Overview Pyrazoloacridine is a 9-methoxy acridine compound containing a reducible 5-nitro substituent. Although the precise mechanism of action of this drug is unknown, the acridine compounds are known to cause cytotoxicity by interaction with DNA and RNA. PZA is both an RNA and DNA synthesis inhibitor; however, preferential RNA inhibition occurs at lower concentrations. PZA was selected for clinical development because of its demonstrated in vitro and in vivo activity against solid tumors. In preclinical investigations, PZA demonstrated: 1) selectivity against solid tumor cells relative to leukemic cells in vitro; 2) selectivity against hypoxic cells; 3) favorable activity against noncycling cells; 4) activity against multidrug-resistant tumor cells; and 5) broad spectrum activity in vivo. Pre clinical Toxicology and Pharmacology Acute neurotoxicity was the dose limiting toxicity following intravenous administration of PZA in rodents while delayed myelosuppression was doselimiting in dogs. Neurotoxicity was characterized by ataxia, lethargy, tachypnea and convulsions in rats and mice and emesis in doses. Neurotoxicity appeared to be related to peak drug levels because it occurred immediately after dosing and could be ameliorated by slowing the rate of drug infusion.
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