Fenretinide activity in retinoid-resistant oral leukoplakia.
OBJECTIVE
To test the hypothesis that the retinamide N-(4-hydroxyphenyl)retinamide (fenretinide) would be clinically active potentially via receptor-independent apoptosis and receptor-dependent effects in natural retinoid-resistant oral leukoplakia patients--the first test of this hypothesis in any in vivo setting.


METHODS
A phase II trial of fenretinide (200 mg/d for 3 months) in oral leukoplakia patients who had not responded (de novo resistance) or who had responded and then relapsed (acquired resistance) to previous treatment with natural retinoids. We analyzed apoptosis via the terminal deoxynucleotidyl transferase-mediated nick end labeling in situ DNA fragmentation assay.


RESULTS
We accrued 35 evaluable patients with retinoid-resistant oral leukoplakia, 12 (34.3%) had partial responses to fenretinide (95% confidence interval, 19.2-52.4%), and response was associated with acquired resistance to natural retinoids (P = 0.015, Fisher's exact test). Nine responders progressed within 9 months of stopping fenretinide. Toxicity was minimal and compliance was excellent. Mean apoptosis values (SE) increased from 0.35% (0.25%) at baseline to 1.18% (0.64%) at 3 months (P = 0.001, sign test); this increase did not correlate with clinical response. The increases in 3-month mean serum concentrations of fenretinide (0.23 micromol/L) and N-(4-methoxyphenyl)retinamide (0.57 micromol/L) correlated with decreased retinol concentrations [Spearman correlation coefficient of -0.57 (P = 0.001) and -0.43 (P = 0.01), respectively].


CONCLUSIONS
Low-dose fenretinide was clinically active and produced a small increase in apoptosis in retinoid-resistant oral leukoplakia.
Lippman
Scott M
SM
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. slippman@mdanderson.org
Lee
J Jack
JJ
Martin
Jack W
JW
El-Naggar
Adel K
AK
Xu
Xiaochun
X
Shin
Dong M
DM
Thomas
Margaret
M
Mao
Li
L
Fritsche
Herbert A
HA
Zhou
Xian
X
Papadimitrakopoulou
Vassiliki
V
Khuri
Fadlo R
FR
Tran
Hai
H
Clayman
Gary L
GL
Hittelman
Walter N
WN
Hong
Waun Ki
WK
Lotan
Reuben
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D004253:DNA Nucleotidylexotransferase; D004351:Drug Resistance; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007972:Leukoplakia, Oral / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012176:Retinoids / Q000494:pharmacology; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D012176:Retinoids; D017313:Fenretinide; D004253:DNA Nucleotidylexotransferase