Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allogeneic bone marrow transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion (DLI) following BMT. Thus, eradication of blood cancer cells, especially in patients with CML can be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft versus leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. The latter working hypothesis suggested that effective BMT procedures may be accomplished without lethal conditioning of the host, using new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that safe non-myeloablative stem cell transplantation (NST), with no major toxicity can replace the conventional BMT. Thus, NST may provide an option for cure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality.
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PMID:Non-myeloablative allogeneic stem cell transplantation focusing on immunotherapy of life-threatening malignant and non-malignant diseases. 1141 99

Allogeneic bone marrow or blood stem call transplantation (BMT) represents an important therapeutic tool for the treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow and mobilized blood stem cell transplantations were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartments, and therefore highly toxic myeloablative regimens were considered to be mandatory for the effective eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies have indicated that much more effective eradication of the host immunohematopoietic system cells can be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and, less frequently, in patients with other hematologic malignancies, can frequently be accomplished despite the complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience has suggested that graft-vs.-leukemia (GVL) effects might be a useful tool for the eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases, it appears that the induction of host-vs.-graft tolerance as an initial step may allow the durable engraftment of donor immunocompetent lymphocytes, which may be used for the induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, including malignant, genetically abnormal or self-reactive cells. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using safer conditioning as part of the transplant procedure, with the goal being to induce host-vs.-graft tolerance to enable subsequent induction of GVL, possibly graft-vs.-tumor or even graft-vs.-autoimmunity effects, rather than attempting to eliminate host cells with hazardous myeloablative chemoradiotherapy. This hypothesis suggested that effective BMT procedures could be accomplished without lethal conditioning of the host, using new well-tolerated non-myeloablative regimens, thus possibly minimizing immediate and late side-effects related to the myeloablative procedures until recently considered to be mandatory for the conditioning of BMT recipients. Recent clinical data presented in this review suggest that effective BMT procedures may be accomplished with well-tolerated non-myeloablative stem cell transplantation (NST) regimens, with no major toxicity. Thus, new NST approaches may offer the feasibility of safer BMT procedures for a large spectrum of clinical indications in children and elderly individuals, without lower or upper age limits, while minimizing procedure-related toxicity and mortality. Taken together, our data suggest that high-dose chemotherapy and radiation therapy may be successfully replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT.
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PMID:Non-myeloablative stem cell transplantation and donor lymphocyte infusion for the treatment of cancer and life-threatening non-malignant disorders. 1148 52

Allogeneic bone marrow transplantation (BMT) or blood stem cell transplantation represents an important therapeutic tool for the treatment of otherwise incurable malignant and nonmalignant diseases. Until recently. autologous and allogeneic BMT or mobilized blood stem cell transplantation was used primarily to replace a malignant, genetically abnormal, or deficient immunohematopoietic compartment, and therefore highly toxic myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies have indicated that more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus eradication of blood cancer cells, especially in patients with chronic myelogenous leukemia and less frequently in patients with other hematologic malignancies, can frequently be achieved despite complete resistance of such tumor cells to the maximum tolerated doses of chemoradiotherapy. Our cumulative experience suggests that graft vs leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases, it appears that induction of host vs graft tolerance as the first step may allow durable engraftment of immunocompetent donor lymphocytes, which may be used for induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, whether they are malignant, genetically abnormal, or self-reactive. Based on this rationale, we speculate that the therapeutic benefit of BMT may be increased by using safer conditioning as part of the transplantation procedure, with the goal of inducing host vs graft tolerance to enable subsequent induction of GVL, possibly graft vs tumor, or even graft vs autoimmunity effects, rather than attempting to eliminate host cells with hazardous myeloablative chemoradiotherapy. Our hypothesis suggests that effective BMT procedures might be accomplished without lethal conditioning of the host, using new, well-tolerated nonmyeloablative regimens, possibly minimizing immediate and late side effects related to myeloablative procedures. Recent clinical data suggest that effective BMT procedures may be accomplished with nonmyeloablative stem cell transplantation (NST) regimens, with no major toxicity. Thus new NST approaches may make BMT procedures safer for a spectrum of clinical indications in children and elderly individuals without lower or upper age limits, while minimizing procedure-related toxicity and mortality. Our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by more effective alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures with safer and more effective treatment of patients requiring BMT.
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PMID:Nonmyeloablative stem cell transplantation for the treatment of cancer and life-threatening nonmalignant disorders: past accomplishments and future goals. 1158 73

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and nonmalignant diseases, especially acute and chronic leukemias. Until recently, myeloablative regimens were considered mandatory for effective eradication of all malignant cells of host origin. Our preclinical and ongoing clinical studies indicated that eradication of host immunohematopoietic cells, including chemoradiotherapy-resistant leukemia, could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following induction of host-versus-graft transplantation tolerance mediated by engraftment of donor stem cells in the course of BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-leukemia (GVL) effects might be a useful tool for both treatment and prevention of relapse. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host-versus-graft tolerance to enable subsequent induction of GVL effects rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using a new well-tolerated nonmyeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical observations suggest that effective treatment of leukemia may be accomplished with a well-tolerated nonmyeloablative stem cell transplantation (NST) regimen, while avoiding immediate and late toxicity and minimizing procedure-related mortality. Taken together, our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by a more effective biological tool-alloreactive donor lymphocytes-thus setting the stage for innovative immunotherapeutic procedures for more selective and effective treatment of patients in need of BMT, including those resistant to conventional chemoradiotherapy.
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PMID:Treatment of leukemia by alloreactive lymphocytes and nonmyeloablative stem cell transplantation. 1199 94

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow or mobilized blood stem cells transplantation were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimen were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus, eradication of blood cancer cells, especially in patients with CML and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft versus leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases it appears that induction of host versus graft tolerance as step one, may allow durable engraftment of donor immunocompetent lymphocytes, which may be used for induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, malignant, genetically abnormal or self-reactive alike. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host versus graft tolerance to enable subsequent induction of GVL, possibly graft versus tumor or even graft versus autoimmunity effects, rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that effective BMT procedures may be accomplished with well-tolerated non-myeloablative stem cell transplantation (NST) regimen, with no major toxicity. Thus, new NST approaches may offer the feasibility of safer BMT procedure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality. Taken together, our cumulative data suggest that high dose chemotherapy and radiation therapy may be successively replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT.
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PMID:Non-myeloablative stem cell transplantation for the treatment of cancer and life-threatening non-malignant disorders; past accomplishments and future goals. 1235 51

The Leukemia & Lymphoma Society develops and distributes both detailed and easy-to-read booklets intended to help patients and caregivers communicate with healthcare providers about their treatment and support needs. The easy-to-read booklets initially were developed for newly diagnosed patients; however, the society has learned that all patients with cancer are likely to benefit from the information at some point in their journeys. To date, the society has developed easy-to-read booklets about acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, lymphomas, myeloma, and coping with blood cancer. All booklets are free to patients, healthcare providers, and the general public, and most titles are available in Spanish-language versions. They can be ordered through the society's Information Resource Center (800-955-4572, infocenter@lls.org, or www.lls.org) or its 68 chapters. This article focuses on the development of the booklet Myeloma: A Guide for Patients and Caregivers and includes a handout based on its content.
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PMID:Easy to write? Creating easy-to-read patient education materials. 1772 63

Cancer stem cells (CSCs) are believed to be the initiating cells for many types of blood cancer and some solid tumors, and curative therapies of these cancers require eradicating CSCs. Specific targeting of CSCs but not normal stem cell counterparts is a correct strategy for developing new anti-cancer therapies, and the success of this approach relies on identification of specific target genes in CSCs. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a cancer model, we recently identified arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in CML. Without Alox5, BCR-ABL fails to induce CML in mice due to the impairments of the functions of LSCs. The lack of Alox5 does not significantly affect the functions of normal hematopoietic stem cells. In addition, Zileuton, a specific 5-LO inhibitor, also causes the impairments of the functions of LSCs in a similar manner. Our results prove the principle that CSC-specific genes that play key roles in cancer development can be identified and inhibition of these genes can lead to eradication of these cells for cure. Here, we further discuss the mechanisms of Alox5 in CML, and the use of Zileuton as a potential and promising drug in eradicating LSCs in CML and other myeloproliferative diseases. We believe that our discovery of the role of Alox5 in regulating the function of LSCs in CML reminds us of viewing CSCs at a different angel. We predict that CSCs in other types of cancer also utilize specific regulatory pathways to control their survival and self-renewal, and inhibition of these pathways profoundly suppresses CSCs but not their normal stem cell counterparts. Specific targeting of CSCs without causing significant harm to normal stem cells should be a correct direction to go in developing novel therapeutic strategies in the future.
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PMID:The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia. 1982 23

Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia, offering a possible explanation for the efficacy of HU against this malignancy.
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PMID:The in vivo toxicity of hydroxyurea depends on its direct target catalase. 2045 79

We investigated associations between metabolic factors and blood cancer subtypes. Data on body mass index (BMI), blood pressure, blood glucose, total cholesterol, and triglycerides from seven prospective cohorts were pooled (n = 578,700; mean age = 44 years). Relative risks of blood cancers were calculated from Cox regression models. During mean follow-up of 12 years, 2,751 incident and 1,070 fatal cases of blood cancers occurred. Overall, higher BMI was associated with an increased blood cancer risk. In gender-specific subgroup analyses, BMI was positively associated with blood cancer risk (p = 0.002), lymphoid neoplasms (p = 0.01), and Hodgkin's lymphoma (p = 0.02) in women. Further associations with BMI were found for high-grade B-cell lymphoma (p = 0.02) and chronic lymphatic leukemia in men (p = 0.05) and women (p = 0.01). Higher cholesterol levels were inversely associated with myeloid neoplasms in women (p = 0.01), particularly acute myeloid leukemia (p = 0.003), and glucose was positively associated with chronic myeloid leukemia in women (p = 0.03). In men, glucose was positively associated with risk of high-grade B-cell lymphoma and multiple myeloma, while cholesterol was inversely associated with low-grade B-cell lymphoma. The metabolic syndrome score was related to 48 % increased risk of Hodgkin's lymphoma among women. BMI showed up as the most consistent risk factor, particularly in women. A clear pattern was not found for other metabolic factors.
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PMID:Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can). 2258 28

In the development of anti-blood cancer drugs, the chronic myelocytic leukemia (KU812), acute myelocytic leukemia (KG-1) and lymphoma (U937) cell lines are commonly used in preclinical pharmacology studies as human cancer xenograft models in mice. In the present study, mRNA expression levels of typical human ATP-binding cassette (ABC) transporters in these human blood cancer cell lines were analyzed by real-time polymerase chain reaction (RT-PCR). Based on the results, the expression level of multidrug resistance-associated protein 4 (MRP4) was found to be extremely high in KU812 cells compared with those of other transporters. Additionally, MRP4 expression levels were found to be relatively high in U937, KG-1 and a blood cell line derived from a healthy subject (RPMI 1788). In addition, to elucidate the contribution of MRP4 to the methotrexate (MTX) distribution in normal blood cells and tissues, [(3)H]MTX was intravenously (i.v.) administered to two groups of rats. Animals in one group received [(3)H]MTX only; the other group was concomitantly administered i.v. MK-571, a typical inhibitor of MRP transporters. No marked difference was observed between the two groups; the Kp values (tissue concentration/plasma concentration) of the concomitant group showed slightly higher values compared with those of the MTX alone group in erythrocytes (1.4 times, P<0.001), spleen (1.3 times, P<0.05) and thymus (1.2 times, P<0.05), respectively. Although in the present study we could not evaluate the direct involvement of MRP4 in blood cancer cells in which MRP4 expression was excessively high, these results suggest a possible functional role of MRP4 in blood cancer cells and albeit only slightly in normal blood cells/tissues.
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PMID:Expression levels of multidrug resistance-associated protein 4 (MRP4) in human leukemia and lymphoma cell lines, and the inhibitory effects of the MRP-specific inhibitor MK-571 on methotrexate distribution in rats. 2318 Nov 30


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