Max W Sung1, Samuel Waxman. 1. Division of Hematology-Oncology, Department of Medicine, Box 1129 Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA. max.sung@mssm.edu
Abstract
BACKGROUND: Phenylbutyrate (PB), a histone deacetylase inhibitor (HDACi), has been shown in laboratory studies to potentiate growth inhibition by 5-fluorouracil (FUra) of human colon carcinoma cells. PATIENTS AND METHODS: Phase I trial of FUra (24-hour continuous intravenous infusion (CIV)) with dose escalation (2 g/m2 to 2.3 g/m2), in combination with PB (120 hour CIV at fixed dose 410 mg/kg/d x 5), repeated weekly, in patients with advanced colorectal cancer. RESULTS: Nine patients with metastatic colorectal cancer were treated, 8 of whom were evaluable for toxicity. Toxicities were dose-dependent, reversible and included somnolence, fatigue, confusion, hearing loss, triglyceridemia and hyperuricema. Three out of 4 patients who completed at least 8 weeks of treatment had stable disease (SD) lasting 12+, 25 and 54 weeks (2 out of the 3 patients with SD have had multiple prior chemotherapy regimens). CONCLUSION: Weekly infusions of FUra followed by PB were fairly well tolerated with disease stabilization in 3/4 (75%) of patients. This is the first report to demonstrate the feasibility of combining a cytotoxic agent with a HDACi as a cancer treatment.
BACKGROUND:Phenylbutyrate (PB), a histone deacetylase inhibitor (HDACi), has been shown in laboratory studies to potentiate growth inhibition by 5-fluorouracil (FUra) of humancolon carcinoma cells. PATIENTS AND METHODS: Phase I trial of FUra (24-hour continuous intravenous infusion (CIV)) with dose escalation (2 g/m2 to 2.3 g/m2), in combination with PB (120 hour CIV at fixed dose 410 mg/kg/d x 5), repeated weekly, in patients with advanced colorectal cancer. RESULTS: Nine patients with metastatic colorectal cancer were treated, 8 of whom were evaluable for toxicity. Toxicities were dose-dependent, reversible and included somnolence, fatigue, confusion, hearing loss, triglyceridemia and hyperuricema. Three out of 4 patients who completed at least 8 weeks of treatment had stable disease (SD) lasting 12+, 25 and 54 weeks (2 out of the 3 patients with SD have had multiple prior chemotherapy regimens). CONCLUSION: Weekly infusions of FUra followed by PB were fairly well tolerated with disease stabilization in 3/4 (75%) of patients. This is the first report to demonstrate the feasibility of combining a cytotoxic agent with a HDACi as a cancer treatment.
Authors: Micheline J Moussalli; Yuanqing Wu; Xiangsheng Zuo; Xiu L Yang; Ignacio Ivan Wistuba; Maria G Raso; Jeffrey S Morris; Jessica L Bowser; John D Minna; Reuben Lotan; Imad Shureiqi Journal: Cancer Prev Res (Phila) Date: 2011-08-31
Authors: M Mokhtarani; G A Diaz; W Rhead; S A Berry; U Lichter-Konecki; A Feigenbaum; A Schulze; N Longo; J Bartley; W Berquist; R Gallagher; W Smith; S E McCandless; C Harding; D C Rockey; J M Vierling; P Mantry; M Ghabril; R S Brown; K Dickinson; T Moors; C Norris; D Coakley; D A Milikien; S C Nagamani; C Lemons; B Lee; B F Scharschmidt Journal: Mol Genet Metab Date: 2013-10-08 Impact factor: 4.797