A STRATEGY FOR SELECTIVE ANTICANCER DRUG CONCENTRATION INCREASE IN RAT GLIOMA TISSUE WITH CA2-CHANNEL BLOCKER COADMINISTRATION - CALCIUM KINETICS IN INTRA-GLIOMA ARTERIOLAR SMOOTH-MUSCLE CELLS()

A rat glioma model was employed to estimate the Ca2+ kinetics in the t umor arteriolar smooth muscle cells. Electron microcytochemistry revea led that the density of intracellular Ca2+ deposits in the intra-tumor arteriolar smooth muscle cells was significantly greater, with slight ly higher membrane Ca2+-adenosine triphosphatase (ATPase) activity, co mpared to the contralateral cerebral arterioles. Furthermore, the admi nistration of tyrphostin, a tyrosine kinase inhibitor, specifically in creased only the intra-tumor blood flow These findings suggest that th e condition of the intra-tumor arteriole alters the susceptibility to contraction by the accelerated Ca2+ influx into the cytoplasm mediated through the tyrosine kinase pathway. After the administration of dilt iazem, which also has a blocking effect on the Ca2+-channel mediated t hrough this pathway, the local intra-tumor blood flow showed an increa se of 39% with a marked decrease of intracellular Ca2+ concentration o f the arteriolar smooth muscle cells in the tumor, while the blood flo w in the basal ganglia increased by only 8%. The intra-tumor concentra tion of Nimustine-HCl (ACNU) with co-administration of diltiazem was s ignificantly increased compared to that without the co-administration. Co-administration of diltiazem may be a valuable strategy in chemothe rapy for glioma in affording the selective increase of intra-tumor con centration of the anti-cancer drug.