Penetration of intra-arterially administered vincristine in experimental brain tumor

Abstract

Vincristine is an integral part of the "PCV" regimen that is commonly administered to treat primary brain tumors. The efficacy of vincristine as a single agent in these tumors has been poorly studied. This study was designed to determine whether vincristine enters normal rat brain or an intracranially or subcutaneously implanted glioma and to assess the presence of the efflux pump P-glycoprotein (P-gp) on tumor and vascular endothelial cells. The 9L rat gliosarcoma was implanted intracranially and subcutaneously in three Fischer 344 rats. On day 7, [3H]vincristine (50 microCi, 4.8 microg) was injected into the carotid artery, and the animals were euthanized 10 or 20 min later. Quantitative autoradiography revealed that vincristine 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 the expected pattern with intraarterial delivery. Vincristine levels in the s.c. tumor were 2-fold higher than levels in the i.c. tumor. P-gp was detected with JSB1 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 the s.c. tumor. These results demonstrate that vincristine has negligible penetration of normal rat brain or i.c. 9L glioma despite intra-arterial delivery and the presence of blood-brain barrier dysfunction as demonstrated by Evan's blue. Furthermore, this study suggests that P-gp-mediated efflux from endothelium may explain these findings. The lack of penetration of vincristine into brain tumor and the paucity of single-agent activity studies suggest that vincristine should not be used in the treatment of primary brain tumors.

Fig. 1

Evans blue staining and immunohistochemistry results. A. Albumin macromolecules, bound to Evans blue, penetrate the blood-brain barrier of the i.c. tumor and the s.c tumor, but not normal brain. B–D. JSB1 immunocytochemistry for P-gp. Staining is demonstrated in cerebral capillaries of the tumor (arrow, B) and in the liver (arrow, C), but not in the tumor cells in either location or in the s.c. capillaries (D); 40×magnification.

Fig 2

Vincristine levels in each animal (fmol/mg, mean and 95% confidence intervals) determined by quantitative autoradiography. Levels in the liver are significantly higher than those in other organs, with normal brain being the lowest in each animal.