Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms.

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma).

Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion.

Histone deacetylase inhibitors activate NF-kappaB in human leukemia cells through an ATM/NEMO-related pathway.

Mechanisms underlying histone deacetylase inhibitor (HDACI)-mediated NF-kappaB activation were investigated in human leukemia cells. Exposure of U937 and other leukemia cells to LBH-589 induced reactive oxygen species (ROS) followed by single strand (XRCC1) and double strand (gamma-H2AX) DNA breaks. Notably, LBH-589 lethality was markedly attenuated by small interfering RNA (siRNA) knockdown of the DNA damage-linked histone, H1.

Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma.

Purpose: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically.

Experimental Design: A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.

Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions.

The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclin-dependent kinase inhibitor flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation.

Chromatin-dependent regulation of the MMTV promoter by cAMP signaling is mediated through distinct pathways.

The nucleoprotein structure of the mouse mammary tumor virus (MMTV) promoter defines its response to cAMP signaling. A stably replicating MMTV template in highly organized chromatin is repressed in the presence of cAMP, whereas a transiently transfected template with a disorganized structure is activated. In this study, we investigate the nature of the cAMP-induced signal(s) by which these opposing responses occur to gain insight into their mechanism.