sdz-psc-833 and Carcinoma--Renal-Cell

Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2).. To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3).. Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given in combination with the ABCB1 (P-glycoprotein) antagonist valspodar (PSC 833) and received the CYP3A4 phenotyping probe midazolam on more than 1 occasion. Genotyping was conducted in CYP3A4, CYP3A5, and ABCB1 to rule out potential pharmacogenetic influences. Clinical data were followed-up by Western blotting and reporter assays in HepG2 and NIH3T3 cells treated with vinblastine over a dose range of 150-4800 ng/mL for 48 hours.. In 6 patients with cancer, vinblastine increased the median (95% CI) clearance of the CYP3A4 phenotyping probe midazolam from 21.7 L/h (12.6 to 28.1) to 32.3 L/h (17.3 to 53.9) (p = 0.0156, Wilcoxon signed-rank test). No obvious effect of polymorphisms in CYP3A4, CYP3A5, and ABCB1 on midazolam clearance was observed. In vitro, vinblastine induced CYP3A4 protein. Furthermore, cell-based reporter gene assays using transiently transfected HepG2 and NIH3T3 cells indicated that vinblastine (150-4800 ng/mL) weakly activated human and mouse full-length NR1I2, but had no influence on NR1I3.. Collectively, these findings suggest that vinblastine is able to induce CYP3A4, at least in part, via an NR1I2-dependent mechanism, and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates.

Topics: Adult; Aged; Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Carcinoma, Renal Cell; Constitutive Androstane Receptor; Cyclosporins; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Enzyme Induction; Female; Genes, Reporter; Hep G2 Cells; Humans; Kidney Neoplasms; Male; Mice; Midazolam; Middle Aged; NIH 3T3 Cells; Pharmacogenetics; Polymorphism, Genetic; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Vinblastine

P-glycoprotein (Pgp) inhibitors have been under clinical evaluation for drug resistance reversal for over a decade. Valspodar (PSC 833) inhibits Pgp-mediated efflux but delays drug clearance, requiring reduction of anticancer drug dosage. We designed an infusional schedule for valspodar and vinblastine to mimic infusional vinblastine alone. The study was designed to determine the maximally tolerated dose of vinblastine, while attempting to understand the pharmacokinetic interactions between vinblastine and valspodar and to determine the response rate in patients with metastatic renal cell cancer.. Thirty-nine patients received continuous infusion valspodar and vinblastine. Vinblastine was administered for 3 days to compensate for the expected delay in clearance and the required dose reduction. Valspodar was administered initially at a dose of 10 mg/kg/d; the dose of vinblastine varied.. The maximum-tolerated dose of vinblastine was 1.3 mg/m(2)/d. As suggested previously, serum valspodar concentrations exceeded those needed for Pgp inhibition. Consequently, the dose of valspodar was reduced to 5 mg/kg, allowing a vinblastine dose of 2.1 mg/m(2)/d to be administered. Pharmacodynamic studies demonstrated continued inhibition of Pgp at lower valspodar doses by functional assay in Pgp-expressing CD56+ cells and by (99m)Tc-sestamibi imaging. A 15-fold range in cytochrome p450 activity was observed, as measured by midazolam clearance. No major responses were observed.. These results suggest that the pharmacokinetic impact of cytochrome P450 inhibition by valspodar can be reduced although not eliminated, while preserving Pgp inhibition, thus separating the pharmacokinetic and pharmacodynamic activities of valspodar.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Renal Cell; Constipation; Cyclosporins; Dose-Response Relationship, Drug; Fatigue; Female; Humans; Infusions, Intravenous; Kidney Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Treatment Outcome; Vinblastine

PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion.. Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study.. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response.. PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

Topics: Administration, Oral; Adolescent; Adrenal Cortex Neoplasms; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Renal Cell; Cyclosporins; Drug Administration Schedule; Emulsions; Humans; Infusions, Intravenous; Kidney Neoplasms; Lymphocyte Count; Middle Aged; Radioimmunoassay; T-Lymphocytes; Vinblastine

The multidrug resistance (MDR) P-glycoprotein ABCB1 plays a major role in MDR of malignant cells and is regulated by various transcription factors, including Wnt/β-catenin/TCF4. The transcription factor PITX2 (Pituitary homeobox-2) is essential for embryonic development. PITX2 operates by recruiting and interacting with β-catenin to increase the expression of growth-regulating genes, such as cyclin D1/2 and c-Myc. The importance of PITX2 in malignancy is not yet known. Here we demonstrate that in the renal cancer cell lines ACHN and A498, the level of ABCB1 expression and function correlate with nuclear PITX2 localization and PITX2-luciferase reporter gene activity (A498 > ACHN). In A498 cells, doxorubicin toxicity is augmented by the ABCB1 inhibitor, PSC833. PITX2 overexpression increases ABCB1 expression and cell survival in ACHN cells. Silencing of PITX2 by siRNA downregulates ABCB1 and induces a greater chemotherapeutic response to doxorubicin in A498 cells, as determined by MTT cell viability and clonogenic survival assays. Two PITX2 binding sequences were identified in the ABCB1 promoter sequence. PITX2 binding was confirmed by chromatin immunoprecipitation. β-Catenin is not required for PITX2 upregulation of ABCB1 because ABCB1 mRNA increased and doxorubicin toxicity decreased upon PITX2 overexpression in β-catenin(-/-) cells. The data show for the first time that ABCB1 is a target gene of PITX2 transcriptional activity, promoting MDR and cell survival of cancer cells.

Topics: Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; beta Catenin; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Chromatin Immunoprecipitation; Cyclosporins; Doxorubicin; Gene Expression Regulation, Neoplastic; Homeobox Protein PITX2; Homeodomain Proteins; Humans; Kidney Neoplasms; Promoter Regions, Genetic; RNA Interference; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Transcription Factors; Transcriptional Activation

Tc-99m sestamibi is a substrate of P-glycoprotein (Pgp) that has been proposed for use as a functional imaging agent for the multidrug resistance-1 phenotype. In vitro, retention of sestamibi by cells that overexpress Pgp can be modified by the presence of Pgp antagonists. In a Phase I trial of the Pgp reversal agent PSC 833, we show that the effects of this reversal agent can also be demonstrated in patients. Nine patients with metastatic renal carcinoma were studied three times: at baseline, approximately 1 day after vinblastine infusion, and while on PSC 833. One patient with metastatic adrenocortical cancer was also studied. Time activity curves and areas under the curve (AUCs) were obtained for tumor, liver, lung, and myocardium, and organ:heart AUC ratios were generated. With PSC 833, tumor visualization was enhanced, and statistically significant increases were found in AUC ratios for tumor and liver compared to baseline. For the liver, significant differences were also found between the vinblastine versus PSC 833 scans but not between the baseline versus vinblastine scans. This study demonstrates that sestamibi retention by tumor and liver is altered in the presence of the reversal agent PSC 833, presumably reflecting inhibition of Pgp. Thus, sestamibi may be useful in vivo as a means of monitoring the effects of this and other reversal agents on various tumors and normal tissues that express Pgp.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Renal Cell; Cyclosporins; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Sestamibi; Tissue Distribution; Vinblastine