Mutagenicity of hycanthone in mammalian cells

Clive, D.; Flamm, W.G.; Machesko, M.R.

doi:10.1016/0027-5107(72)90055-3

Cited by 59 publications

(8 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, it has no mutagenic, teratogenic or carcinogenic effects in animals (D. Lorke: personal communication). Therefore, metrifonate appears to be not only a suitable alternative to, but also has a considerably lower risk-to-benefit ratio than a widely used antischistosomal compound, hycanthone, whose mutagenic properties have been demonstrated in bacterial and mammalian cell systems in vitro (Hartman, Levine, Hartman & Berger, 1971;Clive, Flamm & Machesko, 1972), as well as in a host-mediated mammalian cell assay (G. A. Fischer: personal communication) and which has been found to be teratogenic in mice (Moore, 1972). These factors should receive especial attention when the treatment of urinary schistosomiasis is considered for children and other individuals with a long life expectancy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition by metrifonate and dichlorvos of cholinesterases in schistosomes

Bueding

Liu

Rogers

1972

British J Pharmacology

View full text Add to dashboard Cite

Summary1. No species differences between Schistosoma haematobium and Schistosoma mansoni were detected when the 150 of metrifonate for the acetylcholinesterases (AChE) and the cholinesterases (ChE) of these two trematodes were determined in isolated enzyme preparations or following exposure of the intact worms to this drug in vitro. 2. S. haematabium appeared to be more affected by AChE inhibition because, after administration of metrifonate to hamsters, a hepatic shift of the parasites was observed with a dose of metrifonate (150 mg (0-6 mmol) per kg) which produced no shift of S. mansoni, although AChE inhibition was comparable in both species. 3. Administration of a possible metabolite of metrifonate, dichlorvos, to hamsters resulted in a greater inhibition of AChE and ChE activities of S. haematobium than those of S. mansoni. Furthermore, when schistosomes were incubated with dichlorvos, inhibition of AChE activity of female S. haematobium was significantly greater (P<0 005) than that of both sexes of S. mansoni and of male S. haematobium. 4. The discrepancy between the lack of a significant chemotherapeutic effect of metrifonate in hamsters infected with S. haematobium and the clinical results obtained with this organophosphorus compound in human schistosomiasis haematobium is discussed, and the need to conduct similar studies in primates is pointed out.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition by metrifonate and dichlorvos of cholinesterases in schistosomes

Bueding

Liu

Rogers

1972

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Downloaded by [New York University] at 07:12 14 July 2015 This preponderance of negative data in germ cell tests with hycanthone is in strong contrast to results obtained with somatic mammalian cells either in vitro or in vivo. A dose-related increase in point mutations in hycanthone-treated mouse lymphoma cells was reported by Clive et al (1972). Obe (1973) reported a significant increase in chromatid and chromosome breaks in human lymphocyte cultures treated with 10~s M (4.5 /xg/ m O hycanthone furoate.…”

Section: Discussionmentioning

confidence: 94%

A comparative study on the genetic effects of hycanthone and oxamniquine

Ray

Holden

Ellis

et al. 1975

Journal of Toxicology and Environmental Health

View full text Add to dashboard Cite

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.

show abstract

“…Using cultures of mouse lymphoma cells, it was demonstrated that the elevation in mutant frequency induced by 10-4 M HC was approximately equivalent to what 120 R of X-rays would induce in the system under identical conditions (Clive et al 1971).…”

Section: Introductionmentioning

confidence: 97%

“…No psychoneurologic phenomena, as is seen with lucanthone treatment, were observed in this study. The increased efficacy of HC combined with low toxicity and ease of administration has led to the inauguration of extensive antischistosomal campaigns in Brazil and parts of Africa (Clive et al 1971). While treatment programs have been expanding, information has been accu mulating on the mutagenic action of hycanthone on a variety of cells.…”

Section: Introductionmentioning

confidence: 99%