Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura.
OBJECTIVE
The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2'-deoxycytidine (DAC) in patients with thoracic malignancies.


METHODS
Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure.


RESULTS
Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m(2) depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues.


CONCLUSIONS
Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.
Schrump
David S
DS
Thoracic Oncology Section Surgery Branch, Cancer Therapy Evaluation Program, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA. davidschrump@nih.gov
Fischette
Maria R
MR
Nguyen
Dao M
DM
Zhao
Ming
M
Li
Xinmin
X
Kunst
Tricia F
TF
Hancox
Ana
A
Hong
Julie A
JA
Chen
G Aaron
GA
Pishchik
Vitaliy
V
Figg
William D
WD
Murgo
Anthony J
AJ
Steinberg
Seth M
SM
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; C104948:CTAG1B protein, human; C072013:MAGEA3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine