Combination of cytotoxic-differentiation therapy with 5-fluorouracil and phenylbutyrate in patients with advanced colorectal cancer.
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.


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).


CONCLUSIONS
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.
Sung
Max W
MW
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
Waxman
Samuel
S
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000009:adverse effects
D010654:Phenylbutyrates; D005472:Fluorouracil