sdz-psc-833 and Brain-Neoplasms

The aim of this study was to explore whether (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second-generation MDR1 inhibitors (PSC833, MS-209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR-resistant sublines compared to those of drug-naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR-resistant cells than drug-naive cells in each line. Volume distribution (V(d)) of (99m)Tc-MIBI was negatively correlated with MDR1 mRNA expression among drug-naive and VCR-resistant cells. MDR1 inhibitors decreased surviving fractions and increased V(d) of (99m)Tc-MIBI significantly in VCR-resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that (99m)Tc-MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of (99m)Tc-MIBI revealed higher uptake in drug-naive cells at basal ganglia compared with VCR-resistant cells at the opposite basal ganglia of rats. Oral administration of the second-generation MDR1 inhibitors significantly increased (99m)Tc-MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using (14)C-methyl-L-methionine ((14)C-Met) and MIB-5 index. (14)C-Met uptake and MIB-5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of (99m)Tc-MIBI accumulation is considered informative for detecting MDR1-mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Autoradiography; Brain Neoplasms; Carcinoma 256, Walker; Cell Line, Tumor; Cell Proliferation; Cyclosporine; Cyclosporins; Cytotoxins; Drug Resistance, Neoplasm; Drug Synergism; Predictive Value of Tests; Quinolines; Radiopharmaceuticals; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Technetium Tc 99m Sestamibi; Tomography, Emission-Computed, Single-Photon; Vincristine

P-glycoprotein (Pgp) in the blood-brain barrier limits the brain's uptake of many anticancer drugs. We have investigated whether the Pgp inhibitors cyclosporin A, valspodar (PSC833) and elacridar (GF120918) increase the accumulation of docetaxel in the brain. Pgp knockout mice served as a reference model for the complete absence or complete inhibition of Pgp. Plasma and tissues were analysed by high-performance liquid chromatography. Cyclosporin A, valspodar and elacridar significantly increased the brain concentrations of docetaxel in wild-type mice to 38%, 56% and 59%, respectively, of those achieved in Pgp knockout mice. Valspodar and cyclosporin A also increased the docetaxel concentration in plasma and other tissues by 2- and 3-fold, whereas elacridar did not change the clearance. All three inhibitors therefore inhibit Pgp in the blood-brain barrier. Elacridar increases the accumulation of docetaxel in the brain without significant effects on systemic exposure. Further clinical tests with this latter combination are warranted.

Topics: Acridines; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain Chemistry; Brain Neoplasms; Cyclosporins; Docetaxel; Drug Interactions; Female; Mice; Mice, Knockout; Taxoids; Tetrahydroisoquinolines

Malignant astrocytomas have been found to express P-glycoprotein (Pgp, mdr1 gene product). It was hypothesized that in addition to conferring multidrug resistance, Pgp is intimately associated with the development of astrocytomas. Accordingly, we studied the effect of PSC 833 (PSC, Novartis), a potent inhibitor of Pgp, on the growth of Pgp-expressing astrocytoma cells. The results showed that in all the cell lines tested, PSC (10-60 microM) inhibited the growth as well as induced cell death. Cells exposed to PSC exhibited DNA ladder characteristic of apoptosis. PSC-induced cell death could be reversed by Z-VAD-fmk, a general caspase inhibitor, indicating that PSC-induced cell death was characteristic of caspase-mediated apoptosis. These results suggest a novel therapeutic strategy in the treatment of malignant astrocytomas by inhibitors of Pgp.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Astrocytoma; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain Neoplasms; Caspases; Cyclosporins; Cysteine Proteinase Inhibitors; Humans; Tumor Cells, Cultured

Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. In vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C(4) (LTC(4)), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS.

Topics: Animals; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Capillaries; Cells, Cultured; Cyclosporins; Glioblastoma; Glioma; Humans; Paclitaxel; Swine; Tumor Cells, Cultured