title: Fenretinide activity in retinoid-resistant oral leukoplakia.
abstract: 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.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. slippman@mdanderson.org
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Jack W
authors.initials: JW
authors.lastname: Martin
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Xu
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Margaret
authors.initials: M
authors.lastname: Thomas
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Fritsche
authors.forename: Xian
authors.initials: X
authors.lastname: Zhou
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Hai
authors.initials: H
authors.lastname: Tran
authors.forename: Gary L
authors.initials: GL
authors.lastname: Clayman
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
mesh_terms: 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
chemical_list: D016588:Anticarcinogenic Agents; D012176:Retinoids; D017313:Fenretinide; D004253:DNA Nucleotidylexotransferase