Increase in brain tumor permeability in glioma-bearing rats with nitric oxide donors.
OBJECTIVE
The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats.


METHODS
The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured.


RESULTS
Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/or hydroxyurea.


CONCLUSIONS
Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Dali
D
Yin
Xiao
X
Wang
Bindu M
BM
Konda
John M
JM
Ong
Jinwei
J
Hu
Manuel R
MR
Sacapano
Minhee K
MK
Ko
Andres J
AJ
Espinoza
Dwain K
DK
Irvin
Yan
Y
Shu
Keith L
KL
Black
D000284:Administration, Oral; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002956:Citrulline / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D005910:Glioma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006918:Hydroxyurea / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D020030:Nitric Oxide Donors; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D006918:Hydroxyurea