Assessing effect of glioblastoma associate pathophysiological changes on the therapeutic agent delivery to the brain

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor It is also the most aggressive and hard to be cured brain cancer There are many reasons for unsatisfactory therapeutic outcomes in GBM One of the main reasons is the difficulty to delivery drugs to the target cancer cells In clinical setting therapeutic agents are usually given to the patient after cerebral edema is under control In the previous studies we found cerebral edema often occurs along with GBM and it causes blood-brain barrier (BBB) disruption and up-regulation of inflammatory cytokines One of the most commonly used drugs in GBM is Temozolomide (TMZ) which kills cancer cell by interfering with tumor DNA repair It is offen used in patients after the glioma induced edema is controlled with dexamethasone (DEX a steroid) In this study we hypotheses the efficacy of TMZ treatment may be enhanced if it is used in edema stage To clarify our hypothesis we use a GBM-induced cerebral edema animal model which established previously and we divide the rats into five groups: (1) control group; (2) GBM-induced edema animal model treated with DEX; (3) GBM-induced edema animal model treated with TMZ; (4) GBM-induced edema animal model treated with DEX and TMZ separately to mimic clinic setting; (5) GBM-induced edema animal model co-treated with DEX and TMZ Our previous studies showed that the sizes of brain tumor and cerebral edema were small on day 7 after tumor graft but were well developed on 14 days after tumor injection Therefore in group 2 4 and 5 animals were treated with DEX on day10 to day12 with the following dosages: 5mg 2mg and 1mg/kg/day In group 3 and 5 animals were treated with TMZ on day10 to day16 with a dosage of 10mg/kg/day Only the animals in group 4 the separated treatment group were treated with TMZ on day13 to day16 The T2-weight MRI images showed that the tumor size and the cerebral edema area of control group increased rapidly on day 10 to day 16 and we found hydrocephalus which appeared at the right ventricle and extending to the left side The images also showed the tumor size and cerebral edema area of group 5 were smaller than group 1 2 and 3 which corresponded to the increased survival time of group 5 According to the results we conclude that cancer-induced complication of hydrocephalus and cerebral edema may lead to death of the control group Our results also showed that the efficacy of co-treatment with DEX and TMZ was better than DEX alone (group 2) and TEX alone (group 3) The results of western blot showed the expression of GFAP and AQP4 decreased significantly with treatments from day 13 to day 16 (n=3 P

Date of Award	2016 Jan 12
Original language	English
Supervisor	Chun-I Sze (Supervisor)