Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation.
The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.
Andersson
U
U
Department of Radiation Sciences, Oncology, Umeå University, Sweden.
Grankvist
K
K
Bergenheim
A T
AT
Behnam-Motlagh
P
P
Hedman
H
H
Henriksson
R
R
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D005452:Fluoresceins / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007124:Immunoenzyme Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014700:Verapamil / Q000494:pharmacology; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D002121:Calcium Channel Blockers; D017931:DNA Primers; D005452:Fluoresceins; D012333:RNA, Messenger; D014700:Verapamil; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C007740:fluorexon