High Dose Pulse 13cisRA

For 13-cis-RA to be active in NB, effective drug levels (5-10 pM) have to be achieved. A 10-day exposure to 10-pM ATRA produced prolonged arrest of NB cell proliferation in vitro (Reynolds et al. 1991). Sustained growth arrest and down-regulation of MYCN expression in vitro were achieved with sequential -week courses of 5 pM 13-cis-RA (Reynolds et al. 1994).

In a phase-I trial of intermittent 13-cis-RA (divided quarterly 12 h daily for 2 weeks alternating with 2 weeks of mucocutaneous recovery for up to 12 courses) in post-BMT patients, MTD was 160 mg/m2 day-1 with dose-limiting toxicity being hypercalcemia (Villablanca et al. 1995). Peak plasma 13-cis-RA level at MTD was 7.4±3 pM and trough was 4.0±2.8 pM (Villablanca et al. 1995; Khan et al. 1996). Four complete responses were observed in marrow metastases and two had prolonged remission past 2 years (Villablanca et al. 1995). The latter observation suggested that high-dose, pulse 13-cis-RA might delay or prevent tumor recurrence if given in a setting of minimal residual disease after completion of myeloabla-tive therapy.

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