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)

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.
 ...
PMID:Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer. 1461 30

Imatinib mesylate, an orally administered 2-phenylaminopyrimidine derivative that inhibits BCR/ABL tyrosine kinase activity, has shown great promise in the treatment of chronic myelogenous leukemia (CML). This small molecule, tyrosine kinase inhibitor, has also been shown to be effective against metastatic gastrointestinal stromal tumors (GISTs) expressing the stem cell factor (SCF) receptor kit. However, the threat of resistance in patients has prompted investigators to uncover the mechanisms whereby malignant cells develop resistance to imatinib, and has also led to the establishment of strategies designed to over-ride imatinib resistance. Here, we provide a comprehensive overview of the effectiveness of imatinib in the treatment of chronic, accelerated and blast crisis-phase CML, Philadelphia chromosome-positive (Ph+) acute lymphoid leukemia (ALL) and metastatic GIST. Established mechanisms of resistance to imatinib are discussed, as are novel therapeutic approaches to improving drug responsiveness by reversing development of imatinib resistance in patients.
 ...
PMID:Resistance to imatinib (Glivec): update on clinical mechanisms. 1464 93

The epidemiology, genetics/genomics and molecular biology of cancer all point to the involvement of a large number of genes in the malignant progression of the vast majority of human cancers. Our current conceptual models of cancer are discussed here and are integrated with an assessment of the strategies required for treating and potentially curing human cancers driven by multiple genome abnormalities. There are settings in which excellent responses will be seen in cancers driven primarily by single genomic abnormalities, e.g., imatinib in chronic myeloid leukemia and gastrointestinal stromal tumors. Other multigenic cancers will require drug cocktails or single drugs acting on multiple downstream targets.
 ...
PMID:Strategies for treating cancers caused by multiple genome abnormalities: from concepts to cures? 1476 25

Despite major progress in treating hematologic malignancies and, to a lesser extent, metastatic solid tumors, much work remains ahead. With the anticancer potential of immunotherapy not yet fully exploited, patients with leukemia, malignant lymphoma, and other hematologic malignancies for which high-dose chemoradiotherapy is frequently recommended in conjunction with stem cell transplantation (SCT) can now benefit from the advantages of immunotherapy mediated by cytokines or alloreactive donor lymphocytes, while minimizing procedure-related toxicity and mortality. The feasibility of applying allogeneic cell-mediated immunotherapy in conjunction with allogeneic SCT following reduced-intensity conditioning, with minimal toxicity and no serious transplant-related complications, makes it possible to undertake such procedures on an outpatient basis as well as to offer an option for cure to elderly individuals and patients with less than optimal performance status. Being well tolerated, reduced-intensity transplants also offer a chance for cure to patients with otherwise resistant leukemia and malignant lymphoma who have relapsed after autologous SCT. Thus, the traditional obstacle of very high transplant-related toxicity and mortality due to multiorgan failure from cumulative toxicity of multiple anticancer agents and radiation therapy is overcome. Although immunotherapy mediated by allogeneic lymphocytes can be most effective, the immune potential of donor lymphocytes should be maximized by nonspecific or specific activation in vitro or in vivo, or both, for more effective eradication of resistant tumor cells, including in patients with bulky disease. More important is the challenge to target donor lymphocytes to the tumor and minimize their capacity to induce responses against normal host tissues, which frequently results in severe acute and chronic graft-versus-host disease (GVHD). Alternatively, donor lymphocytes should be eliminated as soon as tumor eradication is completed, or as soon as severe GVHD becomes prohibitive. Based on available experience, clinical application of innovative therapy, especially at the stage of minimal residual disease (MRD), may open new horizons for the treatment of malignancies considered until recently to be incurable. The feasibility of controlling cancer by targeted chemotherapy, best illustrated by the phenomenal activity of imatinib in patients with chronic myelogenous leukemia and, more recently, in gastrointestinal stromal tumors (including in patients fully resistant to all known anticancer agents) suggests that in the future, tumor-specific chemotherapy may represent the ultimate goal for achieving a stage of MRD with minimal multiorgan toxicity. Together, the combination of immunotherapy and targeted chemotherapy may provide the most logical approach for making real progress in controlling resistant hematologic malignancies and metastatic solid tumors.
 ...
PMID:Nonmyeloablative stem cell transplantation: reduced-intensity conditioning for cancer immunotherapy--from bench to patient bedside. 1497 Sep 32

Several mechanisms of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis have been discussed. One hypothesis suggests that the somatic stem cells of the liver, the so-called oval cells, may undergo malignant transformation. Oval cells are derived from the biliary cells of the canal of Hering and are characterized by c-kit-positivity, the transmembrane receptor of stem cell factor. Constitutively activated tyrosine kinases have been identified as major pathogenetic mechanisms in the development of malignant diseases like gastrointestinal stromal tumors (c-kit) and chronic myelogenous leukemia (bcr-abl). The prognosis of these diseases improved enormously since the drug imatinib, a tyrosine kinase inhibitor of c-kit and bcr-abl, was introduced. Here we report the successful cure of a patient with liver cancer by this tyrosine kinase inhibitor.
 ...
PMID:Successful treatment of hepatocellular carcinoma with the tyrosine kinase inhibitor imatinib in a patient with liver cirrhosis. 1505 46

Imatinib mesylate is remarkably effective in treating chronic myeloid leukemia and metastatic gastrointestinal stromal tumors. Meanwhile, anaplastic thyroid carcinoma (ATC) remains a fatal malignancy for which there are currently no effective curative interventions. In chronic myeloid leukemia and gastrointestinal stromal tumors, imatinib inhibits the constitutive tyrosine kinase activity of BCR-ABL and c-KIT, respectively. Reports suggest that imatinib may also be effective against ABL and platelet-derived growth factor receptor kinase-dependent pathological conditions. These mechanisms provide a wide scope of possible clinical applications for the drug. Potentially, diseases instigated by constitutive kinase activity that can be inhibited with imatinib should be treatable with this drug. We evaluated the effects of imatinib on the viability, cycling, and tyrosine phosphorylation of ATC cells in vitro. Our data indicate that imatinib has negligible antineoplastic activity against ATC cell lines within established therapeutically useful concentrations. No constitutive kinase activity was detected in these cell lines that could be exploited as a therapeutic target by imatinib. We conclude that imatinib mesylate monotherapy would not be effective in ATC patients. Current preclinical data do not warrant future clinical studies of imatinib monotherapy for ATC.
 ...
PMID:Imatinib mesylate (gleevec; STI571) monotherapy is ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro. 1512 30

Imatinib mesylate (Gleevec), Glivec, formerly STI571; Novartis Pharma AG; Basel, Switzerland) is a rationally-designed, molecularly-specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer. It has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant gastrointestinal stromal tumors. Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low. Adverse effects most commonly include mild-to-moderate edema, nausea and vomiting, diarrhea, muscle cramps, and cutaneous reactions. Hepatic transaminase level elevations and myelosuppression occur less frequently and resolve with interruption of imatinib therapy. In general, the incidence and severity of adverse effects tend to correlate with imatinib dose and, in chronic myeloid leukemia patients, the phase of disease; but, patient age and other factors are also associated with some types of reactions. With prompt and appropriate intervention, adverse effects in imatinib-treated patients have proven to be manageable across the spectrum of severity, and they seldom require permanent cessation of therapy. Dose reduction is not usually necessary, and reduction to subtherapeutic levels is not recommended.
 ...
PMID:Indications for imatinib mesylate therapy and clinical management. 1516 82

The robust clinical activity of imatinib and trastuzumab for treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and breast cancer has demonstrated that blocking pathogenic tyrosine kinases can alter the natural history of human tumors. On the other hand, EGF receptor inhibitors have shown overall modest activity. The contrast in the development of these agents implies that both molecular target dependence and patient selection are essential for the successful outcome of this process. We will contrast lessons derived from the development of inhibitors of Abl, c-Kit, HER2/neu (erbB2), and EGFR, highlight successes and limitations in the field, and propose new approaches for clinical development of tyrosine kinase inhibitor therapy.
 ...
PMID:Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them? 1519 55

Imatinib mesylate (STI571), a potent tyrosine kinase inhibitor, is successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. However, the intended chronic oral administration of imatinib may lead to development of cellular resistance and subsequent treatment failure. Indeed, several molecular mechanisms leading to imatinib resistance have already been reported, including overexpression of the MDR1/ABCB1 drug pump. We examined whether imatinib is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump that is frequently overexpressed in human tumors. Using a panel of well-defined BCRP-overexpressing cell lines, we provide the first evidence that imatinib is a substrate for BCRP, that it competes with mitoxantrone for drug export, and that BCRP-mediated efflux can be reversed by the fumitremorgin C analog Ko-143. Since BCRP is highly expressed in the gastrointestinal tract, BCRP might not only play a role in cellular resistance of tumor cells but also influence the gastrointestinal absorption of imatinib.
 ...
PMID:Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. 1525 80

STI571, a specific tyrosine kinase inhibitor, exhibits a substantial therapeutic activity in patients with chronic myeloid leukaemia and gastrointestinal stromal tumors. In this study we examined the activity of STI571 on the growth and invasiveness of three human epithelial breast cancer cell lines of low (MCF-7) and high (ZR-75-1 and MDA-MB-231) invasive potential. Growth of all cell lines in serum-containing medium was significantly inhibited by STI571 in a dose-dependent manner, with an average IC50 of approximately 5-6 microM. Flow cytometric analysis revealed that this effect is characterized by an accumulation of all breast cancer cell types tested in the G2/M-phase of the cell cycle with a concomitant decrease of the percentage of cells in the S-phase. Interestingly, no increase in apoptosis was observed, indicating that the effect of this kinase inhibitor is cytostatic rather than cytotoxic. In addition, STI571 exerts a significant inhibition effect on the invasion of the highly invasive breast cancer cell lines ZR-75-1 and MDA-MB-231. These results encourage further preclinical investigations on the mechanisms underlying the inhibitory effects of STI571, which may be of great value in breast cancer treatment.
 ...
PMID:STI571 as a potent inhibitor of growth and invasiveness of human epithelial breast cancer cells. 1527 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>