PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model.
The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (K(Ca)) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB "opener", bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhances anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors.
Black
Keith L
KL
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800E, Los Angeles, California 90048, USA. Keith.Black@cshs.org
Yin
Dali
D
Ong
John M
JM
Hu
Jinwei
J
Konda
Bindu M
BM
Wang
Xiao
X
Ko
MinHee K
MK
Bayan
Jennifer-Ann
JA
Sacapano
Manuel R
MR
Espinoza
Andreas
A
Irvin
Dwain K
DK
Shu
Yan
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D009389:Neovascularization, Pathologic / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013395:Sucrose / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D016019:Survival Analysis; D019108:Tight Junctions / Q000187:drug effects / Q000648:ultrastructure; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
D000970:Antineoplastic Agents; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D013395:Sucrose; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D006152:Cyclic GMP