Pyrazoloacridine (PZA), a DNA intercalator, is a rationally synthesized acridine derivative that has been shown to have a broad spectrum of activity against tumor cells in vitro and in vivo (Jackson et al. 1990; LoRusso et al. 1990; Sebolt et al. 1987). Pyrazoloacri-dine binds nucleic acids (preferentially ribonucleic acid) and inhibits the activity of topoisomerase I and II, causing DNA fragmentation, and thus DNA strand breaks. It is effective against cells in a hypoxic environment as well as the normal oxygen environment, and it is equally effective in cycling and non-cycling cells (Cole 1990; Adjei et al. 1998). It has the further advantage of activity in cells that over-express P-gly-coprotein or MRP, as well as in cells that have lost topoisomerase I or II (Cole 1990; Adjei et al. 1998; Sebolt et al. 1989). Preclinical data suggest that prolonged exposure to PZA may increase cytotoxicity (Grem et al. 1996). A recent in vitro study of resistant neuroblastoma cell lines showed that PZA effectively induced cytotoxicity in multi-drug-resistant neuro-blastoma cell lines, as well as in drug-resistant p53 non-functional neuroblastoma cell lines. Pyra-zoloacridine sensitivity could be shown even under hypoxic conditions, but only with PZA exposure times that exceeded those tested in previous clinical trials. The in vitro data demonstrated that PZA cytotoxicity is dose- and time dependent (Keshelava et al. 2003). Phase-I and phase-II clinical studies have been conducted, mostly using a short infusion schedule of <6 h, with hematologic toxicity as the main complication. Despite occasional reports of responses, the overall results in pediatric phase-II trials have been disappointing and failed to confirm the anti-cancer activity found in preclinical models (Berg et al. 2000). A possible explanation is that adequate PZA dose levels in humans were not achieved (Berg et al. 1998; LoRusso et al. 1995; Rowinsky et al. 1995). In children and young adults where 640 mg/m2 of PZA was administered as a 1- or 24-h infusion (Berg et al. 1998), myelosuppression was the dose-limiting toxicity, in contrast to neurotoxicity in the adults.

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