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)

Monoclonal antibodies, specific for antigens expressed on lymphoid malignancies, which have been conjugated to toxins such as ricin, hold promise in the therapy of childhood leukemia and lymphoma. Anti-B4-blocked ricin (anti-B4-bR) is such an agent, and a phase I study of this agent was conducted in children with relapsed or refractory B-lineage leukemia and lymphoma. Anti-B4-bR was given as two 7-day continuous infusions separated by 7 days. Twenty patients were enrolled and 19 received the drug. Two dosage levels (30 and 40 microg/kg per day) were evaluated. Forty micrograms per kilogram per day was the maximally tolerated dose. Dose-limiting toxicity was capillary leak syndrome. Grade 3 reversible elevation in transaminases was also encountered. Human antimouse antibodies or human antiricin antibodies were detected in five patients. No complete remissions or partial remissions were seen.
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PMID:Phase I trial of anti-B4-blocked ricin in pediatric patients with leukemia and lymphoma. 1175 74

Multidrug resistance (MDR) can be mediated, in part, by overexpression of P-glycoprotein (P-gp) and is characterized by broad resistance to several structurally, chemically, and pharmacologically distinct chemotherapeutic compounds. It has been hypothesized that immunological approaches to cytolysis may be used to overcome drug resistance. RV+ is a P-gp-expressing variant of the human myeloid leukemic cell line HL60 that displays a typical MDR phenotype. MDR RV+ cells displayed relative resistance to the immunotoxin (IT) HuM195-gelonin and to free rGelonin. K562 leukemia cells retrovirally infected to overexpress P-gp are also resistant to HuM195-gelonin. In addition, a monoclonal antibody capable of inhibiting the function of P-gp was able to partially reverse resistance to the IT. These data indicated that the expression of P-gp may contribute to IT resistance in RV+. Resistance to the IT was not mediated through decreased binding to cells, nor reduced internalization into the cell because the IT displayed similar kinetics of binding and internalization for both the parental HL60 and MDR RV+ cell lines. Comparison of the cytotoxicity of other ribosome-inactivating toxins indicated that RV+ cells were not universally resistant to toxins: RV+ cells were sensitive to the actions of ricin A chain, which acts on precisely the same RNase target as gelonin. Sensitivity of the MDR RV+ cells to the protein synthesis inhibitor cycloheximide, saponin, and Pseudomonas exotoxin A additionally confirmed that the resistance was not mediated through the ribosome and that pathways downstream from the inactivation of protein synthesis leading to cell death were not substantially perturbed in the MDR cells. Resistance could be partially abrogated by bafilomycin A, which inhibits lysosomal function. Moreover, direct visualization by confocal microscopy of the intracellular trafficking route of the IT showed that the IT accumulated preferentially in the lysosome in MDR RV+ cells but not in sensitive cells. These observations implicated the process of increased lysosomal degradation as the most likely basis for resistance. Such pathways of resistance may be important in the therapeutic applications of ITs, now becoming available for human use.
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PMID:Immunotoxin resistance in multidrug resistant cells. 1251 80

The anti-CD19 (HD37-dgRTA) and anti-CD22 (RFB4-dgRTA) immunotoxins (ITs) are murine IgG(1) monoclonal antibodies (Mabs) conjugated to a deglycosylated ricin A chain (dgRTA). They are effective in killing B-lineage non-Hodgkin's lymphoma (NHL) cells in vitro, in vivo and in adult patients with B-lineage NHL. The potential of these agents for the treatment of childhood B-precursor acute lymphoblastic leukemia (ALL) is unknown. The anti-CD19 and anti-CD22 ITs should have anti-tumor activity against childhood B-lineage ALL since both target antigens are expressed on the surface of these cells. We have previously shown that, in vitro these two ITs selectively kill leukemia cells obtained from children with leukemia. To evaluate the efficacy of our ITs in an in vivo model we injected the human pre-B ALL cell line, NALM-6-UM1, into severe combined immunodeficient (SCID) mice. We tested the ability of two ITs to prolong survival or cure mice of both early and advanced tumors. In early disease, treatment with HD37-dgRTA, RFB4-dgRTA, or Combotox (an equimolar concentration of the two ITs) significantly improved their survival. In advanced disease, treatment with RFB4-dgRTA or Combotox significantly improved survival. Overall there were 10 long-term survivors who were cured, as determined by survival beyond 150 days with no evidence of disease as determined by polymerase chain reaction (PCR) analysis.
Leukemia 2003 Feb
PMID:Treatment of SCID/human B cell precursor ALL with anti-CD19 and anti-CD22 immunotoxins. 1259 32

The cytolytic activity of human plasma free platelets treated with various stimulators (Ca-ionophore, PAF (platelet activating factor), PHA, and ricin) has been studied on human erythroid leukemia cell line (K562). The 14 kDa and 28 kDa platelet cytotoxic factors (PCF) have been purified from the supernatant obtained from platelets stimulated by 10(-7) M Ca-ionophore. The PCF-14 N-terminal sequence ((1)YAPQXQFGP(9)-) appeared to be homologous to the region 241-249 residues of the human C1s complement component. The PCF-28 N-terminal sequence (DVGLT-) did not display any homology to known human proteins. The PCF-14 and the PCF-28 have been detected both in the supernatants of platelets treated with various stimulators (10(-7) M Ca-ionophore A23187, or 10(-8) M PAF, or 10(-9) M PHA, or 10(-13) M ricin) and in the extracts of disrupted platelets treated by these stimulators. All of these stimulators enhanced the production of thromboxane A(2) by platelets, as evidenced from the accumulation of thromboxane B(2), a spontaneous hydrolysis product of thromboxane A(2). These results indicate that platelet cytotoxicity to the K562 cells and the release of PCF-14 and PCF-28 might be mediated by the stimulation of thromboxane A(2) synthesis, when platelets have been activated through the cycloxygenase pathway.
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PMID:Stimulation of Human Platelet Cytotoxicity by Various Activators in the Absence of Antibodies: Release of Thromboxane A2 and Soluble Cytotoxic Factors. Purification and Partial Characterisation of 14 and 28 kDa Cytotoxic Proteins. 1268 2

We have previously reported the identification of a unique thymocyte-specific surface molecule, JL1, which was detected using the monoclonal antibody (mAb), anti-JL1. Interestingly, JL1 was shown to be expressed in most leukemias, irrespective of their immunophenotype, and subpopulations of normal bone marrow (BM) mononuclear cells (MNCs). Here we investigated the potential usefulness of the anti-JL1 mAb as a therapeutic tool for leukemia. We demonstrated that the proliferation of cultured human leukemia cells was dramatically inhibited in vitro by anti-JL1 mAb conjugated with the polypeptide toxin, gelonin, but not by gelonin alone. We then systematically investigated the reactivity of the anti-JL1 mAb against normal human tissues to evaluate possible side effects along with various hematopoietic and nonhematopoietic tumor cell lines. All of 33 types of normal tissues except thymus and subpopulation of BM MNCs were clearly devoid of JL1 expression. Among tumor cell lines, all the nonhematopoietic cell lines tested were negative for JL1 expression, while some hematopoietic cell lines contained JL1 antigen. Collectively, the results showed the cytotoxic effects of anti-JL1-based immunotoxin against JL1-positive leukemic cells, sparing most normal tissues other than thymocytes and some BM MNCs. Therefore, we strongly suggest that gelonin-conjugated anti-JL1 mAb immunotoxin could be developed as a potential immunotherapeutic agent in the treatment of various types of JL1-positive acute leukemias.
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PMID:Targeted cytotoxic effect of anti-JL1 immunotoxin against a human leukemic cell line and its clinical implications. 1276 27

Many types of leukemia including multiple myeloma remain essentially incurable despite recent developments in immuno- and chemotherapy. The effectiveness of these therapies might be greatly enhanced by targeting cell surface proteins unique to the malignant clone, which for leukemias of the B cell lineage means clonotypic surface immunoglobulin (sIg). As this immunoglobulin (Ig) is necessarily epitope specific, we are developing ligand-toxin conjugates (LTCs) as a strategy for delivering toxins and other drugs to clonotypic tumor cells. Here we report in vitro studies that illustrate the effectiveness of this approach. LTC comprising the DNP hapten conjugated to ricin A toxin (DNP-RTA) were shown to specifically and effectively kill anti-DNP secreting murine hybridoma (U7.6) cells but not other hybridoma cells (1B12), a murine erythroleukemia cell line (Friend's Leukemia or) normal mouse spleen cells. In addition to direct toxicity, LTC treatment negatively affected the growth characteristics of the few surviving cells as reflected in decreased growth index and an increase in growth inhibition over 72 h post treatment. Interestingly, U7.6 cells that survived one or two LD90 dose(s) of LTC showed no alteration in their dose response to a subsequent attack of LTC indicating that this treatment strategy may not induce drug resistance. These data suggest that LTC therapy may be a new and effective strategy for specific destruction of tumor cells such as myeloma plasma cells and could be extended to other tumors where clonotypic receptors can be identified.
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PMID:Specific destruction of hybridoma cells by antigen-toxin conjugates demonstrate an efficient strategy for targeted drug therapy in leukemias of the B cell lineage. 1276 46

Immunotoxins are presently being evaluated as novel agents for cancer therapy. The direct mechanism by which immunotoxins kill cancer cells is inhibition of protein synthesis, but cytotoxicity due to induction of apoptosis has also been observed with these agents. Some cancers that express high levels of BCL-2 are relatively resistant to apoptosis inducing agents. It is therefore important to determine to what degree the toxicity of ricin, diphtheria toxin, Pseudomonas exotoxin and Pseudomonas exotoxin derived immunotoxins towards cancer cells can be attributed to inhibition of protein synthesis, and to what degree to subsequent induction of apoptosis. We compared the sensitivity of MCF-7 breast cancer cells that were stably transfected with a BCL-2 expression plasmid and thus protected against apoptosis and of MCF-7 cells transfected with a control plasmid towards ricin, diphtheria and Pseudomonas toxin, a Pseudomonas toxin-derived immunotoxin (LMB-7) and tumour necrosis factor alpha (TNF). We found that BCL-2 mediated inhibition of apoptosis renders the cells almost completely resistant (1000-fold) to tumour necrosis factor, but the same cells were only 3-10 fold more resistant to cytotoxicity induced by immunotoxin LMB-7 as well as Pseudomonas exotoxin, diphtheria toxin and ricin. We next studied several leukaemia cell lines with variable levels of BCL-2 expression and found them quite sensitive to a Pseudomonas exotoxin containing immunotoxin independent of the level of BCL-2. Our data indicate that although BCL-2 overexpression can have a modest effect on sensitivity to an immunotoxin, cell lines derived from patients are still very sensitive to immunotoxins.
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PMID:Effects of BCL-2 overexpression on the sensitivity of MCF-7 breast cancer cells to ricin, diphtheria and Pseudomonas toxin and immunotoxins. 1464 54

A major obstacle in the successful delivery of antibody-based therapeutics to tumor cells is the heterogeneity of target antigen expression. We reported previously that retinoic acid (RA) is a potent and selective inducer of the cell-surface antigen CD38 in myeloid leukemia cells. The purpose of this study was to determine whether the RA-induced CD38 antigen could be a target for an anti-CD38-based immunotoxin to induce selective killing of leukemia cells. The combination of RA and the anti-CD38 gelonin immunotoxin induced a synergistic killing of leukemia cells. Thus, coculture of myeloid leukemia cells and cell lines with as little as 1 nM RA in the presence of immunotoxin induced substantial killing (>90%) of leukemia cell clones. More importantly, the blasts of myeloid leukemia patients, irrespective of their morphological and phenotypic features, also responded to the RA and immunotoxin combination when cultured ex vivo. A similar synergistic effect between RA and immunotoxin was observed against a multidrug-resistant variant subline of HL-60 cells. However, another variant of HL-60 cells, HL-60R, in which the retinoid receptor function has been abrogated by a trans-dominant-negative mutation, exhibited complete resistance to the immunotoxin-induced killing effect in the presence or absence of RA. Our results suggest that RA combined with anti-CD38-based therapeutic agent may offer exciting opportunities for the treatment of myeloid leukemias despite their multiplicity of genetic and clinical varieties.
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PMID:Retinoic acid-induced CD38 antigen as a target for immunotoxin-mediated killing of leukemia cells. 1502 55

We recently published the construction and evaluation of a beta-catenin-dependent, highly active promoter, CTP1, and its possible application for the treatment of colorectal cancer using gene-directed enzyme prodrug therapy with adenoviral (Ad) vectors. Alternative Ad-based approaches such as tumor-specific, replication-competent vectors and/or exploiting therapeutic gene products with intrinsic toxic activity, such as gibbon ape leukemia virus fusogenic membrane glycoprotein, diphtheria toxin A (DTA), and ricin, would demand a very tightly regulated promoter to avoid breakthrough replication and toxicity in nontumor tissue and Ad producer cell lines. In this study we optimized the activity/specificity profile of the synthetic beta-catenin-dependent promoter by varying its basal promoter, the number of Tcf binding sites, and the distance between these and the basal promoter. The optimal promoter, CTP4, showed virtually undetectable expression in cells with normal beta-catenin regulation but high level expression in cells deregulated for beta-catenin. Using CTP4 we were able to generate, for the first time to our knowledge, an Ad vector expressing fully active wild-type DTA without the need for time-consuming and cumbersome production systems. CTP4 should be the promoter of choice for Ad-based gene therapies of tumors deregulated for beta-catenin. We provide preliminary evidence that these may include prostate and ovarian as well as colorectal cancer.
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PMID:Optimization of a synthetic beta-catenin-dependent promoter for tumor-specific cancer gene therapy. 1523 50

Immunotoxins composed of cell-selective ligands covalently linked to peptide toxins have been developed for the treatment of chemotherapy relapsed or refractory malignancies including chronic lymphocytic leukemia (CLL). A number of CLL immunotoxins have been clinically tested including T101-ricin A, H65-ricin A, DAB(486)IL2, DAB(389)IL2, RFB4 (dsFv)-PE38 and anti-Tac(Fv)-PE38. Remissions have occurred in some patients without significant myelosuppression, but novel agents continue to be needed. Kay and co-workers in this issue of Leukemia Research have targeted interleukin-4 receptors (IL4R) on CLL B cells with a recombinant IL4 pseudomonas exotoxin fusion protein (IL-4(38--37)-PE38KDEL). A fraction of patients (19%) had CLL cells that were extremely sensitive to the immunotoxin. This novel agent may provide an important new therapeutic for use in the treatment of CLL.
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PMID:CLL immunotoxins. 1603 23


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