Clinical and molecular responses in lung cancer patients receiving Romidepsin.
OBJECTIVE
Our preclinical experiments indicated that Romidepsin (Depsipeptide FK228; DP) mediates growth arrest and apoptosis in cultured lung cancer cells. A phase II trial was done to examine clinical and molecular responses mediated by this histone deacetylase inhibitor in lung cancer patients.


METHODS
Nineteen patients with neoplasms refractory to standard therapy received 4-h DP infusions (17.8 mg/m(2)) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of two identical 21-day cycles. Plasma DP levels were evaluated by liquid chromatography-mass spectrometry techniques. A variety of molecular end points were assessed in tumor biopsies via immunohistochemistry techniques. Long oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after DP exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections.


RESULTS
Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in one individual. No significant cardiac toxicities were observed. Maximum steady-state plasma DP concentrations ranged from 384 to 1,114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in nine patients. DP enhanced acetylation of histone H4, increased p21 expression in lung cancer cells, and seemed to shift global gene expression profiles in these cells toward those detected in normal bronchial epithelia.


CONCLUSIONS
Although exhibiting minimal clinical efficacy at this dose and schedule, DP mediates biological effects that may warrant further evaluation of this histone deacetylase inhibitor in combination with novel-targeted agents in lung cancer patients.
Schrump
David S
DS
Thoracic Oncology Section Surgery Branch, Center for Cancer Research and Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, MD 20892, USA. david.schrump@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
Kruchin
Evgeny
E
Wright
John J
JJ
Rosing
Douglas R
DR
Sparreboom
Alex
A
Figg
William D
WD
Steinberg
Seth M
SM
D000107:Acetylation / Q000187:drug effects; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D047630:Depsipeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006657:Histones / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D006657:Histones; C087123:romidepsin