Phase II study of tariquidar, a selective P‐glycoprotein inhibitor, in patients with chemotherapy‐resistant, advanced breast carcinoma

Abstract

BACKGROUNDThe primary objective of this study was to determine whether addition of the selective P‐glycoprotein (P‐gp) inhibitor tariquidar (XR9576) to chemotherapy could induce an objective tumor response in patients who previously were resistant to the same agents. The secondary objectives were to evaluate P‐gp expression by immunohistochemistry (IHC), to determine functional activity of the P‐gp transporter before and after administration of tariquidar with serial technetium‐99m (99mTc)‐sestamibi scans, and to correlate those parameters with clinical response.METHODSSeventeen women with Stage III–IV breast carcinoma were included in the study who progressed (n = 13 women) or had stable disease (n = 4 women) on doxorubicin‐containing or taxane‐containing chemotherapy regimens. During the study, the same chemotherapy was continued without dose modifications, but tariquidar (150 mg intravenously) was added to the treatment regimen.RESULTSThirty‐six percent of patients had P‐gp‐positive tumors by IHC, and 5 patients (29%) experienced increases ≥ 10% in sestamibi uptake (median increase, 40%; range, 10–63%) after the administration of tariquidar. There was one partial response in a patient who had the greatest increase in sestamibi uptake and who also showed inducible P‐gp expression. There was one patient who experienced severe doxorubicin/docetaxel‐related toxicity after tariquidar was added to her chemotherapy regimen.CONCLUSIONSTariquidar showed limited clinical activity to restore sensitivity to anthracycline or taxane chemotherapy. Functional imaging of the tumor with 99mTc‐sestamibi scans before and after administration of multidrug‐resistance inhibitor may be useful to identify the small subset of patients who could benefit from multidrug‐resistance modulation in future trials. Cancer 2005. © 2005 American Cancer Society.

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

“…In phase 3 clinical trials, agents such as cyclosporine A, verapamil, and valspodar did not improve clinical outcome. In patients with chemoresistant disease, the addition of the P-gp inhibitor tariquidar (XR9576) had minimal ability to restore sensitivity to chemotherapy (13). A new P-gp inhibitor zosuquidar (LY335979) was evaluated in phase 1 trials and only modestly increased the plasma concentrations of doxorubicin and docetaxel (14).…”

Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer

“…Many cytotoxic drugs, such as anthracyclines (28), taxanes (29), and camptothecins (30), are susceptible to MDR-mediated loss of sensitivity through P-gp and ABCG2, respectively. Actually, several strategies have been developed acting on MDR mostly through inhibition or modulation of P-gp (28) and several phase I and II trials with P-gp inhibitors are ongoing (31). 3 Recently, we synthesized several ligands with high j 2 receptor affinity and only moderate selectivity toward j 1 receptors (32); among these ligands, the cyclohexylpiperazine derivative PB28 displayed j 2 receptor agonist activity in an isolated guinea pig bladder bath (33) as well as antiproliferative and cytotoxic effects in both C6 rat glioma and SK-N-SH human neuroblastoma cell lines (34).…”

Comparative proteomic analysis of paclitaxel resistance-related proteins in human breast cancer cell lines

“…Cell viability was assessed 3 days later using MTT assays, as described previously (13). The cells (5x10 3 per well) were seeded into 96-well culture plates and pre-incubated for 24 h at 37˚C. Paclitaxel was added at various concentrations (0, 0.1, 0.3, 1, 3, 10, 30, 100, 300 and 1000 nM) and then incubated for 3 days at 37˚C.…”

“…The first involves decreased intracellular drug accumulation caused by the overexpression of membrane-bound drug efflux proteins, such as P-glycoprotein. However, clinical trials focusing on P-glycoprotein inhibitors as chemosensitizing agents did not report promising outcomes for patients with relapsing solid tumors and hematological malignancies (3). The other two mechanisms involve mutations in β-tubulin and overexpression of β-tubulin isotypes (2).…”