Synergistic effect and condition of pegylated interferon α with paclitaxel on glioblastoma

Abstract

Glioblastomas are highly vascularized tumors and anti-angiogenic strategy is one of the most promising therapeutic approaches to treat brain tumors. Interferon • (IFN-•) as a single agent or combined with standard chemotherapy has been shown to inhibit various tumors, but the effect of combination anti-angiogenic therapy on brain tumors has not been well studied. We determined the optimal dose and schedule of pegylated IFN-• (PEG-IFN-•) against U-87MG human glioblastoma cells growing orthotopically in nude mice, since several clinical trials reported that PEG-IFN-• administered at higher or lower doses was less effective. The group treated two times per week with injections of 10 KU of PEG-IFN-• for 4 weeks showed significant decreases in cell proliferation and angiogenesis. Moreover, the optimal dose and schedule of PEG-IFN-• determined in this study and combined with paclitaxel treatment potently inhibited tumor growth in vivo. The mechanisms of the significant therapeutic effects were most likely caused by directly inhibiting cell proliferation and angiogenesis, and rendering apoptosis increased. Specifically PEG-IFN-•/paclitaxel combination induced apoptosis of tumor-associated endothelial cells more than that of tumor cells. These results suggest that optimal biological dosage and scheduling of PEG-IFN-• and paclitaxel combination is a potent strategy for glioblastoma patients as a new synergistic anti-endothelial treatment.

Valproic Acid Induced Differentiation and Potentiated Efficacy of Taxol and Nanotaxol for Controlling Growth of Human Glioblastoma LN18 and T98G Cells

“…Our combination therapy showed the anti-angiogenic potential by down regulating expression of VEGF and EGFR in glioblastoma cells. A previous study reported synergistic efficacy of combination of pegylatedinterferon-alpha (PEG-IFN-a) and TX in glioblastoma U87MG cells due to inhibition of proliferation and angiogenesis [31]. Similarly, a Phase II clinical trial of TX and topotecan with filgrastim (also known as G-CSF) showed therapeutic effects in glioblastoma patients [32], indicating importance of TX in the combination therapy to control growth of glioblastoma.…”

Cyclic RGD conjugated poly(ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect

“…Consequently chemotherapy seems essential in the treatment of GBM. A widely used chemotherapeutic drug, paclitaxel, has been proven effective in the treatment of GBM [3][4][5][6][7], acting by promoting the assembly and stabilization of microtubules inhibiting cellular division [8], preventing de-polymerization of the assembled microtubules and thereby halts mitosis or cell division and binding to Bcl-2 which normally blocks the process of apoptosis, allowing apoptosis to proceed [9,10]. However, its high hydrophobicity seriously restricts the practical use.…”

Mitochondrial localization and pro-apoptotic effects of the interferon-inducible protein ISG12a

“…Production of type I IFNs, in particular IFN-b and members of the IFN-a subfamily, is essential for adequate viral clearance and initiation of an adaptive immune response in mammals [1][2][3]. Type I IFNs are used as approved therapeutics for various viral and neurologic diseases, such as hepatitis C virus infection and multiple sclerosis, as well as solid and hematologic cancers, including melanoma, glioblastoma, and various types of leukemia [4][5][6][7][8]. Their growth inhibitory, anti-angiogenic, and immunomodulatory effects likely contribute to the antitumor activity of type I IFNs in the clinical setting and in preventing virus spread in vivo.…”