Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines

Stauffert, I.; Paulini, Hubert; Steinmann, U.; Sippel, Helmuth; Estler, C.‐J.

doi:10.1016/0165-7992(90)90006-6

Cited by 24 publications

(8 citation statements)

References 15 publications

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“…49 However, previous work concludes that DAPI causes no significant mutagenic or genotoxic effects despite its DNA binding properties. 50 We observed autophagosome formation during log phase, differentiation, and starvation occurs in DAPI-stained L. major at a similar rate to that reported in other studies in which parasite DNA is not stained. 21,51 Therefore, DAPI treatment does not appear to exert any significant effect on the Leishmania autophagy pathway.…”

Section: Discussionsupporting

confidence: 74%

Glycosome turnover inLeishmania majoris mediated by autophagy

et al. 2014

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Abbreviations: ATG, autophagy-related; GFP, green fluorescent protein; mC, mCherry fluorescent protein; MVT, multivesicular tubule; RFP, red fluorescent protein; TEM, transmission electron microscopy.Autophagy is a central process behind the cellular remodeling that occurs during differentiation of Leishmania, yet the cargo of the protozoan parasite's autophagosome is unknown. We have identified glycosomes, peroxisome-like organelles that uniquely compartmentalize glycolytic and other metabolic enzymes in Leishmania and other kinetoplastid parasitic protozoa, as autophagosome cargo. It has been proposed that the number of glycosomes and their content change during the Leishmania life cycle as a key adaptation to the different environments encountered. Quantification of RFP-SQL-labeled glycosomes showed that promastigotes of L. major possess »20 glycosomes per cell, whereas amastigotes contain »10. Glycosome numbers were significantly greater in promastigotes and amastigotes of autophagy-defective L. major Datg5 mutants, implicating autophagy in glycosome homeostasis and providing a partial explanation for the previously observed growth and virulence defects of these mutants. Use of GFP-ATG8 to label autophagosomes showed glycosomes to be cargo in »15% of them; glycosome-containing autophagosomes were trafficked to the lysosome for degradation. The number of autophagosomes increased 10-fold during differentiation, yet the percentage of glycosome-containing autophagosomes remained constant. This indicates that increased turnover of glycosomes was due to an overall increase in autophagy, rather than an upregulation of autophagosomes containing this cargo. Mitophagy of the single mitochondrion was not observed in L. major during normal growth or differentiation; however, mitochondrial remnants resulting from stress-induced fragmentation colocalized with autophagosomes and lysosomes, indicating that autophagy is used to recycle these damaged organelles. These data show that autophagy in Leishmania has a central role not only in maintaining cellular homeostasis and recycling damaged organelles but crucially in the adaptation to environmental change through the turnover of glycosomes.

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Section: Discussionsupporting

confidence: 74%

Glycosome turnover inLeishmania majoris mediated by autophagy

et al. 2014

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“…The experiment was repeated in the absence of S9 mix and very similar results were obtained (data not shown). Similar compounds such as pentamidine derivatives, in spite of their binding to DNA minor grooves, have been shown to cause no mutagenic activity in S. typhimurium strains TA98 and TA100 with and without metabolic activation 18,19…”

Section: Resultsmentioning

confidence: 99%

Antimutagenic and antioxidant activity of novel 4-substituted phenyl-2,2'-bichalcophenes and aza-analogs

El‐Sayed¹,

Hussin²

2013

DDDT

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Evaluation of the potential antimutagenic activities of new compounds by Ames assay has been of great interest for the development of novel therapeutics for many diseases including cancer. Ten novel bichalcophenes with in vitro and in vivo broad spectrum activities against various microbial strains were investigated throughout the present study for their cytotoxic, antioxidant, and antimutagenic potential in a Salmonella reverse mutation assay system against sodium azide (NaN3) and benzo[a]pyrene (B[a]P). At nontoxic concentrations, all bichalcophenes alone or in combination with NaN3 (1 μg/plate) or B[a]P (20 μM) with S9 mix were not mutagenic. The bichalcophenes significantly reduced NaN3- and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions in a concentration-independent manner. However, the antimutagenic activity of bichalcophenes against B[a]P varied depending on the exposure regimen, being more effective under pre-exposure conditions. The antimutagenic activity was correlated with a high antioxidant activity that could promote the DNA repair system. Bichalcophenes are least likely to interfere with the microsomal bioactivation of B[a]P. Monocationic bichalcophenes were superior to the corresponding mononitriles as antimutagenic agents against both mutagens investigated, possibly due to the higher nucleophilic centers they have which could bind and protect the bacterial DNA. Three monocationic compounds were shown to have a strong anticancer activity against the 58 cell line. Based on the results of the present investigation, monocationic compounds (1, 4, and 5B) will be selected for further time consuming and costly chemoprevention studies in animal models.

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“…Other studies have shown that the concentration of a population may influence the rate of proliferation of individual trypanosomes (9,10), thus potentially altering the proportions of the population in the different stages of the cell division cycle. While little is known about the mechanism of action of diminazene on trypanosomes, evidence from other systems indicates that diminazene acts on organisms at specific stages of the cell division cycle (11,26,42,50). A full explanation of the results observed in the present study requires an extensive study of the factors which influence trypanosomal cell division and proliferation and of whether there is developmental and/or cell division cycle control of expression of drug resistance in vivo.…”

Section: Discussionmentioning

confidence: 91%

“…In the groups of mice that were infected with 10 6 trypanosomes and treated with diminazene aceturate at doses of 30, 40, or 50 mg/kg of b.w., 13, 4, or 2 of 25 mice, respectively, were detected as parasitemic. Based on these data, the diminazene aceturate CD 50 value determined for mice infected with 10 6 trypanosomes was 29.88 mg/kg of b.w. and was significantly (P Ͻ 0.001) greater than that determined for mice infected with 10 3 trypanosomes (CD 50 , 22.28 mg/kg of b.w.…”

Section: Estimation Of the Proportions Of Resistant Trypanosomes In Imentioning

confidence: 99%

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

Mamman¹,

Gettinby²,

Murphy³

et al. 1995

Antimicrob Agents Chemother

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The frequency of trypanosomes resistant to diminazene aceturate at a dose of 25 mg/kg of body weight was investigated for populations of Trypanosoma congolense IL 3274 which reappeared in infected mice after intraperitoneal treatment with diminazene aceturate at the same dosage. At inoculum sizes of 10 2 , 10 3 , 10 4 , 10 5 , and 10 6 trypanosomes per mouse, the relapse populations were used to initiate infections in five groups of 100 mice each by the intravenous route. Immediately after infection, 50 mice in each group were treated intraperitoneally with diminazene aceturate at the aforementioned dosage; the other 50 mice functioned as untreated controls. Thereafter, all animals were monitored for 100 days for the presence of trypanosomes. In each group, trypanosomes were detected in 50 of 50 control mice, indicating 100% infectivity for all five inoculum sizes. In contrast, in the groups of 50 mice infected with 10 2 , 10 3 , 10 4 , 10 5 , and 10 6 trypanosomes and treated with diminazene aceturate, trypanosomes were detected in 4, 11, 13, 28, and 39 of 50 mice, respectively. By logistic regression, a good fit was found between the number of mice identified as parasitemic and the inoculum sizes. Maximum likelihood estimates for the proportions of trypanosomes resistant to diminazene aceturate at 25 mg/kg of body weight for the inoculum of 10 2 , 10 3 , 10 4 , 10 5 , and 10 6 organisms were 8.335 ؋ 10 ؊4 , 2.485 ؋ 10 ؊4 , 3.02 ؋ 10 ؊5 , 8.3 ؋ 10 ؊6 , and 1.6 ؋ 10 ؊6 , respectively. These findings indicate that the majority of the relapse trypanosomes were susceptible to the drug dosage used for selecting the population and that, surprisingly, the calculated proportion of organisms which survived drug exposure varied inversely with the inoculum size. Further experiments with mice indicated that the inverse relationship did not result from alterations in the pharmacokinetics of the drug with different inoculum sizes. The data therefore suggest that parasite inoculum size and drug dosage are important factors in estimating the apparent frequency of diminazeneresistant trypanosomes in populations of T. congolense occurring in vivo.

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Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines

Cited by 24 publications

References 15 publications

Glycosome turnover inLeishmania majoris mediated by autophagy

Glycosome turnover inLeishmania majoris mediated by autophagy

Antimutagenic and antioxidant activity of novel 4-substituted phenyl-2,2'-bichalcophenes and aza-analogs

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

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Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines

Cited by 24 publications

References 15 publications

Glycosome turnover inLeishmania majoris mediated by autophagy

Glycosome turnover inLeishmania majoris mediated by autophagy

Antimutagenic and antioxidant activity of novel 4-substituted phenyl-2,2&#39;-bichalcophenes and aza-analogs

Frequency of diminazene-resistant trypanosomes in populations of Trypanosoma congolense arising in infected animals following treatment with diminazene aceturate

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Antimutagenic and antioxidant activity of novel 4-substituted phenyl-2,2'-bichalcophenes and aza-analogs