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.