Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL2) fused to ricin B chain (RTB) with modifications of amino acid residues in each of three galactose-binding subdomains (1alpha, 1beta and 2gamma) was expressed in insect cells, purified by immunoaffinity chromatography and reassociated with ricin A chain (RTA). The fusion toxin-bound human leukemic cells with IL2 receptors and the binding was competed with IL2 but not asialofetuin. In contrast, binding was not observed with receptor negative human cell lines, and the fusion molecule very weakly bound asialofetuin (Kd= 10(-6)M), indicating lectin-deficient RTB. The IL2-lectin-deficient RTB-RTA intoxicated IL2 receptor bearing cells as well as ricin or IL2-wild-type RTB-RTA. While ricin and IL2-wild-type RTB-RTA were equally toxic to receptor negative cell lines, the IL2-lectin-deficient RTB-RTA was two-two and one half logs less cytotoxic to these cell lines. The sensitivity of receptor-positive cells to the lectin-deficient fusion protein suggests that high avidity intracellular galactose binding may not be required for ricin intoxication, at least in the case of IL2 receptor-targeted molecules. Furthermore, the potent selective cytotoxicity of the fusion protein suggests that the IL2-lectin-deficient RTB-RTA and similar ricin fusion molecules directed against other leukemic cell surface receptors provide a novel class of fusion toxins for therapy of human leukemias.
Leukemia 1997 Jan
PMID:IL2 fused to lectin-deficient ricin is toxic to human leukemia cells expressing the IL2 receptor. 900 14

A new severe combined immunodeficiency (SCID) mouse model consisting of highly disseminated human B-cell leukemia/lymphoma was developed by i.v. inoculation of BALL-1a, an in vivo adapted malignant B-cell line. A 100% transplantability was achieved in nonpreconditioned SCID mice using various BALL-1a doses between 2.5 x 10(4) and 6 x 10(6) cells. Hind-leg paralysis preceded the death of the mice. Utility of the developed tumor model for the therapeutic studies was investigated by i.v. administration of an anti-B-cell monoclonal antibody SN7 (IgG1) and its conjugate with deglycosylated ricin A chain (dgRA). The therapy was initiated 2, 4, or 6 days after tumor inoculation using 4 x 24 microg of SN7-dgRA or 4 x 20 microg of SN7; the total dose (96 microg) of SN7-dgRA corresponded to 14% of the LD50 dose. SN7-dgRA showed a strong antitumor efficacy in all groups of treated mice. All of the day-2 group mice (n = 7) and six (66.7%) of the day-4 group mice (n = 9) survived healthily for as long as followed (240 days), whereas four (57.1%) of the day-6 group mice (n = 7) survived healthily for as long as followed (200 days). Unconjugated SN7 showed a significant antitumor efficacy but was less effective than SN7-dgRA. A PCR-based assay specific for the clonogenic BALL-1a tumor was developed and applied to determine tumors in various organs of BALL-1a-bearing SCID mice. The assay was highly sensitive in screening for trace quantities of residual tumors in various organs of SCID mice, and it could detect 1 malignant cell/2.5 x 10(5) tissue cells. The PCR-based assay was shown to be much more powerful than the conventional histological analysis in detecting residual tumors. Furthermore, we could estimate quantities of the detected tumors by the PCR-based assay. It is remarkable to find that all examined organs of some of the SN7-dgRA-treated mice were tumor-free as determined by the clonotype-specific PCR-based assay. The present results show the usefulness of the newly developed SCID mouse model, SN7-dgRA, and the clonotype-specific PCR-based molecular assay for the study of therapy of human B-cell leukemia/lymphoma.
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PMID:Development of a severe combined immunodeficiency (SCID) mouse model consisting of highly disseminated human B-cell leukemia/lymphoma, cure of the tumors by systemic administration of immunotoxin, and development/application of a clonotype-specific polymerase chain reaction-based assay. 904 45

Anti-CD7-dgA, DA7, consists of deglycosylated ricin A chain coupled to a mouse monoclonal anti-human CD7 antibody. This study determined the maximally tolerated dose (MTD) of this immunotoxin administered as a one hour infusion over five days to 11 patients with T-cell lymphoma (>30% CD7+ malignant cells). The MTD was 0.2 mg/kg/day or 1 mg/kg/120 hours (maximal toxicity grade 3) with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT). Predictors of severe VLS included age and absence of circulating lymphoma cells. Two partial responses and one minimal response were seen. Patients with minimal lymphoma burden or T-cell large granular lymphocyte (LGL) leukemia showed the best responses. The mean maximal serum concentration of immunotoxin at the MTD was 2.5 ug/ml. The mean alpha-phase half-life was 1.5 hours and the mean beta-phase half-life was 8 hours. Repeated dosing had minimal effects on either peak serum immunotoxin concentrations or serum half-lives. While human antimouse antibodies were observed, they were low in concentration (<55 ng/ml). Human anti-ricin antibody was elevated in one patient (190 ng/ml). VLS presented with hypoalbuminemia, dyspnea, pulmonary edema, aphasia, and peripheral edema and cleared over a two week period. Serum fibronectin levels were measured in three patients and were very low in one patient who developed VLS. No specific binding of DA7 immunotoxin was seen with vascular endothelium in various human tissues.
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PMID:Therapy of patients with T-cell lymphomas and leukemias using an anti-CD7 monoclonal antibody-ricin A chain immunotoxin. 932 91

Despite the strong in vitro activity of some immunotoxins (ITs), clinical application did not result in complete cure. The outcome of therapy may be improved by combining ITs with IT-cytotoxicity enhancing agents. We studied the effect of various agents that influence the intracellular routing of ITs on the activity of the anti-B cell IT CD22-recombinant (rec) ricin A. In protein synthesis inhibition assays the carboxylic ionophores monensin and nigericin enhanced the activity of the IT 117- and 382-fold, respectively, against the cell line Daudi, and 81- and 318-fold, respectively, against the cell line Ramos. IT activity to Daudi and Ramos was enhanced to a lesser extent by the lysosomotropic amines chloroquine (14- and 11-fold, respectively) and NH4Cl (nine- and 10-fold, respectively). However, the combination of NH4Cl and chloroquine induced more than an additive effect (145- and 107-fold, respectively). Cytotoxicity was not influenced by brefeldin A, all-trans retinoic acid (ATRA), verapamil and perhexiline maleate. Bacitracin enhanced the IT cytotoxicity in contrast to the other protease inhibitors aprotinin, leupeptin and soybean trypsin inhibitor, albeit enhancement was weak (two-fold). The enhancers exerted only a negligible effect on bone marrow progenitor cells. We recently developed a flow cytometric cytotoxicity assay in which cell elimination can be assessed. In order to detect enhancement in this assay, we used 5 x 10(-11) M IT (approximately the 50% protein synthesis inhibiting dose (ID50)). This concentration killed 41% of the Daudi cells and 42% of the Ramos cells. In the presence of 10 nM monensin the IT killed 74% and 99% and in the presence of 10 nM nigericin 96% and 99% of the Daudi and Ramos cells, respectively. At 10(-8) M, CD22-rec ricin A eliminated malignant cells originating from three patients with B-CLL (0.42 log) and two with B-ALL (0.19 log) patients. Cytotoxicity to malignant cells was enhanced by NH4Cl, chloroquine, monensin and nigericin. The combination of NH4Cl and chloroquine enhanced the activity most effectively (up to 2.06 log). To determine the applicability of the IT in combination with enhancers in vivo we investigated the effect of human serum. Human serum inhibited IT activity which could not be restored by monensin and nigericin because of complete inhibition of these enhancers by serum. In contrast, chloroquine partially restored the activity of CD22-rec ricin A in the presence of human serum. We conclude that monensin, nigericin and the combination of NH4Cl and chloroquine can be used instead of NH4Cl to potentiate CD22-rec ricin A activity in purging autologous bone marrow transplants contaminated with malignant B cells. Chloroquine might be a promising enhancer of CD22-rec ricin A for treating patients in vivo.
Leukemia 1999 Feb
PMID:Influence of cytotoxicity enhancers in combination with human serum on the activity of CD22-recombinant ricin A against B cell lines, chronic and acute lymphocytic leukemia cells. 1002 98

Human granulocyte-macrophage colony-stimulating factor fused to truncated diphtheria toxin (DT388-GM-CSF) sensitized wild-type and Bcl2-overexpressing HL60 human leukemia cells to intoxication by Ara-C based on proliferation and clonogenic assays. The toxin/drug combination showed dramatic synergistic toxicity with combination indices of < 0.1. Synergy was not seen with two other protein synthesis inhibiting drugs--ricin and cycloheximide nor with GMCSF alone. No changes in Ara-C incorporation into cellular DNA or cell cycle occupancy were seen. As compared to exposure to DT388-GM-CSF or Ara-C alone, co-treatment produced significant increases in cytosolic accumulation of cytochrome c, a higher percentage of cells with loss of mitochondrial membrane potential and an increase in reactive oxygen species and morphologic changes of apoptosis, and a greater induction of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor 45 (DFF45) cleavage activities of caspase 3. Co-treatment did not significantly alter Bcl2, Bcl-xL, Bax or Fas receptor (FasR), but modestly increased Fas ligand (FasL) protein. These finding suggest that co-treatment with DT388-GM-CSF may lead to a lowered apoptotic threshold and clonogenic survival of human AML blasts due to Ara-C. These observations also suggest that clinical trials of combination therapy may be warranted in patients with AML.
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PMID:Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor and Ara-C exert synergistic toxicity against human AML HL-60 cells. 1037 46

The anti-CD25 immunotoxin RFT5.dgA was constructed by coupling the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin A-chain and was administered to patients with relapsed Hodgkin's lymphoma in four bolus infusions over 7 days (day 1, 3, 5 and 7). The maximum tolerated dose in these patients as defined in a previous phase I study was 15 mg/m2. Subsequently, further patients were enrolled at the maximum tolerated dose and a total of 18 patients were treated at this level. All patients had signs of progressive disease and were heavily pretreated. Side-effects in this trial were moderate and related to vascular leak syndrome. Five of 18 patients experienced NCI grade III toxicities including weakness, edema, dyspnea, and myalgia. Eleven of 16 (69%) patients receiving two or more cycles produced human anti-ricin antibodies and human anti-mouse antibodies (>/=1.0 microg/ml). Seventeen of 18 patients were evaluable for clinical response. These included two partial remissions. One patient demonstrated minor response and five patients stable diseases. We conclude that RFT5.dgA is of moderate clinical efficacy in this group of heavily pretreated refractory patients. Leukemia (2000) 14, 129-135.
Leukemia 2000 Jan
PMID:Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin. 1063 88

Monoclonal antibodies (Mabs) conjugated to toxins or their subunits (immunotoxins or ITs) are undergoing clinical testing in adults with a variety of malignancies. The potential impact of this form of therapy in pediatric precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) has yet to be determined. Mabs directed against the cell surface antigens, CD19 and CD22 conjugated to deglycosylated ricin A chain (dgRTA) have been tested in patients with non-Hodgkin's lymphoma (NHL), but not in patients with pre-B ALL. Because of the encouraging performance of these ITs in phase I trials, we evaluated the specific cytotoxicity of anti-CD19 (HD37-dgRTA) and anti-CD22 (RFB4-dgRTA) ITs or their combination (Combotox) on patient-derived pre-B ALL cells maintained in vitro on a stromal feeder layer. After 48 h in culture, cytotoxicity to tumor cells was determined by flow cytometry using propidium iodide (PI) and fluorescein isothiocyanate (FITC)-conjugated anti-CD10, 19, and 22. Both RFB4-dgRTA and HD37-dgRTA induced a statistically significant reduction in the number of viable leukemic cells, and Combotox was even more effective. Our results demonstrate that these ITs are specifically cytotoxic to primary pre-B ALL cells and that they should be further evaluated for the therapy of B-lineage ALL.
Leukemia 2000 May
PMID:Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro. 1080 17

Blast cells from patients with acute myeloid leukemia (AML) commonly express CD64, the high-affinity receptor for immunoglobulin G (FcgammaRI). An immunotoxin (MDX-44) was constructed by coupling humanized anti-CD64 monoclonal antibody (mAb) H22 via a bivalent linker to deglycosylated ricin A-chain (RA). Human leukemia cell lines were incubated with MDX-44 or H22/free RA. The effect of MDX-44 on the proliferation of leukemia cells was assessed by [(3)H]thymidine incorporation. In the presence of interferon-gamma (IFN-gamma), MDX-44 significantly inhibited the proliferation of CD64(+) HL-60, NB4, and U937 cells in 72-h cultures in a dose-dependent manner. The mechanism of action appeared to be the induction of apoptosis, as measured by propidium iodide staining and flow cytometry analysis. However, CD64(-) KG-1a and Daudi cells were not affected by MDX-44/IFN-gamma. Incubating HL-60 cells with MDX-44/IFN-gamma resulted in a 99% decrease in colony-forming units, whereas colony-forming cells in normal bone marrow were not significantly suppressed by such treatment. Cells from 60% of AML patients (6/10) were inhibited by MDX-44/IFN-gamma, and the inhibition was correlated with CD64 expression on these cells (r = 0.65). In a human AML model in NOD/SCID mice, MDX-44/IFN-gamma inhibited 95-98% of peritoneal exudate AML cell proliferation and 85-90% of solid leukemia masses. The effect of MDX-44 on AML cells was dependent on activation of cells by IFN-gamma. MDX-44/IFN-gamma may have value in the therapy of AML cells expressing cell-surface CD64.
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PMID:Cytotoxicity of anti-CD64-ricin a chain immunotoxin against human acute myeloid leukemia cells in vitro and in SCID mice. 1127 63

We generated a monoclonal antibody (mAb) 6G7, which recognizes a 220-kD antigen on selected subpopulations of normal myeloid and lymphoid cells and their malignant counterparts. 6G7 reacts with 90-95% of peripheral blood B cells, 70-80% of CD8(+) cells, 30-35% of CD4(+) cells, 20-40% of monocytes, and 20-40% of CD34(+) cells from bone marrow. 6G7 reacts with leukemic blasts in acute myeloid leukemia (14/16), adult acute lymphoblastic leukemia (ALL) (5/5), pediatric ALL (5/9), chronic lymphocytic leukemia (8/8), follicular lymphoma (7/7), and Burkitt's lymphoma (1/1). Long-term bone marrow culture of 6G7(+/-) cells showed the majority of clonogenic hematopoietic cells were in mAb 6G7 subpopulation. An immunotoxin of 6G7 and ricin A chain was cytotoxic to 6G7(+) leukemia cell lines. mAb 6G7 has potential clinical applications for targeted immunotherapy of both leukemia and lymphoma.
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PMID:Characterization of a new monoclonal antibody 6G7 that recognizes a unique antigen on myeloid and lymphoid cells. 1135 71

Stealth monensin liposomes (SML) were prepared using dipalmitoyl phosphatidylcholine, cholesterol, distearoyl glycerophosphoethanolamine coupled to polyethylene glycol, stearylamine, and N-succinimidyl pyridodithiopropionate linked to stearyl amine, in the molar ratio of 10:5:1.4:1.4:1.5. SML was conjugated to the anti-MY9 antibody by a disulfide linkage to form stealth monensin immunoliposomes (SMIL) by an already established procedure. The encapsulation concentrations of monensin in SML and SMIL were 10(-7) and 4.9x10(-8) M, respectively. More than 20% of monensin remained in circulation after 24 h in BALB/c mice. The ability of SML and SMIL to potentiate the effect of anti-MY9 immunotoxin (anti-MY9-IT) was tested against human leukemia HL-60 sensitive and resistant tumor cells in vitro. SML and SMIL potentiated the activity of anti-MY9-IT by 10-20 times against HL-60 sensitive tumor cell lines. However, greater potentiation of anti-MY9-IT was observed in combination with SML and SMIL against HL-60 resistant tumor cells, found to be 200 and 500 times, respectively. The potentiation of anti-MY9-IT by SMIL was more than two-fold compared with SML against both HL-60 sensitive and resistant tumor cells. Transmission electron microscopy studies conducted with HL-60 resistant cells incubated with anti-MY9-IT and monensin liposomes showed significant dilation of the golgi, which was reversible after re-incubation in fresh medium. Our studies show that SML and SMIL can be successfully used to potentiate the activity of ricin based anti-MY9-IT in vitro, and further in vivo studies will demonstrate the usefulness of this approach.
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PMID:Stealth monensin immunoliposomes as potentiator of immunotoxins in vitro. 1143 19


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