Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small molecule tyrosine kinase inhibitors (TKIs) are developed to block intracellular signaling pathways in tumor cells, leading to deregulation of key cell functions such as proliferation and differentiation. Over 25 years ago, tyrosine kinases were found to function as oncogenes in animal carcinogenesis; however, only recently TKIs were introduced as anti cancer drugs in human cancer treatment. Tyrosine kinase inhibitors have numerous good qualities. First, in many tumor types they tend to stabilize tumor progression and may create a chronic disease state which is no longer immediately life threatening. Second, side effects are minimal when compared to conventional chemotherapeutic agents. Third, synergistic effects are seen in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents. In this article, we will give an update of the tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development, and we will discuss the future role of TKIs in the treatment of solid tumors. The following TKIs are reviewed: Imatinib (Gleevec/Glivec), Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva), Lapatinib (GW-572016, Tykerb), Canertinib (CI-1033), Sunitinib (SU 11248, Sutent), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).
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PMID:Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. 1710 52

On January 26, 2006, sunitinib (Sutent) received regular approval as monotherapy for the treatment of patients with gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec). Time-to-tumor progression (TTP) of sunitinib-treated patients was superior to that of placebo-treated patients. Median TTP of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (p < .0001). Partial responses were observed in 6.8% of sunitinib-treated patients and no placebo-treated patients. Sunitinib also received accelerated approval on January 26, 2006, as monotherapy for treatment of advanced renal cell carcinoma (RCC). In two single-arm trials of sunitinib in patients with metastatic RCC, partial responses were observed in 25.5% (95% confidence interval [CI], 17.5, 34.9) and 36.5% (95% CI, 24.7, 49.6) of patients. Median response durations in the two trials were 27.1 weeks (95% CI, 24.4, incalculable) and 54 weeks (95% CI, 34.3, 70.1). Treatment-emergent adverse events in sunitinib-treated patients included diarrhea, mucositis, skin abnormalities, altered taste, electrolyte abnormalities, hypertension, and diminution in left ventricular ejection fraction. Cardiac safety of sunitinib in patients with preexisting cardiac abnormalities remains unknown. Based on nonclinical findings, physicians prescribing sunitinib should monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection. Caution should be exercised when administering sunitinib in combination with known CYP3A4 inducers or inhibitors.
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PMID:Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. 1722 5

Sunitinib (SU11248, Sutent) is a class III/V receptor tyrosine kinase (RTK) inhibitor that exhibits potent anti-angiogenic and anticancer activities. Preclinical studies demonstrated that the sunitinib effects are attributed to inhibition of VEGFR and PDGFR phosphorylation. However, even in colon cancer cells lacking sunitinib-targeted RTKs, sunitinib effectively inhibits tumor growth in a xenograft model, and this raises a question about the mechanism underlying the in vivo anticancer action of sunitinib. Since hypoxia is a critical microenvironment that tumors face, we addressed the possibility that sunitinib deregulates tumor adaptation to hypoxia. First we found that sunitinib limits the colony growth of HT-29, which is a colon adenocarcinoma cell line lacking the RTKs, and that HIF-1alpha in the colonies is decreased by sunitinib. In cultured HT-29 cells, sunitinib suppressed HIF-1alpha under hypoxic conditions. Moreover, sunitinib repressed the activity of HIF-1alpha and subsequently decreased the expressions of HIF-1 downstream genes. Mechanistically, sunitinib blocked the 5'-UTR-dependent translation of HIF-1alpha. The HIF-1alpha suppression by sunitinib was also reproduced in a VHL-null renal cell carcinoma cell line, where HIF-1alpha is not degradable. In conclusion, the sunitinib inhibition of HIF-1 signaling could restrain tumor progression in hypoxic regions, which may contribute to anticancer effect of sunitinib.
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PMID:Sunitinib deregulates tumor adaptation to hypoxia by inhibiting HIF-1alpha synthesis in HT-29 colon cancer cells. 2059 38

Cancer growth and metastasis are often driven by activating mutations in, or gene amplications of, specific tyrosine or serine/threonine kinases. Kinase inhibitors (KIs) promised to provide targeted therapy-specifically inhibiting the causal or contributory kinases driving tumor progression while leaving function of other kinases intact. These inhibitors are of 2 general classes: (1) monoclonal antibodies that are typically directed against receptor tyrosine kinases or their ligands and (2) small molecules targeting specific kinases. The latter will be the focus of this review. This class of therapeutics has had some remarkable successes, including revolutionizing the treatment of some malignancies (eg, imatinib [Gleevec] in the management of chronic myeloid leukemia) and adding significantly to the management of other difficult to treat cancers (eg, sunitinib [Sutent] and sorafenib [Nexavar] in the management of renal cell carcinoma). But in some instances, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Herein we will explore the mechanisms underlying the cardiotoxicity of small-molecule KIs, hoping to explain how and why this happens, and will further examine strategies to deal with the problem.
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PMID:Why do kinase inhibitors cause cardiotoxicity and what can be done about it? 2072 98

Class 3 semaphorins are axonal guidance mediators and regulators of angiogenesis and tumor progression. Semaphorin 3A and 3F (SEMA3A&F) act by depolymerizing F-actin, resulting in cytoskeleton collapse. A key signaling step is that SEMA3A&F activates ABL2 tyrosine kinase, which activates p190RhoGAP, which in turn inactivates RhoA, thereby diminishing stress fiber formation and ensuing cell migration. We now demonstrate that Gleevec (imatinib, STI571), an ABL2 tyrosine kinase inhibitor, abrogates SEMA3A&F-induced stress fiber loss in glioblastoma cells and endothelial cells and diminishes their ability to inhibit migration. On the other hand, Sutent (sunitinib), a receptor tyrosine kinase inhibitor, did not rescue SEMA3A&F-induced collapsing activity. These results describe a novel property of Gleevec, its ability to antagonize semaphorins.
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PMID:Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility. 2475 31