Background: The blood-brain barrier (BBB) is a major obstacle in the treatment of brain
tumors. Intra-arterial (IA) administration with osmotic BBB disruption (BBBD) allows greater drug
delivery to the central nervous system (CNS). Its use with temozolomide (TMZ), the first-line agent
in the treatment of glioblastoma, has never been reported in an animal glioma model.
Objective: This study was designed to investigate whether increased TMZ delivery would improve
survival in the Fischer-F98 glioma model.
Methods: Alternative methods of administration for TMZ (200 mg/m2) were tested, comparing intravenous
infusions (IV, n=13) to IA (n=13) or BBBD with IA (n=13). IA normal saline (NS) was used
as a control group (n=13). Five rats per group also underwent radiotherapy. Survival and adverse effects
were measured. TMZ was quantified in plasma, CSF and brain at three time-points post-TMZ
infusion (IV, IA or IA+BBBD) by LC-MS\MS.
Results: Compared to IV, higher peak TMZ concentrations were observed in brain tumor (BT) tissues
with IA and IA+BBBD infusions (4-fold and 5-fold, respectively). No difference in survival was observed
between the IA with/without BBBD vs. IV/control groups. Radiotherapy increased survival
independently of the method of TMZ delivery.
Conclusion: We show that the enhanced delivery of TMZ by IA infusion (with/without BBBD) does
not improve survival in this resistant model. However, the method of TMZ administration has a significant
impact on CNS delivery. Bypassing the BBB with judicious use of local delivery approaches
and appropriate therapeutic agents has potential for the treatment of glioblastomas.