A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy.
ABSTRACT Our intention was to (a) to investigate the safety and tolerability of a potent P-glycoprotein modulator, zosuquidar trihydrochloride (LY335979), when administered i.v. alone or in combination with doxorubicin, (b) to determine the pharmacokinetics of zosuquidar and correlate exposure to inhibition of P-glycoprotein function in a surrogate assay, and (c) to compare the pharmacokinetics of doxorubicin in the presence and absence of zosuquidar. Patients and Methods: Patients with advanced malignancies who provided written informed consent received zosuquidar and doxorubicin administered separately during the first cycle of therapy and then concurrently in subsequent cycles. Zosuquidar was given i.v. over 48 h in a cohort-dose escalation manner until the occurrence of dose-limiting toxicity or protocol specified maximum exposure. Doxorubicin doses of 45, 60, 75 mg/m(2) were administered during the course of the trial.
Dose escalation proceeded through 9 cohorts with a total of 40 patients. The maximal doses administered were 640 mg/m(2) of zosuquidar and 75 mg/m(2) of doxorubicin. No dose-limiting toxicity of zosuquidar was observed. Pharmacokinetic analysis revealed that, in the presence of zosuquidar at doses that exceeded 500 mg, there was a modest decrease in clearance (17-22%) and modest increase in area under the curve (15-25%) of doxorubicin. This change was associated with an enhanced leukopenia and thrombocytopenia but was without demonstrable clinical significance. The higher doses of zosuquidar were associated with maximal P-glycoprotein inhibition in natural killer cells.
Zosuquidar can be safely coadministered with doxorubicin using a 48 h i.v. dosing schedule.
Article: Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML).[show abstract] [hide abstract]
ABSTRACT: Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the P-gp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts. The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test. Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp. These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients.BMC Cancer 02/2008; 8:51. · 3.01 Impact Factor
Article: Reversion of P-glycoprotein-mediated multidrug resistance in human leukemic cell line by carnosic acid.[show abstract] [hide abstract]
ABSTRACT: One of the common hindrances to successful chemotherapy is the development of multidrug resistance (MDR) by tumor cells to multiple chemotherapeutic agents. In this regard, P-glycoprotein (P-gp) acts as an energized drug pump that reduces the intracellular concentration of drugs, even of structurally unrelated ones. The modulators of P-gp function can restore the sensitivity of MDR cells to anticancer drugs. Therefore, to develop effective drug-resistance-reversing agents, we evaluated the P-gp modulating potential of carnosic acid (CA) in multidrug-resistant K562/AO2 cells in the present study. The reversing effect of CA was evaluated by determining the inhibition rates of cell viability with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assays. The intracellular adriamycin fluorescence intensity and the expression of P-gp were measured by flow cytometry (FCM). Meanwhile, the subcellular distribution of adriamycin was detected via Laser Scanning Confocal Microscopy (LSCM). The mRNA expression of mdrlwas then detected via semiquantitative reverse transcription polymerase chain reaction (RT-PCR). The findings showed that CA decreased apparently the Inhibition Concentration 50% (IC50) of adriamycin by increasing its intracellular concentration and thus enhancing the sensitivity of K562/AO2 cells. Adriamycin was distributed evenly in the cytoplasm when the cells were treated with CA. The expression of mdrl was decreased. Overall, the results indicated that CA can serve as a novel, non-toxic modulator of MDR, and it can reverse the MDR of K562/AO2 cells in vitro by increasing intracellular adriamycin concentration, down-regulating the expression of mdrl, and inhibiting the function of P-gp.The Chinese journal of physiology 01/2009; 51(6):348-56. · 0.56 Impact Factor
Article: Therapeutic options for triple-negative breast cancers with defective homologous recombination[show abstract] [hide abstract]
ABSTRACT: Breast cancer is the most common malignancy among women in developed countries, affecting more than a million women per year worldwide. Over the last decades, our increasing understanding of breast cancer biology has led to the development of endocrine agents against hormone receptor-positive tumors and targeted therapeutics against HER2-expressing tumors. However, no targeted therapy is available for patients with triple-negative breast cancer, lacking expression of hormone receptors and HER2. Overlap between BRCA1-mutated breast cancers and triple-negative tumors suggests that an important part of the triple-negative tumors may respond to therapeutics targeting BRCA1-deficient cells. Here, we review the features shared between triple-negative, basal-like and BRCA1-related breast cancers. We also discuss the development of novel therapeutic strategies to target BRCA1-mutated tumors and triple-negative tumors with BRCA1-like features. Finally, we highlight the utility of mouse models for BRCA1-mutated breast cancer to optimize (combination) therapy and to understand drug resistance.Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.