CisRA vs All Trans Retinoic Acid

All-trans retinoic acid (ATRA) was used in treating acute promyelocytic leukemia (APL) with excellent results and little toxicity (Warrell et al. 1991). Although 13-cis-RA has never been compared directly with ATRA in APL, most investigators felt that ATRA was superior. The ATRA was more effective then 13-cis-RA against APL cells in vitro when tested at 0.1-1 pM (Chomienne et al. 1990), a dose range achieved at 45 mg/m2 day-1 in patients (Smith et al. 1992a). Dose escalation beyond 60 mg/m2 in children was limited by pseudotumor cerebri, and ATRA rapidly induces an increase in its own metabolism, such that peak levels and drug half-life significantly decrease after a few days of therapy (Smith et al. 1992b). In contrast, drug levels obtained in the post-BMT phase-I trial of 13-cis-RA were considerably higher (4-7 pM) (Villablanca et al. 1995; Khan et al. 1996) The differences in pharmacokinetic properties of 13-cis-RA and ATRA are summarized in Fig. 15.4.

Because of minimal binding of 13-cis-RA to retinoic acid receptors, it was previously assumed that 13-cis-RA would be less potent then ATRA; however, at clinically achievable drug levels, 13-cis-RA was superior to ATRA in inducing morphological differentiation and growth arrest of NB cell lines. In addition, 13-cis-RA caused down-regulation of MYCN gene expression (Reynolds et al. 1994). These data, and the documentation of anti-NB activity for 13-cis-RA in patients (Villablanca et al. 1995; Reynolds et al. 1991; Matthay et al. 1999), suggests that either 13-cis-RA acts via mechanisms that are independent of retinoic acid receptors, or that (more likely) 13-cis-RA serves as a pro-drug for ATRA, resulting in delivery of higher levels of ATRA inside tumor cells then are achievable in vivo with direct ATRA treatment.

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