Bortezomib, N pyrazinecarbony,l L phenylalanine, L leucine boronic acid previously known as PS 341, a modified dipeptidyl boronic acid derived from leucine and phenylalanine that reversibly hinders the threonine buildup of the 26S proteasome, a catalytic complex that assumes a vital part in the cell by regulating degradation of proteins in a synchronized fashion. Proteins that are never again required comprised of those associated with cell cycle control apoptosis and cell signaling are labeled with ubiquitin, which guides them to the proteasome, which therefore debases them. The synchrony of balance between stimulatory and inhibitory protein associated with the cell cycle is essential for optimum physiology of the cell, and small frailty may lead to the altered fate of the cell. In this context restraint of the proteasome, the key degenerative protein of the cell cycle brings about the significant alteration of the stringent regulatory procedure that maturates the cell cycle and ultimately leading to the cell demise 218 219. Recent mechanistic exploration of Bortezomib also evidenced dysregulation of intracellular calcium metabolism and subsequent actuation of caspase and apoptosis 220 Landowski et al 2005. Collectively the prime biological impact of Bortezomib includes repression of NF κ B and CDK development inhibition of angiogenesis cell adhesion and canonization of p53 p21 p27 PTEN ROS, and ultimately apoptosis 221 222. Preclinical proof demonstrated that Bortezomib initiates growth capture by means of arresting G2 M, stage of cell cycle and actuates apoptosis in human glioblastoma cell lines 223. However, phase I clinical trials on patients with recurrent glioblastoma demonstrated a partial response in a small percentage of the patient population getting Bortezomib treatment 224.
In spite of the fact that consolidating Histone deacetylase inhibitors HDAC and proteasome inhibitors had appeared in vitro synergistic cytotoxicity in GBM cell lines, however, phase II clinical trial with Vorinostat HDAC inhibitor in combination with Bortezomib in intermittent glioblastoma demonstrated no change both in progression-free and overall survival in glioblastoma patients 225. The most widely recognized toxicities with Bortezomib monotherapy documented in clinical trials were gastrointestinal manifestations, like nausea, vomiting, diarrhea nausea, vomiting diarrhea constipation in associated with thrombocytopenia peripheral neuropathy and asthenia fatigue malaise and weakness 226 227. Vatalanib Vatalanib PTK787 ZK 222584 is a novel oral anti-angiogenic small molecule developed by Schering in collaboration with Novartis AG.
It is a selective potent vascular endothelial growth factor receptors VEGFR 1 2 tyrosine kinase inhibitor, in addition, it can also repress platelet-derived growth factor PDGF receptor c KIT and CSF1R and ultimately suppress the growth and metastasis of the malignant tumor. Initially, it has been clinically investigated in phase I, II as mono therapeutic or as combination regimen with other cytotoxic chemotherapeutics 228 229 Administration of Vatalanib as mono therapeutic agent in 47 recurrent GBM patients resulted 4 of partial response along with 56 stability of disease Reardon et al 230 detailed the consequences of Vatalanib in combination with either Temozolomide or Lomustine in 51 patients. The combination of Vatalanib and Temozolomide resulted in four months of progression-free survival whereas 10 weeks was the outcome of the Vatalanib Lomustine combination. Report of a recent phase I clinical trial from the same investigator has demonstrated well tolerability of maximum 1000 mg twice a day dose in combination with Imatinib and Hydroxyurea 23. Vandetanib Vandetanib Caprelsa developed by AstraZeneca Pharmaceuticals LP is selective oral repressor of VEGFR 2 tyrosine kinase in associated with additional inhibitory impact on VEGFR 3 and EGFR 232 233 In preclinical rat glioma model combination of Vandetanib and radiation therapy have demonstrated remarkable anti gliomagenic effect Ciardiello 2003 7 id Currently Phase I II clinical evaluation are elucidating the utilization of Vandetanib as single agent or in combination with chemoradiation in malignant glioma patients however as of now no clinical information are available 2017 1674 id.