Oncogenicity study of trifluralin in B6C3F1 mice

Francis, Paul C.; Emmerson, John L.; Adams, Elizabeth R.; Owen, N.V.

doi:10.1016/0278-6915(91)90047-b

Cited by 17 publications

(7 citation statements)

References 4 publications

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“…Trifluralin is not genotoxic, as indicated by the standard tests, such as the Salmonella/microsome mutagenicity test, the yeast genotoxicity assay, the mouse lymphoma assay, the sister chromatid exchange assay, the in vitro chromosome aberration assay, and the in vivo micronucleus test for mammalian genotoxicity (Humburg 1989; Garriott et al 1991; Ebert et al 1992). Oncogenicity tests in rats and mice and embryotoxicity tests in rats and rabbits revealed neither carcinogenic nor teratogenic potential when taken orally (Francis et al 1991; Ebert et al 1992). In addition tubulins, as new targets affected by trifluralin, are encoded by multiple copies of genes, and thus drug resistance may be less likely to develop (Croft 1988; Fairlamb 1989; Seeback et al 1990).…”

Section: Resultsmentioning

confidence: 95%

Treatment of Experimental Chronic Chagas Disease with Trifluralin

Zaidenberg

Luong

Lirussi

et al. 2006

Basic Clin Pharma Tox

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Abstract:We tested trifluralin against Trypanosoma cruzi in a model of chronic Chagas disease in mice. CF1 mice (nΩ 148) were intraperitoneally infected with 10 5 trypomastigotes of T. cruzi, H510C8C3 clone. One hundred mice were partially treated with benznidazole. Mortality was 100% at day 41 in the control group (nΩ48). At day 90 of the chronic disease (74% survival) mice were divided into three groups and treated orally with trifluralin (50 mg/kg/day, nΩ26), benznidazole (50 mg/kg/day, nΩ25) and vehicle (peanut oil; control group, nΩ23) for 60 days. Electrocardiography (under pentobarbital anaesthesia, 30 mg/kg/dose), serologic immunofluorescence and microstrout were performed at the beginning and at the end of the treatment. Mice were sacrificed at day 10 after treatment; cardiac tissue was studied histopathologically and polymerase chain reaction (PCR) was performed. Spontaneous mortality was 30.43%, 3.85% and 4% in the control, trifluralin and benznidazole groups, respectively (significant survival, PΩ0.03). Microstrouts were negative in all three groups. Negative immunofluorescence titers were 0%, 16% (PΩ0.05) and 29% (PϽ0.02) in the control, trifluralin and benznidazole groups, respectively. The prevailing electrocardiographic disorder was prolongation of the PR interval in the control group, which was not significantly altered in trifluralin-and benznidazole-treated mice, suggesting that trifluralin and benznidazole improve or even stop the damage caused by the disease on the conduction system. Trifluralinand benznidazole-treated animals showed similar histologic patterns of myocarditis. PCR results were negative for benznidazole and trifluralin (100% and 70.8%, respectively). These results show the therapeutic potential of trifluralin in the treatment of chronic Chagas disease.

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Section: Resultsmentioning

confidence: 95%

Treatment of Experimental Chronic Chagas Disease with Trifluralin

Zaidenberg

Luong

Lirussi

et al. 2006

Basic Clin Pharma Tox

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“…Trifluralin is not genotoxic, as indicated by the standard tests, such as the Salmonella /microsome mutagenicity test, the yeast genotoxicity assay, and the in vivo micronucleus test for mammalian genotoxicity [21–23]. Embryotoxicity tests in rats and rabbits revealed no potential when taken orally [23,24].…”

Section: Resultsmentioning

confidence: 99%

Trifluralin Toxicity in a Chagas Disease Mouse Model

Zaidenberg

Marra

Gómez³

et al. 2007

Basic Clin Pharma Tox

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Even though trifluralin ( α , α , α -2,6-dinitro-N-N-dipropyl-p-toluidine) is effective for the treatment of experimental Chagas disease, more preclinical toxicity studies need to be performed. Cell toxicity of trifluralin was studied in Hep-G2 and Vero C76 cells treated with 50 and 150 µ M trifluralin. The results show that duplication time, amount of cellular protein and cell protein/DNA values were normal. Histological, haematological and chemical parameters were measured in CF1 mice after oral trifluralin administration. Acute toxic effects were assayed by administration of 50 or 200 mg / kg body weight daily for 30 days, and chronic effects by administration of 200 mg / kg body weight once a week for 90 days (n = 20). In the acute scheme treatment, hepatic (glutamic-pyruvic, glutamic-oxalacetic and alkaline phosphatase activities; proteins and albumin plasma concentrations) and pancreatic (amylase, glycaemia) functions were normal. Mean corpuscular volume, haemoglobin and haematocrit decreased. Creatine phosphokinase, lactate dehydrogenase and glutamic-oxalacetic activity increased, suggesting lesion in myocardial tissue. Histology was normal, excepting for the heart (mild myocarditis). Similar results were observed in acutely treated animals. There were no differences in body weight gain for treated mice compared to controls. In view of the published therapeutic effects of trifluralin on CF1 Chagas disease model and considering the present results, trifluralin seems to be a moderately toxic drug with a potential selective effect on the myocardium.

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“…The NO 2 groups on trifluralin have previously been linked to questions about carcinogenicity (4, 7). Our reading of the literature (2,12,14,15,32,38) suggests that the trifluralin used in the carcinogenicity tests was contaminated with residual N-nitrosodi-n-propylamine (38) as a result of the reaction of dipropylamine [HN(C 3 H 7 ) 2 ] with chloralin in the last step of trifluralin synthesis (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…4). Nitrosoamines are potent carcinogens and their presence could easily account for the one study out of three that linked carcinogenic potential with trifluralin (2,12,14,15). Although NO 2 groups can also be carcinogenic, it would be shortsighted to rule out active compounds solely on the basis of whether they contain these substituents, since these moieties are present in similar currently prescribed drugs (for example, nifedipine).…”

Section: Discussionmentioning

confidence: 99%

Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds

Callahan¹,

Kelley²,

Pereira³

et al. 1996

Antimicrob Agents Chemother

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Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predicted and tested active analogs in a Leishmania promastigote assay; thus, we have identified the putative mechanism of action of this class of drugs in Leishmania species. Potentially, this will allow the design of noncarcinogenic, active drugs.

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Oncogenicity study of trifluralin in B6C3F1 mice

Cited by 17 publications

References 4 publications

Treatment of Experimental Chronic Chagas Disease with Trifluralin

Treatment of Experimental Chronic Chagas Disease with Trifluralin

Trifluralin Toxicity in a Chagas Disease Mouse Model

Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds

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