Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats.
Our aim was to assess the ability of convection-enhanced drug delivery (CED), a novel approach of direct delivery of drugs into brain tissue and brain tumors, to treat brain tumors using salirasib (farsnesyl thiosalicylic acid). CED was achieved by continuous infusion of drugs via intracranial catheters, thus enabling convective distribution of high drug concentrations over large volumes while avoiding systemic toxicity. Several phase II/III CED-based trials are currently in progress but have yet to overcome two major pitfalls of this methodology (the difficulty in attaining efficient CED and the significant nonspecific neurotoxicity caused by high drug doses in the brain). In this study, we addressed both issues by employing our previously described novel CED imaging and increased efficiency methodologies to exclusively target the activated form of the Ras oncogene in a 9L gliosarcoma rat model. The drug we used was salirasib, a highly specific Ras inhibitor shown to exert its suppressive effects on growth and migration of proliferating tumor cells in in vitro and in vivo models, including human glioblastoma, without affecting normal tissues. The results show a significant decrease in tumor growth rate in salirasib-treated rats relative to vehicle-treated rats as well as a significant correlation between CED efficacy and tumor growth rate with no observed toxicity despite drug concentrations an order of magnitude higher than previously detected in the brain. The results show that CED of salirasib is efficient and nontoxic for the treatment of glioblastoma in a rat model, thus suggesting that it may be considered for clinical application.
Goldberg
Liat
L
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
Ocherashvilli
Aharon
A
Daniels
Dianne
D
Last
David
D
Cohen
Zvi R
ZR
Tamar
Gregory
G
Kloog
Yoel
Y
Mardor
Yael
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002408:Catheters, Indwelling; D016503:Drug Delivery Systems / Q000379:methods*; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012459:Salicylates / Q000008:administration & dosage* / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins