N-(4-hydroxyphenyl) retinamide or fenretinide (4-HPR is a synthetic retinoid; Fig. 15.6) inhibits NB growth in vitro at 1-10 pM (Ponzoni et al. 1995) and was highly active against retinoic-acid resistant NB lines at 5-10 pM (Reynolds et al. 2000). In contrast to 13-cis-RA and ATRA, 4-HPR does not induce matu-rational changes, but is cytotoxic, causing both apop-tosis and necrosis (Maurer et al. 1999). Toxicity of 4-HPR in chemoprevention clinical trials has been minimal. The major clinical toxicity of 4-HPR is decreased night vision, due to decreased plasma retinol levels. No hematologic toxicity has been reported (Reynolds and Lemons 2001). In pediatrics, fenre-tinide has been well tolerated (Garaventa et al. 2003), and the MTD of oral 4-HPR given for 7 days every 3 weeks is 2475 mg/m2 day-1, which achieved 4-HPR plasma levels of 6-10 pM (Villablanca et al. 2002).

4-HPR has been shown to achieve multi-log cytotoxicity in NB cell lines resistant to ATRA and 13-cis-RA (Reynolds et al. 2000). Resistance to 13-cis-RA in NB cell lines appears to involve selection for increased expression of MYCN or c-myc, and such retinoic acid-resistant NB cell lines are collaterally hypersensitive to 4-HPR; thus, pre-clinical data suggest that sequential use of 13-cis-RA, followed by 4-HPR, could be an effective approach to treating minimal residual disease in NB patients after myeloabla-tive therapy.

The mechanisms by which 4-HPR achieves antitumor cytotoxicity are not completely understood. One mechanism by which 4-HPR stimulates apopto-sis is the induction of reactive oxygen species in NB cells (Maurer et al. 1999; Lovat et al. 2003a). Other possible mechanisms include induction of lipo-oxy-genase, the stress-induced transcription factor GADD153 (Lovat et al. 2002; Corazzari et al. 2003), and Bak, a pro-apoptotic member of the bcl-2 family (Lovat et al. 2003b).

A major portion of fenretinide cytotoxicity for NB cell lines at high concentrations (~ 5-10 pM) is via non-apoptotic mechanisms (Maurer et al. 1999). Fenretinide stimulated large increases of ceramide in NB cell lines, which may account for its non-apoptotic

Figure 15.6

Structure of the cytotoxic retinoid N-(4-hydroxyphenyl) retinamide=fenretinide (4-HPR) and a summary of its properties cytotoxicity (Reynolds et al. 2004). Agents that modulate ceramide metabolism can increase the anti-tumor activity of 4-HPR. Drugs that inhibit glu-cosylceramide synthase/1-O-acylceramide synthase or sphingosine kinase, or safingol (L-threo-dihy-drosphingosine), which modulate ceramide metabolism and/or action, can significantly increase 4-HPR anti-tumor activity with minimal toxicity to normal fibroblasts or bone marrow myeloid progenitors (CFU-GM; Maurer et al. 2000). Fenretinide has also been shown to inhibit NB-induced angiogenesis (Ri-batti et al. 2001), and the anti-angiogenic activity of 4-HPR may be in part mediated via ceramide (Erd-reich-Epstein et al. 2002). The latter data suggest that 4-HPR alone or in combination with ceramide mod ulators may achieve anti-tumor activity in vivo by both direct effects against tumor and anti-angiogen-esis.

One limitation with fenretinide is the need for large administered doses to achieve effective drug levels. Although the currently available oral capsular dose form of 4-HPR is poorly bioavailable and difficult to administer to small children, a phase-II study of the 4-HPR oral capsule formulation in recurrent NB is ongoing in the Children's Oncology Group (COG). Pre-clinical studies have been reported with a liposome formulation of 4-HPR targeted to NB via an anti-GD2 monoclonal antibody looks promising (Raffaghello et al. 2003). New oral and intravenous formulations of fenretinide have been developed via the NCI RAID program and these are entering clinical trials in 2004 (www.nant.org). These new formulations are likely more bioavailable, and will enable the administration of 4-HPR to small children.

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