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)

Bone marrow transplantation is an established form of therapy for aplastic anemia and severe combined immunodeficiency. It is also a therapeutic option for acute leukemia in remission. Unfortunately, compatible donors are not available for most patients who could benefit from it. Further refinement of the techniques involved may make it suitable for more patients. Graft rejection, recurrent leukemia, graft-versus-host disease and interstitial pneumonia continue to be the main unsolved complications of bone marrow transplantation, but recent advances have decreased their frequency and severity. Most of the complications of allogeneic bone marrow transplantation may be eliminated with the use of autologous stem cells. For further refinement bone marrow transplantation should continue to be performed in large centres that combine treatment with research.
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PMID:Bone marrow transplantation in Canada. 699 51

ADA deficiency manifests as a severe combined immunodeficiency with profound T-lymphocytopenia. Affected individuals have variable defects of both T- and B-lymphocyte function and greatly increased morbidity and mortality caused by frequent viral and bacterial infection. In 1990 a clinical protocol for the treatment of this disease using retrovirus mediated transfer of the ADA gene into peripheral lymphocytes was begun and in 1993 an amendment permitting gene transfer to CD34+ stem cells isolated from peripheral blood or from umbilical cord blood was approved. Five patients have been treated on this protocol and have been analyzed for the persistence of cells containing the transferred gene and for immunologic reconstitution.
Leukemia 1995 Oct
PMID:Retrovirus mediated gene transfer as therapy for adenosine deaminase (ADA) deficiency. 747 19

Graft-versus-host disease (GVHD) is uniformly lethal in recipients of HLA-mismatched marrow. In patients with severe combined immunodeficiency disease, this major obstacle can be overcome by rigorous T-cell depletion before transplantation. In leukaemia patients, however, the benefit of preventing GVHD is offset by graft rejection or graft failure. Very recently, this problem was overcome by supplementing T cell-depleted bone marrow transplants with megadoses of peripheral blood stem cells collected by leukapheresis after mobilization of the donor stem cells with granulocyte colony-stimulating factor (G-CSF). In the present study, we further demonstrate in a mouse model (C57BL/6-->C3H/Hej) that escalation of bone marrow doses by four- to fivefold leads to full donor-type chimerism in sublethally irradiated (6.5 Gy) recipients. Thus, the new source of G-CSF mobilized human haematopoietic stem cells may enable extending the use of mismatched bone marrow transplants to patients with non-malignant diseases for whom supralethal conditioning is not a prerequisite.
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PMID:Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. 748 7

B-cell precursor (BCP) leukemia is the most common form of childhood cancer and represents one of the most radiation-resistant forms of human malignancy. In this study, we examined the antileukemic efficacy of the B43 (anti-CD19)-pokeweed antiviral protein (B43-PAP) immunotoxin against radiation-resistant BCP leukemia cells. B43-PAP caused apoptosis of radiation-resistant primary BCP leukemia cells, killed greater than 99% of radiation-resistant primary leukemic progenitor cells from BCP leukemia patients, and conferred extended survival to severe combined immunodeficiency (SCID) mice xenografted with radiation-resistant human BCP leukemia. Furthermore, the combination of B43-PAP and total body irradiation (TBI) was more effective than TBI alone in two SCID mouse bone marrow transplantation models of radiation-resistant human BCP leukemia. Thus, B43-PAP may prove useful in the treatment of radiation-resistant BCP leukemia.
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PMID:In vitro and in vivo antileukemic activity of B43-pokeweed antiviral protein against radiation-resistant human B-cell precursor leukemia cells. 749 81

Modest progress has been achieved over the past two decades in the treatment of adult acute lymphocytic leukemia (ALL). With modern therapy, response rates are 70% to 80%, but cure rates only average 25% to 30%. Improved in vivo models are needed to investigate the biology of adult ALL and to test new treatment concepts. Fresh leukemia samples from children with ALL have been successfully transplanted into mice with severe combined immunodeficiency (SCID), but no experience exists for adult ALL. We treated SCID mice with 2 mg cyclophosphamide 24 hours before intravenously injecting 20 x 10(6) viable leukemia cells obtained from 13 patients with newly diagnosed adult ALL within five defined phenotype/karyotype subcategories. Ten (76%) of 13 injected leukemia specimens representing all five categories engrafted. The median survival duration of mice was 20 weeks from the time of leukemia cell injection. The rate of engraftment by ALL subset was as follows: two of two T-cell, two of three t(11q23), two of two hyperdiploid, two of three t(9;22), and two of three diploid ALL. The pattern of organ involvement by leukemia in the mice was similar to that of the human disease. Immunohistochemistry and flow cytometry documented the stability of each leukemic phenotype after passage through SCID mice. Cells transplanted from the spleen and bone marrow of mice engrafted with ALL into recipient mice resulted in consistent engraftment. The survival duration in passage groups was similar to that in groups injected with primary cells. The high frequency of engraftment, availability of frozen original specimens, and successful passages in SCID mice provide an in vivo model of adult ALL suitable for further studies of the disease biology and for design of drug studies for the different subtypes of previously untreated adult ALL.
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PMID:Growth and biologic properties of karyotypically defined subcategories of adult acute lymphocytic leukemia in mice with severe combined immunodeficiency. 749 88

Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P-glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr-1 cells were slightly more sensitive to anti-B4-bR than Namalwa cells; IC37 values were approximately 4 pmol/L and 8 pmol/L, respectively. When anti-B4-bR was combined simultaneously with doxorubicin or etoposide, additive to supra-additive killing of Namalwa and Namalwa/mdr-1 cells was observed. In xenografts of Namalwa/mdr-1 cells in severe combined immunodeficiency (SCID) mice, doxorubicin and etoposide at their maximum tolerated doses (3 mg/kg x 3 or 15 mg/kg x 3) showed no therapeutic effect. However, treatment with 5 daily bolus injections of anti-B4-bR (50 micrograms/kg) followed by treatment with doxorubicin or etoposide significantly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population expressed lower levels of P-glycoprotein, and this decrease may account for the synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with current treatment regimens and further hint at a promising role for this immunotoxin in treatment of disease at the minimal residual disease stage, where cells may be resistant to chemotherapy.
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PMID:Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors. 749 89

Transformation of hematopoietic cells by the p210bcr/abl tyrosine kinase appears to require the expression of a functional MYC protein, suggesting that simultaneous targeting of BCR-ABL and c-myc might be a rational strategy for attempting treatment of Phil-adelphia leukemia. To test this hypothesis, severe combined immunodeficiency mice injected with Philadelphia leukemic cells were treated systemically with equal doses of bcr-abl or c-myc antisense oligodeoxynucleotides (ODNs) or with both ODNs in combination. Compared with the mice treated with individual agents, the disease process was much slower in the group treated with both ODNs, as revealed by flow cytometry, clonogenic assay, and reverse transcriptase-polymerase chain reaction analysis to detect leukemic cells in mouse tissue cell suspensions, and by enumeration of liver metastases. The retardation of the disease process was positively correlated with a markedly increased survival of leukemic mice treated with both ODNs. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Leukemia treatment in severe combined immunodeficiency mice by antisense oligodeoxynucleotides targeting cooperating oncogenes. 750 9

The study of central nervous system (CNS) leukemia has been hampered by the lack of a suitable animal model. We report that severe combined immunodeficiency (SCID) mice invariably develop rapidly progressive fatal CNS leukemia within 3 weeks after intravenous injection of NALM-6 pre-B acute lymphoblastic leukemia (ALL) cells. Colonization of the dura mater and subarachnoid space, usually of the distal spinal cord with occasional extension into the Virchow-Robin spaces of blood vessels subjacent to the meninges, followed involvement of bone marrow in the skull, vertebrae, and, occasionally, the appendicular skeleton. Occult CNS leukemia was detectable by polymerase chain reaction amplification of human DNA as early as 8 days postinoculation of leukemia cells. We used this in vivo model of human CNS leukemia to examine the therapeutic efficacy and toxicity of intrathecally administered B43 (anti-CD19)-pokeweed antiviral protein (PAP), an anti-B-lineage ALL immunotoxin directed against the pan-B-cell antigen CD19/Bp95. Intrathecal therapy with B43 (anti-CD19)-PAP immunotoxin at nontoxic dose levels significantly improved survival of SCID mice and was superior to intrathecal methotrexate therapy.
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PMID:Biotherapy for xenografted human central nervous system leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin. 753 20

Throughout the 1970s, graft-versus-host disease (GVHD) was uniformly lethal in recipients of HLA-mismatched bone marrow. This major obstacle was overcome in 1980 by the introduction of rigorous T-cell depletion prior to transplantation into patients with severe combined immunodeficiency. However, in leukemia patients, the benefit of preventing GVHD was offset by graft rejection or graft failure. In this article, Yair Reisner and Massimo Martelli discuss how this problem may be overcome by intensification of the conditioning protocol in conjunction with a major increase in the dose of transplanted stem cells.
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PMID:Bone marrow transplantation across HLA barriers by increasing the number of transplanted cells. 754 8

Human mixed lineage leukemia cell line RS4;11 with the t(4;11)(q21;q23) translocation causes disseminated and invariably fatal leukemia in mice with severe combined immunodeficiency. Whereas an immunotoxin constructed from the murine anti-CD19(B43) monoclonal antibody and the plant toxin pokeweed antiviral protein (B43-PAP) has a potent in vitro anti-leukemic effect against clonogenic RS4;11 cells, its activity is further potentiated by the active cyclophosphamide congener mafosfamid. These intriguing observations prompted us to evaluate the in vivo antileukemic efficacy of combined immunochemotherapy employing B43-PAP immunotoxin plus cyclophosphamide against human t(4;11) leukemia cells in an RS4;11 severe combined immunodeficiency (SCID) mouse model system. Intravenous injections of B43-PAP or cyclophosphamide improved survival of SCID mice challenged with RS4;11 leukemia, as reflected by markedly prolonged median survival times. After intravenous inoculation of 5 x 10(7) RS4;11 leukemia cells, the median survival times were 41 days for saline-treated control mice (n = 12), 44 days for control mice treated with unconjugated B43 monoclonal antibody and PAP (n = 12), 56 days for mice treated with the control immunotoxin G17.2 (anti-CD4)-PAP (n = 6), 79 days for B43-PAP-treated test mice (n = 12), and 80 days for cyclophosphamide-treated test mice (n = 16). Notably, combined immunochemotherapy using B43-PAP plus cyclophosphamide was significantly more effective than either B43-PAP or cyclophosphamide alone. The median survival time for a total of 22 SCID mice undergoing combined immunochemotherapy with B43-PAP followed by cyclophosphamide (n = 12) or cyclophosphamide followed B43-PAP (n = 10) was > 150 days. The Kaplan-Meier estimates and standard errors of the probability of event-free survival at 5 months after inoculation of 5 x 10(7) RS4;11 cells were 21 +/- 13% for B43-PAP-treated mice, 7 +/- 6% for cyclophosphamide-treated mice, 90 +/- 10% for mice treated with B43-PAP followed by cyclophosphamide (n = 12), and 90 +/- 10% for mice treated with cyclophosphamide followed by B43-PAP (n = 10). Our results lead us to recommend that initial consideration be given to combined immunochemotherapy protocols using B43-PAP immunotoxin plus cyclophosphamide for treatment of refractory or relapsed t(4;11) leukemias.
Leukemia 1993 Feb
PMID:Effective immunochemotherapy of human t(4;11) leukemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide. 767 81


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