A comparative study on the genetic effects of hycanthone and oxamniquine.
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 15 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 150 mg/kg administered parenterally. Oxamniquine produced a weak response in the frameshift mutant, TA1538, 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.
D000818:Animals; D001681:Biological Assay; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000187:drug effects; D005260:Female; D005799:Genes, Dominant / Q000187:drug effects; D005804:Genes, Lethal / Q000187:drug effects; D006801:Humans; D006826:Hycanthone / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009153:Mutagens; D009154:Mutation / Q000187:drug effects; D009600:Nitroquinolines / Q000494:pharmacology*; D010073:Oxamniquine / Q000494:pharmacology*; D011247:Pregnancy; D012486:Salmonella typhimurium / Q000187:drug effects; D013892:Thioxanthenes / Q000494:pharmacology*; D013997:Time Factors
D009153:Mutagens; D009600:Nitroquinolines; D013892:Thioxanthenes; D010073:Oxamniquine; D006826:Hycanthone