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)

The cytogenetic responses during the first chronic phase of 11 patients with chronic myeloid leukaemia (CML) treated with all-trans retinoic acid (ATRA) + interferon (IFN) were compared with those of 9 other CML patients treated with IFN alone. Metaphase and interphase cytogenetics and a semi-quantitative polymerase chain reaction were used to evaluate the cytogenetic responses. Two of the 11 patients in the ATRA + IFN group were withdrawn, one of them because of IFN intolerance, and the other because of non-compliance. Of the 9 remaining ATRA + IFN-treated patients 6 exhibited major cytogenetic responses, 3 of which were complete. Of the 9 patients treated with IFN alone, only 2 showed major cytogenetic responses. No severe adverse effects were observed. The preliminary results suggest that the ATRA + IFN combination may be superior in achieving cytogenetic remission in the first chronic phase of CML.
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PMID:Effect of retinoic acid treatment on cytogenetic remission of chronic myeloid leukaemia. 1262 92

Modulation of the signaling pathways that are aberrant in cancer cells has the potential to provide an effective nontoxic approach to patient management in a broad range of cancers. This quest has taken a major leap forward with the demonstration that STI-571 (imatinib mesylate) induces clinical and molecular remissions in the majority of patients with interferon-refractory chronic myelogenous leukemia and gastrointestinal stromal tumors through inhibition of the Bcr/Abl fusion protein required for the initiation and progression of chronic myelogenous leukemia and inhibition of a mutant, activated c-kit present in gastrointestinal stromal tumors. Support for the concept of targeting products of fusion genes found in specific cancers was first provided by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia where the RARalpha all-trans retinoic acid target is the target of multiple different chromosomal rearrangements. In breast cancer, trastuzumab, which alters the function of the HER2 proto-oncogene overexpressed in a portion of breast cancers, provides an additional example of targeting specific molecular aberrations present in cancer cells. Although the target for these signal transduction modulators is functional in normal cells, acceptable therapeutic indices sufficient to prevent tumor growth without unacceptable toxicities have been observed. Whether STI-571 and other signal transduction modulators also target the stroma, and specifically the neovasculature, in addition to the tumor remains an open question. The presence of the target in the cancer cells or in the surrounding stroma appears to be required but not sufficient for the action of molecular therapeutics. Thus, linking molecular diagnostics to identify patients where the target is amplified or activated and driving the pathophysiology of the patients' tumor to effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for breast cancer patients. This review will focus on the phosphatidylinositol 3-kinase pathway and novel molecules targeting this pathway to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast cancer.
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PMID:Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer. 1461 30

Over the past several decades, improvements in chemotherapeutic agents and supportive care have resulted in significant progress in treating patients with acute myeloid leukemia (AML). More recently, advances in understanding the biology of AML have resulted in the identification of new therapeutic targets. The success of all-trans-retinoic acid in acute promyelocytic leukemia and of imatinib mesylate in chronic myeloid leukemia have demonstrated that targeted therapy may be more effective and less toxic when well defined targets are available. At the same time, understanding mechanisms of drug resistance and means to overcome them has led to modification of some of the existing cytotoxic agents. Rational design and conduct of clinical trials is necessary to ensure that the full potential of these new agents is realized.
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PMID:New agents in acute myeloid leukemia and other myeloid disorders. 1474 59

The aims of this study were to evaluate the safety and efficacy of all-trans retinoic acid (ATRA) in the treatment of the accelerated and blastic phase of chronic myeloid leukemia (CML) and to evaluate in vitro correlates of biological activity. ATRA was administered in an intermittent schedule to patients with CML in the accelerated or blastic phases for a 6 week induction period, which was continued if there was evidence of clinical response or stable disease. If the patient was progressing at 6 weeks, interferon-alpha could be added to the ATRA. Laboratory correlative studies were performed prior to treatment and at intervals during treatment to evaluate effects on maturation and differentiation, and on CML progenitor cell growth by assessment of colony-forming cells (CFC). Eighteen patients were enrolled. There was 1 complete response, 1 partial response and 2 with hematological improvement. A fifth patient was stable on ATRA and interferon for several months. Laboratory data for the responders demonstrated high sensitivity of primary CFC to ATRA prior to treatment and low serial CFC counts on ATRA therapy. ATRA demonstrated clinical and hematological activity in 5 of 18 patients with the accelerated phase of CML, and there was evidence of a biological effect in laboratory studies of 3 of the 5 patients' progenitor cells. Combination therapy with other differentiating agents may be useful in this disease.
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PMID:Phase II study of all-trans retinoic acid in the accelerated phase or early blastic phase of chronic myeloid leukemia: a study of the Eastern Cooperative Oncology Group (E1993). 1562 27

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.
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PMID:[Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial]. 1574 26

The translocation (15;17) is a typical marker of acute promyelocytic leukemia, whereas t(9;22) is predominantly associated with chronic myelogenous leukemia, and seldom with acute myelogenous leukemia. Furthermore, the association between t(15;17) and t(9;22) in the same cell is extremely rare. We present a case of therapy-related acute promyelocytic leukemia (t-APL) with a subclone accompanied by karyotype 46, XX, t(9; 22)(q34;q11), t(15 ;17)(q22;11 to approximately 12) at onset. A 75-year-old woman was diagnosed as having non-Hodgkin lymphoma of the thyroid gland in July 1997. She was treated with a CHOP-like regimen, but complete remission (CR) was not achieved. She then underwent surgical resection of her thyroid gland, and was treated with etoposide (total dose 16775 mg) from February 1998 to May 2000. In June 2000, having developed t-APL, she was referred to our department. The patient attained CR following treatment with chemotherapy containing all-trans retinoic acid. Ten months later she relapsed, but lost the t(9;22), while maintaining the t(15;17).
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PMID:[Therapy-related acute promyelocytic leukemia with a t(9;22)(q34;q11) and t(15;17)(q22;q11 to approximately 12) subclone]. 1644 Aug 7

The induction of differentiation represents a new and promising approach to cancer therapy, well illustrated by the treatment of acute promyelocytic leukemia (APL) with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid (ATRA). Using combinations of low, nontoxic concentrations of either 1,25-(OH)2D3 or ATRA and differentiation-enhancing chemicals, adverse effects such as hypercalcemic effects have been ameliorated, and long-term survival has been improved. Indirubin has been demonstrated to exert anti-leukemic effects in cases of chronic myelocytic leukemia. Previously, we synthesized a series of indirubin derivatives and evaluated their anti-proliferative properties against cancer cells. In this study, we determined the enhancing activities of these derivatives on 1,25-(OH)2D3- and ATRA-induced differentiation of human promyelocytic leukemia HL-60 cells. Importantly, some of these derivatives were found to synergistically enhance the differentiation of HL-60 cells in a concentration-dependent manner when coupled with low doses of either 1,25-(OH)2D3 or ATRA. The ability of indirubin derivatives to enhance the differentiation potential of 1,25-(OH)2D3 or ATRA may improve the ultimate outcomes of APL therapy.
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PMID:Enhancing effect of indirubin derivatives on 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced differentiation of HL-60 leukemia cells. 1676

During the past years targeted therapies have gained a major role in the treatment of cancer patients, including those with hematological malignancies. Extramedullary involvement is a rare manifestation of acute and chronic leukemias and of multiple myeloma. Nevertheless, with the expanding use of targeted treatments there is an impression that the incidence of extramedullary relapses is increasing. We reviewed the reports on this phenomenon in patients treated with all-trans-retinoic acid and arsenic trioxide for acute promyelocytic leukemia, thalidomide and bortezomib for multiple myeloma and imatinib for chronic myeloid leukemia. The pathogenetic mechanisms suggested are: life prolongation by these treatments allowing for disease progression arising from dormant cells; poor penetration of the drugs to sanctuary sites like the central nervous system; the requirement of some of these drugs, especially thalidomide, for the marrow microenvironment to exert their action; and finally, a possible active role for some of the drugs, like all-trans-retinoic acid. Since the use of these targeted therapies is expanding we should be aware of this association.
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PMID:Extramedullary disease and targeted therapies for hematological malignancies--is the association real? 1679 May 18

p62(DOK1) (DOK1) and p56(DOK2) (DOK2) are sequence homologs that act as docking proteins downstream of receptor or nonreceptor tyrosine kinases. Originally identified in chronic myelogenous leukemia cells as a highly phosphorylated substrate for the chimeric p210(bcr-abl) protein, DOK1 was suspected to play a role in leukemogenesis. However, p62(DOK1-/-) fibroblast knockout cells were found to have enhanced MAPK signaling and proliferation due to growth factors, suggesting negative regulatory capabilities for DOK1. The role of DOK1 and DOK2 in leukemogeneis thus is enigmatic. The data in this report show that both the DOK1 and the DOK2 adaptor proteins are constitutively expressed in the myelomonoblastic leukemia cell line, HL-60, and that expression of both proteins is induced by the chemotherapeutic differentiation causing agents, all-trans retinoic acid (atRA) and 1,25-dihydroxyvitamin D3 (VD3). Ectopic expression of either protein enhances atRA- or VD3-induced growth arrest, differentiation, and G(0)/G(1) cell cycle arrest and results in increased ERK1/2 phosphorylation. DOK1 and DOK2 are similarly effective in these capabilities. The data provide evidence that DOK1 and DOK2 proteins have a similar role in regulating cell proliferation and differentiation and are positive regulators of the MAPK signaling pathway in this context.
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PMID:All-trans retinoic acid induces p62DOK1 and p56DOK2 expression which enhances induced differentiation and G0 arrest of HL-60 leukemia cells. 1682 27

The aim of this study was to evaluate the value of CD117/CD11b phenotypic analysis to diagnosis and prognosis of acute promyelocytic leukemia (APL). Three- or four-color flow cytometry with a series of 22 monoclonal antibodies and CD45/Side Scatter (SSC) gating strategy were used to identify immunophenotypic characteristics of APL as compared to CML in chronic phase (CML-CP). PML/RAR alpha fusion gene was detected by using reverse-transcription polymerase chain reaction (RT-PCR) technique. The results showed that MPO, CD13 and CD33 were almost expressed in all patients with APL and CML-CP whereas HLA-DR and CD34, the hematopoietic progenitor cell markers, were rarely expressed. The positive rate of CD15 in APL was significantly lower than those in CML-CP (P < 0.01). CD117 was positive in 78.3% of the APL cases and in none of the cases of CML-CP. On the other hand, CD11b was almost positive in all cases of CML-CP, but only 16.9% of the APL cases were found positive for this antigen. The CD117+ CD11b- phenotype was present in 72.3% of APL cases while none of cases with CML-CP with this phenotype. Almost all of the cases with CML-CP had the phenotype of CD117- CD11b+. CD117- CD11b+ phenotype was detected in all patients recovering from APL with CD117+ CD11b- phenotype at diagnosis and after treatment with all-trans-retinoic acid (ARTA) for 2 months. PML/RAR alpha fusion gene was positive in 80.6% (25/31) of the APL cases, of which, 64% of the cases belonged to the type L while only 36% of the cases were showed type S for this fusion gene. The positive rates of CD117 were 87.5%, 44.4% and 33.3% in type L group, S group and negative group respectively. It is concluded that analysis of both CD117 and CD11b phenotype may be helpful to the diagnosis, therapy and prognosis of APL in children and adults and to differentiation of APL from recovering benign myeloid proliferation.
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PMID:[Expressions of CD117 and CD11b in patients with APL at diagnosis and post-treatment]. 1692 91


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