© 2004 by Society
© 2004 by the Society forNeuro-Oncology
Penetration of intra-arterially administered vincristine in experimentalbrain tumor
Bill Walsh Cancer Research Laboratories, Royal NorthShore Hospital, Sydney, NSW 2065, Australia (F.M.B.); Sidney Kimmel Cancer Center at Johns Hopkins MedicalCenter, Baltimore, MD 21231, USA (S.L.E., S.A.G.)
3 Address correspondence to Frances M. Boyle, Department of Medical Oncology,Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, 2065Australia(franb{at}bigpond.net.au).
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Abstract |
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Vincristine is an integral part of the "PCV" regimen that iscommonly administered to treat primary brain tumors. The efficacy ofvincristine as a single agent in these tumors has been poorly studied. Thisstudy was designed to determine whether vincristine enters normal rat brain oran intracranially or subcutaneously implanted glioma and to assess thepresence of the efflux pump P-glycoprotein (P-gp) on tumor and vascularendothelial cells. The 9L rat gliosarcoma was implanted intracranially andsubcutaneously in three Fischer 344 rats. On day 7, [3H]vincristine(50 µCi, 4.8 µg) was injected into the carotid artery, and the animalswere euthanized 10 or 20 min later. Quantitative autoradiography revealed thatvincristine levels in the liver were 6- to 11-fold greater than in the i.c.tumor, and 15- to 37-fold greater than in normal brain, the reverse of theexpected pattern with intra-arterial delivery. Vincristine levels in the s.c.tumor were 2-fold higher than levels in the i.c. tumor. P-gp was detected withJSB1 antibody in vascular endothelium of both normal brain and the i.c. tumor,but not in the tumor cells in either location, or in endothelial cells in thes.c. tumor. These results demonstrate that vincristine has negligiblepenetration of normal rat brain or i.c. 9L glioma despite intra-arterialdelivery and the presence of blood-brain barrier dysfunction as demonstratedby Evan's blue. Furthermore, this study suggests that P-gp-mediated effluxfrom endothelium may explain these findings. The lack of penetration ofvincristine into brain tumor and the paucity of single-agent activity studiessuggest that vincristine should not be used in the treatment of primary braintumors.
Received September 5, 2003; Accepted May 28, 2004
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