Results were consistent with AML or the presence of leukemic myeloblasts (in high-risk MDS) in all but 2 individuals (1 T-lineage and 1 B-lineage ALL). were more common in P-gp+individuals. P-gp manifestation and cytogenetics were correlated, though self-employed prognostic factors. We conclude that zosuquidar did not improve end result in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is definitely authorized atwww.clinicaltrials.govas #NCT00046930. == Intro == The manifestation of P-glycoprotein (P-gp), a member of the adenosine triphosphate-binding cassette family of transmembrane proteins is one (S)-Tedizolid element responsible for multidrug resistance in acute myeloid leukemia (AML). Manifestation of P-gp correlates with a reduced full remission (CR) rate and shorter durations (S)-Tedizolid of overall survival (OS) or disease-free survival (DFS) and may, in part, account for the poorer end result of older adults with AML.15A potential benefit to pharmacologic modulation of P-gpmediated efflux was reported by the Southwest Oncology Group (SWOG 9126) trial in which individuals with relapsed or refractory AML who received cyclosporine A (CSA), a competitive modulator of P-gp, had a superior event-free survival compared with individuals who received placebo.6However, subsequent randomized tests of CSA or PSC-833, a nonimmunosuppressive and nonnephrotoxic analog of CSA, failed to demonstrate an improvement in outcome.711Potential explanations for the lack of good thing about P-gp modulation with PSC-833 in AML include suboptimal modulation of efflux and increased treatment toxicity because of inhibition of clearance of anthracyclines via interference with P-gpmediated hepatobiliary excretion or metabolism. Therefore, a more potent and specific modulator that does not prolong the clearance of daunorubicin may demonstrate an improved restorative (S)-Tedizolid index. Zosquidar is a potent (Ki = 59nM) and highly selective modulator of P-gp that restored the level of sensitivity of cell lines selected for resistance based on P-gp manifestation.12,13Preclinical studies exhibited that zosuquidar had minimal effect on the pharmacokinetic profile of coadministered P-gp substrates. Zosuquidar does not inhibit additional members of the adenosine triphosphate-binding drug transporter family, such as the multidrug resistance-related protein (MRP1) or the breast cancer resistance protein BCRP) or impact P450 isozymes at concentrations below the micromolar range.14Phase I tests of intravenous or dental zosuquidar with doxorubicin in individuals with solid tumors exhibited only a moderate decrease in clearance and increase in the area under the curve for doxorubicin.15,16Increasing plasma concentrations of zosuquidar resulted in higher inhibition of rhodamine-123 efflux in CD56+natural killer cells isolated from your peripheral blood of treated subjects.17Zosuquidar was generally well tolerated, with reversible grade 1 or 2 2 neurologic toxicity the most common side effect.15,16A phase 1 trial of zosuquidar administered with standard doses of Rabbit polyclonal to ABHD12B daunorubicin and cytarabine to patients with newly diagnosed AML confirmed an acceptable safety profile.18Therefore, the Leukemia Committee of Eastern Cooperative Oncology Group (ECOG) carried out a double-blind, placebo-controlled trial of zosuquidar administered with conventional-dose induction chemotherapy in newly diagnosed AML or high-risk myelodysplastic syndromes (MDSs) who have been more than 60 years. == Methods == == Eligibility criteria == The protocol was examined and approved in the participating institutions’ human subject review boards, and all patients signed knowledgeable consent in accordance with the Declaration of Helsinki. Individuals more than 60 years with newly (S)-Tedizolid diagnosed refractory anemia with excess blasts in transformation (RAEB-t), high-risk RAEB, and de novo or secondary AML were eligible for enrollment. Secondary AML was defined as a history of an antecedent hematologic disorder or a history of prior chemotherapy or radiation therapy. Patients were considered to have high-risk RAEB if the bone marrow blast percentage was 11% to 20% or cytogenetics were poor risk.19Eligible individuals were required to have an ECOG performance status 3, a serum total bilirubin less than 3 mg/dL, and a serum creatinine less than 2 mg/dL. A resting left ventricular cardiac ejection fraction of greater than 45% by either a gated blood pool study or echocardiogram was needed. == Sign up and randomization methods == Patients were authorized and randomized to either placebo or zosuquidar. There were 2 stratification criteria at randomization, age (< 70 years or 70 years) and leukemia type ([1] de novo AML or RAEB-t, [3] RAEB, or [3] secondary AML). The original stratification level for leukemia type had been de novo versus secondary AML or RAEB-t (reflecting the modification of the definition of AML from the World Health Corporation) and AML or RAEB-t versus high-risk RAEB, but after randomization of the first 11 individuals, the.
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