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Intra-arterial Temozolomide, Osmotic Blood-brain Barrier Disruption and Radiotherapy in a Rat F98-Glioma Model

[ Vol. 4 , Issue. 2 ]

Author(s):

Annie I. Drapeau, Marie-Belle Poirier, Guru-Swamy Madugundu, J. Richard Wagner and David Fortin*   Pages 135 - 144 ( 10 )

Abstract:


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.

Keywords:

Blood-brain barrier, Blood-brain barrier disruption, Drug delivery, F98 cells, Glioblastoma multiforme, Temozolomide.

Affiliation:

Department of Surgery, Universite de Sherbrooke, Sherbrooke, QC, J1H 5N4, Department of Surgery, Universite de Sherbrooke, Sherbrooke, QC, J1H 5N4, Department of Nuclear Medicine and Radiobiology, Universite de Sherbrooke, Sherbrooke, QC, J1H 5N4, Department of Nuclear Medicine and Radiobiology, Universite de Sherbrooke, Sherbrooke, QC, J1H 5N4, Department of Surgery, Universite de Sherbrooke, Sherbrooke, QC, J1H 5N4

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