, the paired label technique was used to include a reliable internal control. In an experiment, equal amounts of 125I-SN1-RA and 131I-labelled isotype-matching control IgG (IgG1-kappa)-RA were mixed and administered i.v. into tumor-bearing nude mice. In a separate experiment, a mixture of equal amounts of 125I-SN2-RA and 131I-control IgG-RA was administered i.v. This technique allowed us to distinguish the immunospecific uptake from the non-immunospecific uptake of ITs into individual organs. The present results clearly show that both SN1-RA and SN2-RA are specifically localized in tumors after systemic administration. For instance, 24 h after the administration of a radiolabelled mixture, the ratio of 125I/131I in the tumor was 7.0 and 23.5, respectively, for the SN1-RA/control IgG-RA mixture and the SN2-RA/control IgG-RA mixture. Such high ratios of 125I/131I were detected in the tumors throughout the experiments between 30 min and 24 h after the administration of the paired label mixture.
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PMID:Biodistribution and in vivo antitumor efficacy of the systemically administered anti-human T-leukemia immunotoxins and potentiation of their efficacy by alpha-interferon. 842 82

This study has been designed to verify the specific toxicity of saporin, a type 1 ribosome-inactivating protein (RIP), with the same activity as ricin A chain, targeted by a bispecific monoclonal antibody (bimAb) recognising both the CD25 antigen and the RIP. The CD25 antigen is expressed by lymphoid populations upon activation and by leukaemias and lymphomas with an activated membrane phenotype (Hodgkin's lymphoma, anaplastic large cell lymphoma, adult T cell leukaemia). The bimAb-saporin mixture was tested on CD25+ targets at different bimAb and saporin concentrations. Saporin, in the presence of a bimAb concentration of 10(-9) M, inhibited protein synthesis by CD25+ neoplastic lymphocytes (L540 and MT2 cell lines) with IC50S (concentrations giving 50% of inhibition) ranging from 8 x 10(-12) M to 3 x 10(-11) M. The saporin-bimAb mixture was also effective in blocking the phytohaemagglutinin-driven proliferation of normal lymphocytes, whereas it displayed the same level of toxicity exerted by saporin alone on an irrelevant CD25-negative cell line (EBV-infected B lymphoblastoid cell line). From these results it is possible to envisage a clinical use of this bimAb as a cytotoxic agent for CD25+ leukaemias and lymphomas, as well as an immunosuppressive agent for severe immune disorders such as graft-vs-host disease (GVHD) and transplanted organ rejection.
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PMID:Targeting of saporin to CD25-positive normal and neoplastic lymphocytes by an anti-saporin/anti-CD25 bispecific monoclonal antibody: in vitro evaluation. 851 10

A new anti-CD24 immunotoxin (IT), SWA11.dgA, was constructed by coupling the MAb SWA11 via the bivalent linker SMPT to deglycosylated ricin A-chain (dgA). The effects of SWA11.dgA were evaluated in vitro against the B-precursor leukemia cell line REH, the non-B-non-T acute lymphoblastic leukemia cell line NALM-6 and the Burkitt's lymphoma cell lines BL-2 and BL-38. Binding of SWA11 to the CD24 antigen was assessed by flow cytometry demonstrating high affinity of the MAb for all cell lines tested. SWA11.dgA inhibited the protein synthesis of BL-38, NALM-6, REH and BL-2 cells by 50% at concentrations (IC50) of 4.0 x 10(-11) M, 6.0 x 10(-11) M, 8.0 x 10(-11) M and 3.0 x 10(-9) M, respectively. SWA11.dgA was subsequently used for the treatment of disseminated human BL-38 Burkitt's lymphoma in a newly developed SCID mouse model. The mean survival time (MST) of BL-38-bearing SCID mice was extended from 23 days in untreated controls to more than 230 days when 6 microg SWA11.dgA was applied intraperitoneally one day after tumor challenge. All of the animals achieved continuous complete remissions. SCID mice treated with SWA11.dgA 4 days after tumor cell challenge or a reduced dose of SWA11.dgA (67%) also had a significantly extended MST (45.0 and 51.4 days, respectively, as compared to 22.7 and 23.1 days in the controls). We conclude that SWA11.dgA might be of potential use for the treatment of lymphoma in man.
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PMID:Potent anti-tumor effects of an anti-CD24 ricin A-chain immunotoxin in vitro and in a disseminated human Burkitt's lymphoma model in SCID mice. 863 69

A leukemia-selective immunotoxin was constructed by linking recombinant gelonin (rGel), a single chain ribosome inhibitory protein, to recombinant humanized M195 antibody (HuM195), which recognizes the cell-surface protein designated CD33. CD33 is an antigen found on myeloid leukemia blasts as well as myeloid progenitor cells but it is not expressed in detectable amounts on the ultimate hematopoietic progenitor stem cell. Our previous studies indicated that a non-recombinant humanized immunotoxin displayed specific, potent toxicity towards CD33-positive cells but not to CD33-negative cells in vitro. In the current study, a recombinant humanized immunotoxin, HuM195-rGel, was evaluated in vivo in a nude mouse model of human myeloid leukemias. HuM195-rGel was found to target leukemia cells rapidly in vivo and was subsequently internalized into the cells. For trials in vivo, nude mice were injected (ip) with 10(7) log-phase HL60 human leukemia cells 10 days prior to the start of i.p. HuM195-rGel treatments. HuM195-rGel demonstrated significant tumor suppressive activity in this model. While all mice treated with either saline, rGel alone, or HuM195 plus unconjugated rGel (at 10 or 14 days after transplantation) had rapid tumor growth or early deaths, 50% of mice treated with HuM195-rGel failed to develop leukemic tumors for 5 months and the 50% had significantly retarded tumor growth after treatment with HuM195-rGel. Mice treated at later times (28 days after transplantation of leukemia cells) also showed delayed leukemia cell growth, but no cures. These data show that HuM195-rGel can target leukemia cells in vivo and can result in pronounced anti-leukemic effects.
Leukemia 1996 Feb
PMID:Antileukemic activity of recombinant humanized M195-gelonin immunotoxin in nude mice. 863 41

Site-selective toxin delivery was achieved by coupling monoclonal antibody to the A chain subunit of ricin (RTA-IT). The cell-killing potency of RTA-IT can be drastically increased in vitro by using ionophores such as monensin. To reduce the intrinsic toxicity of monensin and to enhance its in vitro and in vivo activity, we synthesized 7 derivatives characterized by different lipophilicities. These derivatives were also analyzed for ionophoretic activity on intact cells, toxicity, and RTA-IT-enhancing activity. Two different RTA-IT were assayed on a human leukemia cell line. A correlation between lipophilicity, ionophoretic activity, and RTA-IT enhancement was observed. The compounds with the highest polar charge showed low intrinsic toxicity, revealed moderate ionophoretic activity, and were able to enhance RTA-IT only at high concentrations, whereas more lipophilic compounds (with a C28 tail or a phenyl group) showed significant ionophoretic activity and good enhancing properties.
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PMID:Enhancement of ricin toxin A chain immunotoxin activity: synthesis, ionophoretic ability, and in vitro activity of monensin derivatives. 867 1

This study reviews results of a radiation-free preparative regimen consisting of busulfan and cyclophosphamide in 65 unrelated allogeneic bone marrow transplant recipients. Thirty-eight patients had chronic myelogenous leukemia (17 patients chronic phase, 13 patients accelerated phase, eight patients blast phase), 19 patients had acute leukemia (second complete remission or relapse) and eight patients had myelodysplasia. The patients were transplanted at four different medical centers from July 1988 to November 1992. Ages ranged 4-48 years (median 32). Fifty-seven patients received busulfan 16 mg/kg and cyclophosphamide 120 mg/kg, and eight received busulfan at doses between 15 and 17 mg/kg and cyclophosphamide at doses 100-200 mg/kg as preparative regimens. All patients received cyclosporine for graft-versus-host disease prophylaxis; in addition 46 patients received corticosteroid, 38 methotrexate, six anti-CD5 ricin A-immunotoxin, and four T cell-depleted bone marrow. Median follow-up of survivors was 53 months (range 15-68 months). Four year actuarial survival was 24 +/- 12%. Four-year survival based on disease was 29 +/- 27% for chronic myelogenous leukemia (CML) in chronic phase, 20 +/- 9% for chronic myelogenous leukemia in accelerated phase, 0% for chronic myelogenous leukemia in blast phase, 32 +/- 40% for acute leukemia, and 38 +/- 34% for myelodysplasia. Actuarial survival was 66 +/- 40% in patients age < 20 years, vs 23 +/- 13% for patients ages 20 to 40, and 10 +/- 14% for patients age > 40 years. Fifty patients (88%) engrafted. Graft failure occurred in eight patients. Acute graft-versus-host disease grade II-IV occurred in 36 (72%). Two patients relapsed after engraftment with the donor cells and died of leukemia within a month of relapse. The most common causes of death were graft-versus-host disease (37%), and transplant-related toxicity (59%); relapse (4%) was a rare cause of death. Busulfan/cyclophosphamide is an effective preparative regimen in unrelated bone marrow transplantation permitting adequate engraftment and a low relapse rate. Best results are observed in patients less than 20 years old.
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PMID:Unrelated allogeneic bone marrow transplantation using high-dose busulfan and cyclophosphamide (BU-CY) for the preparative regimen. 873 82

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.
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PMID:Prevention of graft-versus-host disease with anti-CD5 ricin A chain immunotoxin after CD3-depleted HLA-nonidentical marrow transplantation in pediatric leukemia patients. 875 Feb 62

An immunotoxin consisting of a monoclonal antibody specific for CD7, a cell surface determinant expressed on T acute lymphocytic leukemia (T-ALL) blast cells, was linked to the potent plant toxin deglycosylated ricin toxin A chain (dgRTA) and is currently under evaluation in phase I clinical trials. Scale-up production of this immunotoxin, called DA7, was simplified using a two-step purification protocol that resulted in a highly purified immunotoxin meeting FDA criteria for IND approval. The anti-CD7 antibody, 3Ale, an IgG2b, was coupled to toxin using two different heterobifunctional cross-linkers, (1) N-succinimidyl-3-(2-pyridyl-dithiolproprionate) (SPDP), considered a standard croslinker and (2) 4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)tolu ene (SMPT), designed to hinder the in vivo breakdown of the toxin/antibody disulfide bond. Since experiments revealed that SPDP-DA7 had similar pharmacokinetics and biodistribution in mice and higher yields than DA7 made with a hindered cross-linker, SPDP-DA7 was scaled up for clinical study. Yield of SPDP-DA7 was 25% relative to starting material. Fractions were collected containing a toxin: antibody ratio of 1:1 to 4:1 rather than only a 1:1 ratio since studies showed that this heterogenous fraction was just as toxic to proliferating CD7-expressing leukemia cells as a homogeneous 1:1 fraction. In vitro, the concentration of heterogenous SPDP-DA7 selectively inhibiting 50% activity (IC50) of the CD7+ CEM cell line was 0.01 microgram/ml to 0.05 microgram/ml for inhibiting activated T cells or T cell lines. In vivo, SPDP-DA7 showed a significant anti-tumor effect against CEM cells administered to scid/scid mice, but even more importantly was effective against primary T cell leukemias taken from patients and injected into scid/scid mice.
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PMID:Laboratory preparation of a deglycosylated ricin toxin A chain containing immunotoxin directed against a CD7 T lineage differentiation antigen for phase I human clinical studies involving T cell malignancies. 889 Aug 95


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