A comparative study on the genetic effects of hycanthone and oxamniquine

Abstract

Oxamniquine (UK‐4271; 6‐hydroxymethyl‐2‐isopropylaminomethyl‐7‐nitro‐1,2,3,4‐tetrahydroquinoline) is a new schistosomicidal agent currently undergoing clinical investigation in South America. Essentially a complete cure rate against Brazilian Schistosoma mansoni has been seen in adults with a single im dose of 7.5 mg/kg or a single oral dose of 7 5 mg/kg. These regimens were tolerated without significant toxicity. To assess its mutagenic potential, oxamniquine was examined in a battery of genetic tests designed to detect mutations at the gene and chromosome levels. For comparative purposes, hycanthone, a schistosomicide with extensively studied mutagenic properties, was evaluated in a similar series of tests. Point mutations were measured in a series of histidineless auxotrophs of Salmonella typhimurium in direct plate and host‐mediated assays. Gross chromosomal aberrations were assessed in human leucocyte cultures and in bone marrow preparations from drug‐treated mice. Effects on germ cells were tested in the dominant‐lethal assay. Hycanthone showed significant mutagenic activity in the direct bacterial tests and the in vivo and in vitro cytogenetic assays. No response was detected in the host‐mediated or dominant‐lethal assays. On the other hand, oxamniquine produced no drug‐related mutagenic effects in the cytogenetic, host‐mediated, or dominant‐lethal tests at doses up to 750 mg/kg administered parenterally. Oxamniquine produced a weak response in the frameshift mutant, TAJ538, of Salmonella typhimurium in direct plate tests with and without liver microsomal enzymes. However, this response was achieved only by using a concentration of compound which was several orders of magnitude higher than that required to produce a similar response to hycanthone.