Purpose: The histone deacetylase inhibitor depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial. Patients and Methods: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, STsegment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage. Results: Cardiac studies from 282 cycles and 736 doses of depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for z6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate^corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects. Conclusion: The data obtained in this study show that the administration of depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate^corrected QT interval prolongation remains under study.

Background: This pharmacodynamic trial evaluated the effect of CBT-1 on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1 is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1 did not alter the pharmacokinetics of paclitaxel or doxorubicin.Methods: CBT-1 was dosed at 500 mg/m 2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m 2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1 administration and on day 6 prior to the paclitaxel infusion. Tc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0 -3 hours (AUC 0 -3 ) was determined for 99m Tc-sestamibi. Results: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56ϩ PBMCs was a statistically significant 51%-100% lower (p Ͻ .0001) with CBT-1. Among 10 patients who completed imaging, the 99m Tc-sestamibi AUC 0 -3 for liver (normalized to the AUC 0 -3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p Ͻ .0001) after CBT-1 administration. Lung uptake was not changed.Conclusion: CBT-1 is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1 to evaluate its ability to modulate drug uptake in tumor tissue.Discussion: Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1Ϫ/Ϫ mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modu...

Flow cytometric analysis was done on the DNA content of nuclei obtained from different sites of small breast tumors. Although specimens for analysis were obtained within a few millimeters of each other, dramatic differences were occasionally observed in the DNA histograms. In a limited study involving 141 consecutive breast specimens submitted for flow cytometry, 52% (74) were found to have at least one DNA aneuploid population. In 18% of DNA aneuploid tumors, one or more specimens from areas grossly identified as tumor had no DNA aneuploid population. Because of the proposed correlation of aneuploidy with a poorer prognosis and possible responsiveness to chemotherapy, multiple sites should be assayed when flow cytometric DNA analysis is done.