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Fenretinide Activity in Retinoid-Resistant Oral Leukoplakia

Authors' Affiliations: Departments of ¹ Clinical Cancer Prevention, ² Thoracic/Head and Neck Medical Oncology, ³ Biostatistics and Applied Mathematics, ⁴ Head and Neck Surgery, ⁵ Pathology, ⁶ Laboratory Medicine, and ⁷ Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁸ Department of Hematology/Oncology, Winship Cancer Institute at Emory University, Atlanta, Georgia

Requests for reprints: Scott M. Lippman, Department of Thoracic/Head and Neck Medical Oncology Unit 432, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-745-5439; Fax: 713-745-2012; E-mail: slippman{at}mdanderson.org.

	Abstract

Top Abstract Patients and Methods Results Discussion References

 
Purpose: 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.

Experimental Design: 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 µmol/L) and N-(4-methoxyphenyl)retinamide (0.57 µmol/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.

Retinoids are among the most extensively studied class of chemoprevention agents in oral IEN to date, and natural retinoids, including retinyl palmitate and 13-cis-retinoic acid (13cRA; which is a natural metabolite of vitamin A and is present endogenously in human serum), are the best-studied retinoids in this setting (6–10). Short-term (3-6 months) natural retinoid therapy was significantly clinically active in randomized oral IEN trials. Most responding oral IEN, however, recurred within months of stopping treatment. Although prolonged retinoid treatment can delay progression, oral IEN becomes resistant to treatment over time, eventually progressing in association with persistent genotypic alterations and cancer development (11, 12). De novo or acquired resistance has proven to be a major obstacle to the use of natural retinoids in the setting of advanced oral IEN, which needs better treatment to prevent or delay oral cancer development (11).

The classic signaling pathways for the effects of 13cRA and other natural retinoids involve the nuclear retinoid receptors—retinoic acid receptors (RAR) and retinoid X receptors. It is thought that the major effect of natural retinoids, mediated by the RARs and retinoid X receptors, is to modulate cell growth and differentiation. Translational studies have shown that 13cRA activates the transcription of genes, such as RAR-ß, containing retinoic acid response elements in their promoter regions (13).

The retinamides are synthetic retinoids that can potently induce apoptosis in cancer cells via a retinoid receptor–independent mechanism in addition to having retinoid receptor–dependent effects (14, 15). The retinamide N-(4-hydroxyphenyl)retinamide (4-HPR, or fenretinide) can induce apoptosis via reactive oxygen species, mitochondrial membrane permeability transition, activation of members of the activator protein-1 transcription factor family and of caspase-8, ceramide generation, and inhibition of nuclear factor-B activation (16–20). Fenretinide can induce apoptosis in cancer cell lines resistant to natural retinoids that work via the classic retinoid-receptor signaling pathways and in receptor-knockout cells (refs. 21–24; summarized in ref. 17). These data suggest that fenretinide (a) may overcome de novo or acquired resistance to 13cRA or other natural retinoids and (b) may eliminate premalignant clones via apoptosis, which would allow effective short-term treatment of oral IEN. We hypothesized that fenretinide would be clinically active in oral IEN via receptor-independent apoptosis in de novo retinoid-resistant lesions and via receptor-independent and receptor-dependent effects in lesions with acquired resistance. The present phase II translational study of short-term therapy with fenretinide in natural retinoid-resistant oral IEN is the first test of this hypothesis in vivo.

	Patients and Methods

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Patient eligibility. All patients had bidimensionally measurable advanced oral IEN, as defined previously (9), that was resistant to a natural retinoid. Lesion resistance was defined as (a) never responding (including no change or progressing) or (b) responding initially but subsequently progressing on prior retinoid therapy. All patients came from our National Cancer Institute randomized trial of 13cRA versus retinyl palmitate, except one who was resistant to 13cRA given off protocol. Other eligibility criteria included adequate renal, hematologic, and hepatic function and a Zubrod PS <2. The protocol was approved by the M. D. Anderson Cancer Center Institutional Review Board, and informed, signed consent was required from each patient.

Clinical trial design. We tested oral fenretinide (200 mg/d) for 3 months in a single-arm phase II trial that included a monthly 3-day drug holiday to prevent fenretinide-related ocular toxicity. The primary end point was the clinical response of oral IEN; secondary end points included toxicity and changes in the biomarkers discussed below. Patients were accrued in two stages, per a standard phase II design (described in the "Statistical Considerations" section), and evaluated every 3 months for 1 year. Fenretinide was supplied by R.W. Johnson Pharmaceutical Research Institute. The full 200 mg dose of fenretinide was recommended to be taken at breakfast. Patients were seen at monthly intervals and evaluated for compliance, drug-related toxicity, and serum drug concentrations. Response and toxicity were assessed according to standard criteria (9).

Serum evaluations for fenretinide, N-(4-methoxyphenyl)retinamide, and retinol. Concentrations of fenretinide and its major metabolite N-(4-methoxyphenyl)retinamide (4-MPR) and retinol were measured in serum samples obtained at two time points (baseline and 3 months of treatment), frozen at –70°C, and protected from light exposure. Determinations of fenretinide and 4-MPR concentrations were made using a previously validated high-performance liquid chromatography assay with 4-ethoxyphenylretinamide as an internal standard (25). The chromatographic separation was done on a Vydac 201TP column (0.46 x 25 cm). The isocratic mobile phase consisted of 55% acetonitrile, 10% n-butyl alcohol, 35% water, and 0.01 mol/L ammonium acetate. The UV detector was programmed at 364 nm for the first 12 minutes, 325 nm for the next 3 minutes, and 364 nm for the last 8 minutes to correspond to the elution times of fenretinide, retinol, and 4-MPR/4-ethoxyphenylretinamide, respectively. Serum concentrations were measured in blood collected before breakfast 24 hours after the 200 mg dose of the previous morning (at breakfast).

Apoptosis assay: terminal deoxynucleotidyl transferase–mediated nick end labeling. Apoptosis in tissue biopsies was analyzed by the terminal deoxynucleotidyl transferase–mediated nick end labeling method as follows: formalin-fixed, paraffin-embedded tissue sections were deparaffinized in xylene, rehydrated in a series of ethanol solutions (100-50%), and first treated with 0.2 N HCl for 10 minutes at room temperature and then with proteinase K (20 µg/mL) for 30 minutes at 37°C. The endogenous peroxidase activity was blocked by incubation in a 3% methanolic hydrogen peroxide solution for 5 minutes at room temperature. Subsequently, the sections were incubated with terminal deoxynucleotidyl transferase buffer (Trevigen, Inc., Gaithersburg, MA) for 5 minutes and then transferred to a terminal deoxynucleotidyl transferase enzyme mixture containing terminal deoxynucleotidyl transferase buffer, terminal deoxynucleotidyl transferase at 1:400 (Roche Biomedical Corp, Indianapolis, IN), biotinylated dUTP at 1:200 (Roche), and 400 µmol/L MnSO₄, and incubated at 37°C for 60 minutes. To detect the positive signal, the sections were incubated with the ABC kit (Vector Laboratories, Burlingame, CA) for 30 minutes in the dark. This was followed by incubation with 3-amino-9-ethylcarbazole (Sigma Chemical Co., St. Louis, MO) solution for 30 minutes to visualize the peroxidase complex. Finally, the sections were mounted with Aqua mount medium under coverslips. Deoxynucleotidyl transferase was omitted to create negative controls. A positive control consisted of cytospun cells, which were obtained from an APO-BRDU Apoptosis kit (Phoenix Flow Systems, San Diego, CA) or from head and neck cancer cells previously treated with 10 µmol/L fenretinide for 12 hours. The stained sections were reviewed independently by two pathologists with an Olympus microscope. The percentage of positive cells was calculated after counting the total cells and positively stained cells.

In situ mRNA hybridization studies of RAR-ß expression. Nonradioactive in situ hybridization of RAR-ß was done using digoxigenin-labeled antisense riboprobes on formalin-fixed, paraffin-embedded tissue biopsies, as described previously (13). The binding specificity of the antisense riboprobes was verified using sense probes as controls. Staining was scored as either detectable or undetectable. RNA quality was verified by in situ hybridization of retinoid X receptor- mRNA, which is expressed constitutively in oral epithelium.

Statistical considerations. We used a Simon's optimal two-stage design for phase II trials. The first stage was designed for 12 patients. With no response or one response in the first stage, the trial would be terminated and fenretinide would be considered inactive. With two or more responses in the first stage, the trial would continue and accrue 23 additional patients. Fenretinide would be considered active if 5 patients responded and inactive if <5 responded. The design would have type I and type II error rates controlled at the 10% level with response rates of 10% and 30% under the null and alternative hypotheses, respectively. Descriptive statistics and frequency tabulation were used to summarize the patient characteristics and toxicity profile. ² test (or the Fisher's exact test for small samples) was applied to associations between unpaired categorical variables, and sign test was applied to associations between paired categorical variables. We calculated the Spearman's rank correlation for associations between retinol, fenretinide and 4-MPR levels in serum. All P values were based on two-sided tests.

	Results

Top Abstract Patients and Methods Results Discussion References

 
A total of 38 patients were registered to this two-stage study. Three of the 12 patients accrued in the first stage responded, and so we initiated the second stage and accrued a total of 35 evaluable patients. Of the three registered patients who were not evaluable, one never started therapy and so was excluded from all analyses and two were excluded from the response analyses for reasons unrelated to fenretinide—death from a pulmonary embolism 23 days after starting the study in one case; refusal of further treatment only 2 days after starting fenretinide because of a sinus infection in the other case. Of the 35 evaluable patients, 10 had initially responded to previous retinoid treatment but then progressed, and 25 had not responded to previous retinoid treatment.

The patient characteristic data are based on all 37 patients evaluable for toxicity. There were 25 men and 12 women and 31 White, 4 Hispanic, 1 Black, and 1 Asian patients. The mean age (SD) was 60.1 (13.4) years; median age was 61 years (range, 26-84). The most common primary lesion sites were the buccal mucosa (n = 15) and ventrolateral tongue or floor of mouth (n = 11). Dysplastic lesions occurred in 10 patients. Baseline smoking statuses were as follows: never (n = 6), former (n = 19), and current (n = 12). Baseline alcohol use statuses were as follows: never (n = 10), former (n = 11), and current (n = 16).

The 3-month response data (in the 35 patients evaluable for response) were as follows: 0 complete responses, 12 partial responses, 15 cases of stable disease, and 8 cases of progressive disease. Nine of the 12 responding patients progressed within 9 months of stopping fenretinide. The primary study end point of overall 3-month clinical response (complete responses + partial responses) was 34.3% (95% confidence interval, = 19.2-52.4%). Prior clinical response to natural retinoids (see Patients and Methods) was significantly associated with subsequent response to fenretinide (P = 0.015, Fisher's exact test)—the response rates to fenretinide were 70% for previous responders versus 20% for previous nonresponders (Table 1 ).

Serum concentrations of fenretinide, 4-MPR, and retinol are listed in Table 2 . The mean 3-month fenretinide and 4-MPR concentrations were 0.23 and 0.57 µmol/L, respectively, and the maximum concentrations were 0.66 and 1.76 µmol/L, respectively. Fenretinide concentrations directly correlated with 4-MPR concentrations (Spearman correlation coefficient of 0.81, P < 0.0001; Fig. 1A ). After 3 months of treatment, the increase in fenretinide correlated with decreased retinol levels (Spearman correlation coefficient of –0.57, P = 0.001; Fig. 1B). Similarly, the 3-month 4-MPR concentrations also correlated with the decrease in retinol concentrations (Spearman correlation coefficient of –0.43, P = 0. 01; Fig. 1C). The combined fenretinide and 4-MPR concentrations at 3 months also correlated with decreased retinol concentrations (Fig. 1D). There was no significant difference between male and female patients in either their baseline or posttreatment serum retinol levels.

View larger version (14K): [in this window] [in a new window]   Fig. 1. Interrelationships of serum level changes for fenretinide (4-HPR), 4-MPR, and retinol from baseline to 3 months (after treatment with 4-HPR). Scatterplots of changes (from baseline to 3 months) for 4-MPR versus 4-HPR (A), retinol versus 4-HPR (B), retinol versus 4-MPR (C), and retinol versus 4-HPR plus 4-MPR (D).

The terminal deoxynucleotidyl transferase–mediated nick end labeling data are presented in Table 3 . The absolute apoptosis values were low at baseline mean (SE) values of 0.35% (0.25%) and were higher at 3 months, 1.18% (0.64%). Comparing the apoptotic values at baseline with those at 3 months shows that values increased in 18 patients, remained the same in 10, and decreased in 3 (P = 0.002, sign test). There was no correlation between apoptosis and IEN response (P = 0.35, Fisher's exact test).

	Discussion

Top Abstract Patients and Methods Results Discussion References

 
Fenretinide was clinically active in patients with oral IEN that was resistant to a natural retinoid. We originally hypothesized that this activity would result in part from retinoid receptor–independent apoptosis, which would eliminate premalignant clones and allow effective short-term oral IEN therapy. Apoptosis induction, however, did not correlate with fenretinide clinical activity. The activity of fenretinide seemed to have been mediated by RAR signaling, as suggested by the following results: present response to fenretinide correlated with prior retinoid response and all responses were partial and generally short-lived (consistent with response to natural retinoids). The correlation between present and prior response possibly involved the (likely) presence of functional or inducible nuclear retinoid receptors (which have been shown to mediate, at least in part, the in vitro response of certain cancer cell types to fenretinide; ref. 16) in lesions of patients with a prior response to retinoic acid therapy (14, 15). This RAR mediation hypothesis, however, does not exclude the possibility that other factors, such as greater IEN differentiation, also could account for the correlation between prior and present IEN response.

In vitro study has shown that fenretinide has dual effects, depending on its concentration—RAR-dependent cell differentiation at low concentrations and RAR-independent apoptosis at high concentrations (21). A low concentration of fenretinide induced differentiation in wild-type but not in RAR--null (or retinoid X receptor--null) cells. Although limited relevant clinical data are available and we were unable to measure fenretinide tissue levels in our present patients' lesions because of a paucity of material, we believe that relatively low tissue levels dictated the nature of fenretinide clinical activity in this study. We conducted a previous study of fenretinide in breast cancer patients (26) that leads us to conclude that fenretinide tissue levels were not high enough (3-5 µmol/L) to induce receptor-independent apoptosis in the present study. Fenretinide levels were 5-fold higher in breast tissue than in plasma at the 200 mg/d dose but still reached only 1.63 µmol/L (26), which is suboptimal for induction of apoptosis in vitro. Furthermore, fenretinide is thought to accumulate in breast tissue partly because of fat cells in the breast, and fat cells are unlikely to play an important role in oral IEN.

We now hypothesize that the specific mediator of fenretinide effects in the present study may have been RAR-, which is the predominate retinoid receptor in normal oral epithelium and, as we have previously shown, is not lost in oral IEN (13). Fenretinide reportedly preferentially transactivates RAR- (27) and our previous work has shown that knocking out RAR- in F9 cells blocks the differentiation activity of low-concentration fenretinide (21). Although not specific to RAR-, other data also support retinoid receptor mediation in the present study (14, 15). Our group has found that the same dose and schedule of fenretinide (200 mg/d) that were used in the present study reduced the expression of human telomerase reverse transcriptase catalytic subunit in lung premalignancy patients (28). Human telomerase reverse transcriptase suppression by low-dose fenretinide may be RAR-mediated because RAR/retinoid X receptor heterodimers can bind and activate estrogen response elements, which have been identified in the human telomerase reverse transcriptase promoter (29). We concluded that RAR-ß did not play a major role in the present study because RAR-ß was present at baseline in all but two of our previously treated patients (which is consistent with RAR-ß up-regulation by natural retinoids; ref. 13).

Although statistically significantly increased (versus baseline), the postfenretinide apoptosis index was modest in degree and, as mentioned above, did not correlate with clinical response. Fenretinide tumor–preventive and apoptosis-induction effects also did not correlate in a recent in vivo study in mouse skin carcinogenesis (30). In vitro studies by our and other groups have shown that very high concentrations of fenretinide (3-5 µmol/L) are necessary for inducing apoptosis and are 10-fold higher than the serum fenretinide concentrations (mean, 0.23 µmol/L; maximal, 0.66 µmol/L) achieved in our patients with the current fenretinide dosing regimen (31). Therefore, we believe that the modest level of apoptosis we observed in this trial resulted from an RAR-dependent mechanism and not from RAR-independent effects of fenretinide.

Although serum fenretinide concentrations in our study vary from some previous reports (32, 33), several factors can contribute to such differences, including the variable disposition of fenretinide pharmacokinetics, timing of the prior fenretinide dose and blood collection, timing between taking fenretinide and meal intake, and food taken with fenretinide (e.g., a high-protein or high-fat meal may enhance fenretinide bioavailability; ref. 34). Concentrations in the current study [mean fenretinide, 0.23 µmol/L (or 90.05 ng/mL); mean 4-MPR, 0.57 µmol/L (or 230.9 ng/mL)] are similar to concentrations (fenretinide, 104.5 ng/mL; 4-MPR, 201.6 ng/mL) in another study by our group of the same daily fenretinide dose and schedule (35). The sums of fenretinide and 4-MPR concentrations are also similar in our present and earlier study. Formelli et al. (32) have reported higher concentrations than we do here but the difference likely is due in large part to different timing of the test [24 hours (present) versus 8 to 12 hours (Formelli) following the dose]. Also, different meals were taken with fenretinide—breakfast (present study) versus dinner (Formelli study), and dinner may contain more protein and thus increase fenretinide serum levels (versus breakfast).

Baseline serum retinol concentrations seem to be higher than have been reported in the literature (36). Retinol levels increase with age, reaching a plateau at or near age 60, which is the mean age of our study population. Although our observed retinol concentration is higher, its SD value overlaps that of the previously reported mean concentration (36). Furthermore, our baseline retinol concentration is similar to that reported in another study by our group of the same dose and schedule of fenretinide (35), conducted in patients with similar characteristics of age, gender, and smoking status. Participants in cancer prevention studies tend to be health-conscious volunteers, and so the participants in our current and prior prevention studies may have taken supplemental vitamin A that boosted serum vitamin A concentrations above the norm.

A recent Italian adjuvant trial in patients with resected oral IEN found that fenretinide at 200 mg/d (the same dose as in our trial) for 1 year significantly prevented relapse or new lesion development (37). These and our data show fenretinide activity in adjuvant and primary oral IEN treatment settings and thus support future clinical trials of (a) fenretinide combined with other agents that potentially can enhance fenretinide clinical activity (38) and (b) promising new retinamides demonstrating significantly greater activity (versus fenretinide) in head and neck cancer cell lines (31).

	Footnotes

 
Grant support: National Cancer Institute, NIH, Department of Health and Human Services grants P01 CA052051 and P30 CA016672 (The University of Texas M.D. Anderson Cancer Center support grant).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S.M. Lippman holds the Charles A. LeMaistre Distinguished Chair in Thoracic Oncology. R. Lotan holds the Irving and Nadine Mansfield and Robert David Levitt Cancer Research Chair at M.D. Anderson Cancer Center. W.K. Hong is an American Cancer Society Clinical Research Professor.

Received 12/ 2/05; revised 2/24/06; accepted 3/ 6/06.

	References

Top Abstract Patients and Methods Results Discussion References

 

1. Jemal A, Murray T, Ward E, et al. Cancer Statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
2. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993;328:184–94.[Free Full Text]
3. O’Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002;8:314–46.[Abstract/Free Full Text]
4. Lippman SM, Hong WK. Molecular markers of the risk of oral cancer (editorial). N Engl J Med 2001;344:1323–6.[Free Full Text]
5. Lee JJ, Hong WK, Hittelman WN, et al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 2000;6:1702–10.[Abstract/Free Full Text]
6. Mayne ST, Lippman SM. Retinoids, carotenoids, and micronutrients. 7th ed. In: DeVita VT, Jr., Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 521–36.
7. Hong WK, Endicott J, Itri LM, et al. 13-Cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501–5.[Abstract]
8. Hong WK, Lippman SM, Itri L, et al. Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck. N Engl J Med 1990;323:795–801.[Abstract]
9. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with ß-carotene to prevent oral carcinogenesis. N Engl J Med 1993;328:15–20.[Abstract/Free Full Text]
10. Lippman SM, Lee JJ. Reducing the "risk" of chemoprevention: defining and targeting high risk-2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res 2006;66:2893–903.[Abstract/Free Full Text]
11. Lippman SM, Hong WK. Cancer prevention by delay. Clin Cancer Res 2002;8:305–13.[Free Full Text]
12. Mao L, El-Naggar AK, Papadimitrakopoulou V, et al. Phenotype and genotype in advanced premalignant head and neck lesions after chemopreventive therapy. J Natl Cancer Inst 1998;90:1545–51.[Abstract/Free Full Text]
13. Lotan R, Xu C, Lippman SM, et al. Suppression of retinoic acid receptor ß in oral premalignant lesions and its upregulation by isotretinoin. N Engl J Med 1995;332:1405–10.[Abstract/Free Full Text]
14. Pergolizzi R, Appierto V, Crosti M, et al. Role of retinoic acid receptor overexpression in sensitivity to fenretinide and tumorigenicity of human ovarian carcinoma cells. Int J Cancer 1999;81:829–34.[CrossRef][Medline]
15. Ozpolat B, Tari AM, Mehta K, Lopez-Berestein G. Nuclear retinoid receptors are involved in N-(4-hydroxyphenyl) retinamide (fenretinide)-induced gene expression and growth inhibition in HL-60 acute myeloid leukemia cells. Leuk Lymphoma 2004;45:979–85.[CrossRef][Medline]
16. Lotan R. Retinoids and apoptosis: implications for cancer chemoprevention and therapy. J Natl Cancer Inst 1995;87:1655–7.[Free Full Text]
17. Dmitrovsky E. Fenretinide activates a distinct apoptotic pathway. J Natl Cancer Inst 2004;96:1264–5.[Free Full Text]
18. Appierto V, Villani MG, Cavadini E, Lotan R, Vinson C, Formelli F. Involvement of c-Fos in fenretinide-induced apoptosis in human ovarian carcinoma cells. Cell Death Differ 2004;11:270–9.[CrossRef][Medline]
19. Kalli KR, Devine KE, Cabot MC, et al. Heterogeneous role of caspase-8 in fenretinide-induced apoptosis in epithelial ovarian carcinoma cell lines. Mol Pharmacol 2003;64:1434–43.[Abstract/Free Full Text]
20. Shishodia S, Gutierrez AM, Lotan R, Aggarwal BB. N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I()B() kinase and nuclear factor-B-regulated gene products. Cancer Res 2005;65:9555–65.[Abstract/Free Full Text]
21. Clifford JL, Menter DG, Wang M, Lotan R, Lippman SM. Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl)retinamide in F9 embryonal carcinoma cells. Cancer Res 1999;59:14–8.[Abstract/Free Full Text]
22. Delia D, Aiello A, Lombardi L, et al. N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid. Cancer Res 1993;53:6036–41.[Abstract/Free Full Text]
23. Sheikh MS, Shao ZM, Li XS, et al. N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. Carcinogenesis 1995;16:2477–86.[Abstract/Free Full Text]
24. Oridate N, Lotan D, Xu XC, Hong WK, Lotan R. Differential induction of apoptosis by all-trans-retinoic acid and N-(4-hydroxyphenyl)retinamide in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res 1996;2:855–63.[Abstract]
25. MacCrehan WA. NIST measurements of (4-hydroxyphenyl)retinamide in serum. Clin Chem 1987;33:1585–92.[Abstract/Free Full Text]
26. Sabichi AL, Modiano MR, Lee JJ, et al. Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide. Clin Cancer Res 2003;9:2400–5.[Abstract/Free Full Text]
27. Fanjul AN, Delia D, Pierotti MA, Rideout D, Qiu J, Pfahl M. 4-Hydroxyphenyl retinamide is a highly selective activator of retinoid receptors. J Biol Chem 1996;271:22441–6.[Abstract/Free Full Text]
28. Soria JC, Moon C, Wang L, et al. Effects of N-(4-hydroxyphenyl)retinamide on hTERT expression in the bronchial epithelium of cigarette smokers. J Natl Cancer Inst 2001;93:1257–63.[Abstract/Free Full Text]
29. Kyo S, Takakura M, Kanaya T, et al. Estrogen activates telomerase. Cancer Res 1999;59:5917–21.[Abstract/Free Full Text]
30. Xu H, Cheepala S, McCauley E, et al. Chemoprevention of skin carcinogenesis by phenylretinamides: retinoid receptor independent tumor suppression. Clin Cancer Res 2006;12:969–79.[Abstract/Free Full Text]
31. Sun SY, Yue P, Kelloff GJ, et al. Identification of retinamides that are more potent than N-(4-hydroxyphenyl)retinamide in inhibiting growth and inducing apoptosis of human head and neck and lung cancer cells. Cancer Epidemiol Biomark Prev 2001;10:595–601.[Abstract/Free Full Text]
32. Formelli F, Clerici M, Campa T, et al. Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations. J Clin Oncol 1993;11:2036–42.[Abstract/Free Full Text]
33. Baglietto L, Torrisi R, Arena G, et al. Ocular effects of fenretinide, a vitamin A analog, in a chemoprevention trial of bladder cancer. Cancer Detect Prev 2000;24:369–75.[Medline]
34. Doose DR, Minn FL, Stellar S, Nayak RK. Effects of meals and meal composition on the bioavailability of fenretinide. J Clin Pharmacol 1992;32:1089–95.[Abstract]
35. Kurie JM, Lee JS, Khuri FR, et al. N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium. Clin Cancer Res 2000;6:2973–9.[Abstract/Free Full Text]
36. Stephensen CB, Gildengorin G. Serum retinol, the acute phase response, and the apparent misclassification of vitamin A status in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2000;72:1170–8.[Abstract/Free Full Text]
37. Chiesa F, Tradati N, Grigolato R, et al. Randomized trial of fenretinide (4-HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long-term results. Int J Cancer 2005;115:625–9.[CrossRef][Medline]
38. Sun SY, Schroeder CP, Yue P, Lotan D, Hong WK, Lotan R. Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations. Cancer Biol Ther 2005;4:407–13.[Medline]

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				B. S. Shumway, L. A. Kresty, P. E. Larsen, J. C. Zwick, B. Lu, H. W. Fields, R. J. Mumper, G. D. Stoner, and S. R. Mallery Effects of a Topically Applied Bioadhesive Berry Gel on Loss of Heterozygosity Indices in Premalignant Oral Lesions Clin. Cancer Res., April 15, 2008; 14(8): 2421 - 2430. [Abstract] [Full Text] [PDF]

				A. L. Sabichi, S. P. Lerner, E. N. Atkinson, H. B. Grossman, N. P. Caraway, C. P. Dinney, D. F. Penson, S. Matin, A. Kamat, L. L. Pisters, et al. Phase III Prevention Trial of Fenretinide in Patients with Resected Non Muscle-Invasive Bladder Cancer Clin. Cancer Res., January 1, 2008; 14(1): 224 - 229. [Abstract] [Full Text] [PDF]

				B. J. Maurer, O. Kalous, D. W. Yesair, X. Wu, J. Janeba, V. Maldonado, V. Khankaldyyan, T. Frgala, B.-C. Sun, R. T. McKee, et al. Improved Oral Delivery of N-(4-Hydroxyphenyl)Retinamide with a Novel LYM-X-SORB Organized Lipid Complex Clin. Cancer Res., May 15, 2007; 13(10): 3079 - 3086. [Abstract] [Full Text] [PDF]

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