A major obstacle for the combination therapy with molecular targeted drugs additive toxicity t that the doses that patients tolerate limit. For example, combinations of EGFR inhibitors with mTOR inhibitors were mixed with a high incidence of dermatologic toxicity Sorafenib Nexavar t And mucositis associated. 51 Ren Another factor with the effectiveness of the molecular targeted drugs st in malignant gliomas can Inadequate penetration into tumor tissue through an intact part BBB efflux or an active drug. Because of the difficulty of tumor tissue in the population of patients with brain tumors, only a few clinical studies have succeeded in measuring drug concentrations in the tumor tissue. However, oncologists, neuro increasingly recognize that it is important to preserve and study the tumor tissue when possible.
37, 52 studies analyzing tissue penetration of the drug to erm Resembled that extent the inhibition of the target in vivo and resistance mechanisms. This information will facilitate the rational design of future studies and should be addicted Be effective in clinical studies. ‘re Targeting intracellular signaling pathways: inhibition of angiogenesis As mentioned tt hnt, growth of new blood vessels was a treatment in e b sartigen gliomas prove to be one of the most promising areas of targeted molecular therapy. To understand this, it is important to examine the current amplification Ndnis to angiogenesis in malignant gliomas, and then analyzed the various approaches Tze used to these events align with therapeutic agents.
Overview of angiogenesis in malignant gliomas Many experimental data support the concept that angiogenesis growth.53 required malignant glioma, 54 method primarily by tumor secreted VEGF driven, but there are a large number of other e secreted pro-angiogenic factors, including normal basic FGF angiopo, tines, PDGF, IL-8, and hepatocyte growth factor scatter /. Endothelial cells in the N eh Tumor express VEGFR2, which creates a paracrine signaling loop stimulates endothelial cell growth and proliferation. The H eh Production of VEGF in tumor cells obtained Ht with the degree of malignancy T. In a study of surgical specimens gliomas, high-grade tumors VEGF produced more than 10 times compared to low-grade tumors.55′m A subset of molecular targeted therapy for malignant gliomas Ren drugs that affect the angiogenesis.
Most anti-angiogenic drugs that have been evaluated in clinical studies so far st with the VEGF pathway Ren by blocking direct ligand or receptor. However, there is an increasing interest in targeting molecules proangiogenic that nontyrosine by other mechanisms.29 example neuropilins receptor kinases that potentiate the binding of VEGF and VEGFR signaling are activated. Neuropilin also facilitates HGF / SF signaling.56 The angiopo tines are stability t involved and maintenance of tumor vasculature. Binding of Ang 2 to its YEARS Ring receptor, Tie2, serves Gef E, which is a requirement of angiogenesis proceed.57 Ang-2 inhibitors therefore of interest as therapeutic agents.58 k Notch inhibitors Can also s destabilize prove to be effective. Notch receptors on tumor cells, endothelial cells activated by transmembrane and shredded.