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Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human(More)
PURPOSE To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. PATIENTS AND METHODS In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2(More)
The action of the new deoxycytidine analogue 2',2'-difluorodeoxycytidine (dFdC) on DNA synthesis was investigated in whole cells and in vitro assay systems with purified DNA polymerases. DNA synthesis in human lymphoblastoid CEM cells was inhibited by dFdC in a concentration-dependent manner that could not be reversed by exogenous deoxynucleosides. The(More)
2',2'-Difluorodeoxycytidine (dFdC) is a new deoxycytidine analogue with good activity against human leukemic cell lines and murine solid tumors, while the activity of 1-beta-D-arabinofuranosylcytosine (ara-C) is established in experimental systems and for the treatment of human adult leukemia. This study compared the cellular metabolism and cytotoxic(More)
Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator(More)
PURPOSE Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete(More)
The objective of this study was to determine the dose rate of 2',2'-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5'-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells(More)
PURPOSE Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of(More)
Despite progress in leukemia therapy, most children who experience relapse have a dismal prognosis. New, effective approaches are needed. We conducted a phase 1 study of a novel nucleoside analog, clofarabine, in pediatric patients with refractory and relapsed leukemia. Clofarabine was infused intravenously over 1 hour each day for 5 days. Six dose levels,(More)
Previous studies have indicated that deoxycytidine kinase (dCK) is requisite and rate limiting in the phosphorylation of 1-beta-D-arabinofuranosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) on the pathway to their respective cytotoxic 5'-triphosphates. In K562 cells, the rate of triphosphate accumulation was maximal during(More)