Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although standard anticancer chemotherapeutic drugs have been designed to inhibit the survival or growth of rapidly dividing tumor cells, it is possible to enhance the efficacy of such drugs by targeting the proliferating host endothelial cells (ECs) of the tumor vasculature. A theoretical advantage of this strategy lies in the possibility of circumventing, or significantly delaying, acquired drug resistance driven by the genetic instability of tumor cells. Here, we show that both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor significantly reduce the pro-apoptotic potency of chemotherapy on both micro- and macrovascular ECs. This cytoprotection to drug toxicity was found to be phosphatidylinositol 3-kinase-dependent and could be recapitulated in the absence of VEGF by overexpressing the dominant-active form of the serine/threonine kinase protein kinase B/Akt. Downstream of phosphatidylinositol 3-kinase, we also show that survivin plays a pivotal role in VEGF-mediated EC protection by preserving the microtubule network. In this respect, its induction effectively protects ECs against chemotherapeutic damage, whereas overexpression of its dominant-interfering mutant (C84A) abrogates the protective effects of VEGF. Accordingly, the potency of VEGF as a chemoprotectant was more pronounced with drugs that interfere with microtubule dynamics than those that damage DNA. These studies implicate a role for survivin up-regulation as a novel mechanism of EC drug "resistance" and support the notion that angiogenic factors that induce the expression of survivin may act to shield tumor ECs from the apoptotic effects of chemotherapy. Thus, exploiting chemotherapeutic drugs as antiangiogenics is likely to be compromised by the high concentrations of proangiogenic survival/growth factors present in the tumor microenvironment; targeting EC survival pathways should improve the antiangiogenic efficacy of antineoplastic agents, particularly microtubule-inhibitor drugs.
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PMID:A role for survivin in chemoresistance of endothelial cells mediated by VEGF. 1191 34

Hypoglycemia is a rare paraneoplastic manifestation of patients with neoplasms. Hypoglycemia can be induced by several causes, including an aberrant increase of hypoglycemic agents and adrenal insufficiency. Sorafenib is the first agent to demonstrate a survival benefit in the treatment of advanced hepatocellular carcinoma (HCC). This small molecule inhibits serine/threonine kinase RAF in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature and decreases tumor growth and angiogenesis. In this paper, we report a case of HCC who was treated with sorafenib and showed severe hypoglycemia. This hypoglycemia might be induced by two causes, both adrenal insufficiency as an adverse effect of sorafenib and activation of the insulin-like growth factor (IGF) signal by excessive secretion of incompletely processed precursors of IGF-II. Although the IGF signal is suggested to be involved in aberrant growth of HCC in some cases, there is no other report showing the influence of sorafenib on HCC with active IGF signal. Unfortunately, the effect of sorafenib was limited in the present case. However, emerging drugs that directly inhibit the IGF signal can be expected to be highly effective in the treatment of HCC with hypoglycemia.
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PMID:IGF-II Producing Hepatocellular Carcinoma Treated with Sorafenib: Metabolic Complications and a Foresight to Molecular Targeting Therapy to the IGF Signal. 2334 2