Phase I trial of continuous infusion 5-aza-2'-deoxycytidine.
OBJECTIVE
To identify a dose of the demethylating agent 5-aza-2'-deoxycytidine (DAC) with acceptable side effects, and to study its effect on the methylation patterns of relevant genes in tumor biopsies before and after treatment with a novel methylation assay using real-time PCR.


METHODS
A group of 19 patients with metastatic solid tumors were treated with DAC by continuous intravenous infusion over 72 h, days 1-3 of a 28-day cycle. Tumor biopsies were taken before and 7 days after starting DAC.


RESULTS
The dose levels studied were 20, 30 and 40 mg/m(2). Grade 4 neutropenia was found in two of five patients at 40 mg/m(2) and one of six patients at 30 mg/m(2). No objective responses were seen in this study. Steady-state DAC levels of 0.1 to 0.2 microM were achieved in the 30 and 40 mg/m(2) cohorts. Changes in methylation were observed, but no single gene consistently demonstrated evidence of demethylation.


CONCLUSIONS
DAC was tolerated at a dose of 30 mg/m(2) per day for a 72-h intravenous infusion. Changes in gene methylation were observed.
Aparicio
A
A
Department of Medicine, Keck/USC School of Medicine, Los Angeles, CA, USA.
Eads
C A
CA
Leong
L A
LA
Laird
P W
PW
Newman
E M
EM
Synold
T W
TW
Baker
S D
SD
Zhao
M
M
Weber
J S
JS
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology; D001706:Biopsy; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016133:Polymerase Chain Reaction
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D000077209:Decitabine; D001374:Azacitidine