Fenretinide (N-4-hydroxyphenyl-retinamide, or 4-HPR) is a semisynthetic retinoid that was initially developed as a low-dose chemopreventative agent.[1-3] Unlike other naturally occurring retinoids such as all-trans, 13-cis, and 9-cis retinoic acids, fenretinide does not induce systemic catabolism that interferes with the maintenance of effective plasma levels during long-term use. This characteristic, combined with the agent’s low toxicity and its ability to block aspects of carcinogenesis, provided the rationale for the development of fenretinide in lower doses as a chemoprevention agent for breast, prostate, and bladder cancer.
More recently, fenretinide has been shown to exert antiproliferative effects on malignant cells that appear to be independent of the cytodifferentiation response common with other retinoids. Two distinct responses to fenretinide were identified in F9 embryonal carcinoma cells. A rapid induction of cell death occurred at 10 µM fenretinide in both wild-type and retinoid-receptor null mutants, and a slower induction of differentiation occurred at 1 µM in wild-type cells only. In myeloid leukemia and lymphoma cell lines, fenretinide concentrations of at least 3 µM were associated with the induction of apoptosis, whereas concentrations lower than 1 µM resulted in cytostatic effects. Similar observations of apoptosis associated with high concentrations of fenretinide in vitro have been reported in various leukemia and lymphoid cells,[6-8] as well as in neuroblastoma,[9-11] small cell and non-small- cell lung cancer, prostate cancer,[14-16] cervical carcinoma,[17,18], bladder cancer, and head and neck squamous carcinoma.[20,21]
Mechanism of Action
The mechanism of action of fenretinide-induced apoptosis is not fully understood. It is hypothesized that this compound can act independently of the nuclear retinoid receptor pathway. Evidence using antioxidants and oxygen radical scavengers in myeloid (HL-60) cells and cervical carcinoma (C33A) cells points to the initiation of apoptosis by fenretinide-induced generation of reactive oxygen species.[22,23] Further data from C33A cells indicate that the molecular site of this fenretinide-induced generation of reactive oxygen species is between the complex II and complex III enzymes of the mitochondrial respiratory chain, presumably coenzyme Q. It has also been reported that fenretinide-induced apoptosis is linked with activation of the stress-activated protein kinase (c-Jun N-terminal kinase, or JNK) in LNCaP prostate carcinoma cells, independent of reactive oxygen species generation and caspase activation. Another reported mechanism of fenretinide cytotoxicity links increased de novo synthesis of ceramide in neuroblastoma cells with cell death in a p53- and caspase-independent manner.[26-28] Evidence from colon carcinoma cells suggests that fenretinide inhibits cell growth by inhibiting the expression of the COX-2 gene leading to diminished prostaglandin synthesis. And finally, other studies suggest that in certain cell types, fenretinide may act by selective activation of nuclear retinoid receptors.[30-32]
Phase I Clinical Experience
In order to determine whether it would be possible to achieve in patients’ plasma the same concentrations of fenretinide that were shown to induce apoptosis in vitro (³ 3 mM), the National Cancer Institute/Cancer Therapy and Evaluation Program (NCI/CTEP) sponsored two phase I studies of high dose fenretinide in adults and children. Both of these trials employed a twice-daily (bid) oral regimen for 7 days, followed by a 2-week rest before repeating the cycle. To increase drug absorption, patients were encouraged to take each dose with 8 oz of whole milk and with morning and evening meals. Doses for adults ranged from 500 to 3,400 mg/m²/d, and pediatric doses ranged from 350 to 3,300 mg/m²/d. In the adult trial, three-times-daily (bid) dosing was explored as a means of increasing fenretinide plasma levels and of improving the tolerability of ingesting the large number of capsules.
Major toxicities among the 31 adults treated were grade 1/2 dry skin and grade 1/2 nyctalopia (night blindness), which were reversible on cessation of drug treatment. Other toxicities were nausea, vomiting, diarrhea (grade 1/2), abdominal cramping (grade 1) and a single case of grade 3 hepatic dysfunction (at a dose level of 4,800 mg/m²) that first manifested 2 weeks after completion of treatment.
Failure to reach toxicity was associated with maximum achievable plasma levels of fenretinide that occurred at 900 mg/m² bid. This is believed to be due to saturable absorption or accumulation of the drug in the gut wall (and possibly in other organs), but not to metabolism to the inactive metabolite 4-methoxyphenyl retinamide (4-MPR). Because similar systemic exposures were observed after bid and tid dosing, and the maximum achievable plasma concentration was reached at the 900 mg/m² bid dose, an adult dose of 900 mg/m² bid is recommended for phase II trials.
Toxicity was more severe among the 50 children who received fenretinide, with individual cases of increased intracranial pressure (grade 4) that appeared to be idiosyncratic, occurring at doses of 600, 800, and 3,300 mg/m²/d. Also reported were hypoalbuminemia and hypophosphatemia (both grade 3) at a dose of 1,860 mg/m²/d, and elevated transaminases (grade 3) at 3,300 mg/m²/d.
Plasma levels of fenretinide were in the range associated with induction of apoptosis in vitro, but lower than expected for the dose given, suggesting saturable absorption. Adults at the 2,400 and 3,400 mg/m²/d dose levels achieved fenretinide plasma levels of 9 to 10 µM , and children achieved plasma levels of 3 to 8 µM at the 600 mg/m² dose level. In both children and adults, there was an increase in the area under the time-concentration curve (AUC) on days 6 to 8 as compared to day 1 of treatment. By day 7 of treatment in children, plasma retinol levels declined to less than 10% of pretreatment levels, but rebounded quickly following discontinuation of the drug. Two adult patients achieved a less than partial response: one with breast cancer through 12 cycles, and one with renal cell cancer through 9 cycles. Notably, 1 child with bone marrow involvement by neuroblastoma achieved a complete response, while 11 additional children with neuroblastoma had stable disease.
Although the maximum tolerated dose of fenretinide has not yet been reached in the pediatric phase I study, it is likely that the recommended phase II dose will be approximately 2,500 mg/m²/d.
1. Costa A, De Palo G, Decensi A, et al: Retinoids in cancer chemoprevention. Clinical trials with the synthetic analogue fenretinide. Ann N Y Acad Sci 768:148-162, 1995.
2. Pienta KJ, Esper PS, Zwas F, et al: Phase II chemoprevention trial of oral fenretinide in patients at risk for adenocarcinoma of the prostate. Am J Clin Oncol 20:36-39, 1997.
3. Sabichi AL, Lerner SP, Grossman HB, et al: Retinoids in the chemoprevention of bladder cancer. Curr Opin Oncol 10:479-484, 1998.
4. Clifford JL, Menter DG, Wang M, et al: Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl) retinamide in F9 embryonal carcinoma cells. Cancer Res 59:14-18, 1999.
5. 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 53:6036-6041, 1993.
6. Chan LN, Zhang S, Shao J, et al: N-(4-hydroxyphenyl) retinamide induces apoptosis in T lymphoma and T lymphoblastoid leukemia cells. Leukemia Lymphoma 25:271-280, 1997.
7. DiPietrantonio AM, Hsieh TC, Olson SC, et al: Regulation of G1/S transition and induction of apoptosis in HL-60 leukemia cells by fenretinide (4HPR). Int J Cancer 78:53-61, 1998.
8. Springer LN, Stewart BW: N-(4-hydroxyphenyl) retinamide-induced death in human lymphoblastoid cells: 50-kb DNA breakage as a means of distinguishing apoptosis from necrosis. Cancer Lett 128:189-196, 1998.
9. Mariotti A, Marcora, E, Bunone G, et al: N-(4-hydroxyphenyl) retinamide: A potent inducer of apoptosis in human neuroblastoma cells. J Natl Cancer Inst 86:1245-1247, 1994.
10. Reynolds CP, Melton LJ, Wang YL: N-(4-hydroxyphenyl) retinamide is highly active against retinoic acid resistant neuroblastoma cell lines. Proc Ann Meet Am Assoc Cancer Res 38:A162, 1997.
11. Pagnan G, Caridi G, Allen TM, et al: Apoptosis of human neuroblastoma cells induced by liposome-encapsulated fenretinide. Proc Ann Meet Am Assoc Cancer Res 38:A607, 1997.
12. Kalemkerian GP, Slusher R, Ramalingam S, et al: Growth inhibition and induction of apoptosis by fenretinide in small-cell lung cancer cell lines. J Natl Cancer Inst 87:1674-1680, 1995.
13. Zou CP, Kurie, JM, Lotan, D, et al: Higher potency of N-(4-hydroxyphenyl) retinamide than all-trans-retinoic acid in induction of apoptosis in non-small-cell lung cancer cell lines. Clin Cancer Res 4:1345-1355, 1998.
14. Hsieh TC, Ng C, Wu JM: The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) exerts antiproliferative and apoptosis-inducing effects in the androgen-independent human prostatic JCA-1 cells. Biochem Mol Biol Int 37:499-506, 1995.
15. Hsieh TC, Wu JM: Effects of fenretinide (4-HPR) on prostate LNCaP cell growth, apoptosis, and prostate-specific gene expression. Prostate 33:97-104, 1997.
16. Roberson KM, Penland SN, Padilla GM, et al: Fenretinide: Induction of apoptosis and endogenous transforming growth factor beta in PC-3 prostate cancer cells. Cell Growth Differ 8:101-111, 1997.
17. Oridate N, Lotan D, Mitchell MF, et al: Inhibition of proliferation and induction of apoptosis in cervical carcinoma cells by retinoids: Implications for chemoprevention. J Cell Biochem 23(suppl):80-86, 1995.
18. Sabichi AL, Hendricks DT, Bober MA, et al: Retinoic acid receptor beta expression and growth inhibition of gynecologic cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide. J Natl Cancer Inst 90:597-605, 1998.
19. Zou C, Wang L, Liebert M, et al: Combined effect of chemopreventive agent N-(4-hydroxyphenyl) retinamide (4-HPR) and g-radiation on bladder cancer cell lines. Int J Oncol 13:1037-1041, 1998.
20. Eicher SA, Lotan R: Differential effects of retinoic acid and N-(4-hydroxyphenyl) retinamide on head and neck squamous cell carcinoma cells. Laryngoscope 106:1471-1475, 1996.
21. Scher RL, Saito W, Dodge RK, et al: Fenretinide-induced apoptosis of human head and neck squamous carcinoma cell lines. Otolaryngol Head Neck Surg 118:464-471, 1998.
22. Delia D, Aiello A, Meroni L, et al: Role of antioxidants and intracellular free radicals in retinamide-induced cell death. Carcinogenesis 18:943-948, 1997.
23. Oridate N, Suzuki S, Higuchi M, et al: Involvement of reactive oxygen species in N-(4-hydroxyphenyl) retinamide-induced apoptosis in cervical carcinoma cells. J Natl Cancer Inst 89:1191-1198, 1997.
24. Suzuki S, Higuchi M, Proske RJ, et al: Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase-3 in N-(4-hydroxyphenyl) retinamide-induced apoptosis in cervical carcinoma cells. Oncogene 18:6380-6387, 1999.
25. Chen YR, Zhou G, Tan TH: c-Jun N-terminal kinase mediates apoptotic signaling induced by N-(4-hydroxyphenyl) retinamide. Mol Pharmacol 56:1271-1279, 1999.
26. Maurer BJ, Metelitsa LS, Seeger RC, et al: Increase of ceramide and induction of mixed apoptosis/necrosis by N-(4-hydroxyphenyl)-retinamide in neuroblastoma cell lines. J Natl Cancer Inst 91:1138-1146, 1999.
27. Maurer BJ, Melton L, Billups C, et al: Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl) retinamide and modulators of ceramide metabolism. J Natl Cancer Inst 92:1897-1909, 2000.
28. Wang H, Maurer BJ, Reynolds CP, et al: N-(4-hydroxyphenyl) retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res 61:5102-5105, 2001.
29. Merritt G, Aliprandis ET, Prada F, et al: The retinoid fenretinide inhibits proliferation and downregulates cyclooxygenase-2 gene expression in human colon adenocarcinoma cell lines. Cancer Lett 164:15-23, 2001.
30. Fanjul AN, Delia D, Pierotti MA, et al: 4-Hydroxyphenyl retinamide is a highly selective activator of retinoid receptors. J Biol Chem 271:22441-22446, 1996.
31. Liu G, Wu M, Levi G, et al: Inhibition of cancer cell growth by all-trans retinoic acid and its analog N-(4-hydroxyphenyl) retinamide: A possible mechanism of action via regulation of retinoid receptors expression. Int J Cancer 78:248-254, 1998.
32. Sharpless SM, Lazzaro G, Marler K, et al: Mechanism of retinoid action in inhibition of growth of human melanoma cells. Proc Ann Meet Am Assoc Cancer Res 38, 1997.
33. Jasti BR, LoRusso PM, Parchment RE, et al: Phase I clinical trial of fenretinide (NSC374551) in advanced solid tumors (abstract 485). Proc Am Soc Clin Oncol 20:122a, 2001.