Effects of N-(4-hydroxyphenyl)retinamide on hTERT expression in the bronchial epithelium of cigarette smokers.
BACKGROUND
Telomerase activation plays a critical role in tumorigenesis. To determine the role of telomerase in early lung carcinogenesis and as a potential biomarker in chemoprevention trials, we analyzed the expression of the human telomerase reverse transcriptase catalytic subunit (hTERT) in bronchial biopsy specimens from cigarette smokers who were enrolled in a randomized, double-blinded, placebo-controlled chemoprevention trial of N-(4-hydroxyphenyl)retinamide (4-HPR).


METHODS
We obtained biopsy specimens from six predetermined sites in the bronchial tree from the 57 participants, before treatment and 6 months after treatment with 4-HPR or placebo. We used in situ hybridization to examine hTERT messenger RNA (mRNA) expression in 266 pretreatment (baseline) and post-treatment site-paired biopsy specimens from 27 patients in the 4-HPR-treated group and from 30 patients in the placebo-treated group. All statistical tests were two-sided.


RESULTS
At baseline, 62.4% (95% confidence interval [CI] = 53.9% to 71%) of the biopsy specimens obtained from the group treated with 4-HPR and 65.2% (95% CI = 57.4% to 73.1%) of the biopsy specimens obtained from the placebo-treated group expressed hTERT mRNA. After 6 months, 45.6% (95% CI = 36.9% to 54.3%) of the biopsy specimens obtained from the 4-HPR-treated group and 68.1% (95% CI = 60.4% to 75.8%) of the biopsy specimens obtained from the placebo-treated group expressed hTERT mRNA. The reduction in hTERT expression observed between the two treatment groups over time was statistically significant (P =.01) when we used the biopsy site as the unit of analysis, but not when we used the individual as the unit of analysis (P =.37).


CONCLUSIONS
Telomerase is frequently reactivated in the lungs of cigarette smokers. The modulation of hTERT expression in 4-HPR-treated smokers suggests that a novel molecular mechanism underlies the potential chemopreventive properties of 4-HPR. hTERT expression is a promising potential biomarker for risk assessment and for the evaluation of the efficacy of chemopreventive agents in lung carcinogenesis.
Soria
J C
JC
Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Moon
C
C
Wang
L
L
Hittelman
W N
WN
Jang
S J
SJ
Sun
S Y
SY
Lee
J J
JJ
Liu
D
D
Kurie
J M
JM
Morice
R C
RC
Lee
J S
JS
Hong
W K
WK
Mao
L
L
D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology*; D020134:Catalytic Domain / Q000187:drug effects; D004268:DNA-Binding Proteins; D004311:Double-Blind Method; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D018570:Risk Assessment; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D019098:Telomerase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017313:Fenretinide; D019098:Telomerase