Limits...
Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin.

Vodnala SK, Ferella M, Lundén-Miguel H, Betha E, van Reet N, Amin DN, Oberg B, Andersson B, Kristensson K, Wigzell H, Rottenberg ME - PLoS Negl Trop Dis (2009)

Bottom Line: Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment.Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites.Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.

ABSTRACT

Background: There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).

Methodology/principal findings: Cordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug.

Conclusions/significance: Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

No MeSH data available.


Related in: MedlinePlus

Cordycepin-resistance strains are not cross resistant to suramin, pentamidine and melarsoprol.Cordycepin-resistant pleomorphic AnTat1.1 A–E) and monomorphic Lister 427 F–J) parasites were induced after selection with increasingly higher concentrations of the cordycepin during four months of culture. Parasites in all sub-panels were incubated with the indicated molar concentrations of the trypanocidal compounds for 70 h, when WST-1 reagent added. Two h after incubation, parasite viability was measured. The fraction of parasites in comparison to untreated controls is depicted. A, F Four months after incubation with cordycepin, parasites reached a 40–60 fold decreased sensitivity to cordycepin. B, G Resistance to different concentrations cordycepin after 4 week-long culture of resistant parasites in absence of the drug is shown. Sensitivity of cordycepin-resistant pleomorphic parasites to melarsoprol C, H), pentamidine D, I) or suramin E, J) is depicted.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2713411&req=5

pntd-0000495-g008: Cordycepin-resistance strains are not cross resistant to suramin, pentamidine and melarsoprol.Cordycepin-resistant pleomorphic AnTat1.1 A–E) and monomorphic Lister 427 F–J) parasites were induced after selection with increasingly higher concentrations of the cordycepin during four months of culture. Parasites in all sub-panels were incubated with the indicated molar concentrations of the trypanocidal compounds for 70 h, when WST-1 reagent added. Two h after incubation, parasite viability was measured. The fraction of parasites in comparison to untreated controls is depicted. A, F Four months after incubation with cordycepin, parasites reached a 40–60 fold decreased sensitivity to cordycepin. B, G Resistance to different concentrations cordycepin after 4 week-long culture of resistant parasites in absence of the drug is shown. Sensitivity of cordycepin-resistant pleomorphic parasites to melarsoprol C, H), pentamidine D, I) or suramin E, J) is depicted.

Mentions: Whether T. b. brucei can develop resistance against cordycepin was then studied. For this purpose T. b. brucei AnTat1.1 and Lister 427 were incubated with low concentrations (1 LD50 or higher doses) of cordycepin for 72 h at 37°C. Parasites surviving the highest concentrations of cordycepin, were then further cultured for 3 days with similar or higher concentrations of cordycepin. This procedure was repeated for four months, after which a 40–60 fold increased resistance to cordycepin, compared to the parental strain was achieved (Figure 8A, F).


Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin.

Vodnala SK, Ferella M, Lundén-Miguel H, Betha E, van Reet N, Amin DN, Oberg B, Andersson B, Kristensson K, Wigzell H, Rottenberg ME - PLoS Negl Trop Dis (2009)

Cordycepin-resistance strains are not cross resistant to suramin, pentamidine and melarsoprol.Cordycepin-resistant pleomorphic AnTat1.1 A–E) and monomorphic Lister 427 F–J) parasites were induced after selection with increasingly higher concentrations of the cordycepin during four months of culture. Parasites in all sub-panels were incubated with the indicated molar concentrations of the trypanocidal compounds for 70 h, when WST-1 reagent added. Two h after incubation, parasite viability was measured. The fraction of parasites in comparison to untreated controls is depicted. A, F Four months after incubation with cordycepin, parasites reached a 40–60 fold decreased sensitivity to cordycepin. B, G Resistance to different concentrations cordycepin after 4 week-long culture of resistant parasites in absence of the drug is shown. Sensitivity of cordycepin-resistant pleomorphic parasites to melarsoprol C, H), pentamidine D, I) or suramin E, J) is depicted.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2713411&req=5

pntd-0000495-g008: Cordycepin-resistance strains are not cross resistant to suramin, pentamidine and melarsoprol.Cordycepin-resistant pleomorphic AnTat1.1 A–E) and monomorphic Lister 427 F–J) parasites were induced after selection with increasingly higher concentrations of the cordycepin during four months of culture. Parasites in all sub-panels were incubated with the indicated molar concentrations of the trypanocidal compounds for 70 h, when WST-1 reagent added. Two h after incubation, parasite viability was measured. The fraction of parasites in comparison to untreated controls is depicted. A, F Four months after incubation with cordycepin, parasites reached a 40–60 fold decreased sensitivity to cordycepin. B, G Resistance to different concentrations cordycepin after 4 week-long culture of resistant parasites in absence of the drug is shown. Sensitivity of cordycepin-resistant pleomorphic parasites to melarsoprol C, H), pentamidine D, I) or suramin E, J) is depicted.
Mentions: Whether T. b. brucei can develop resistance against cordycepin was then studied. For this purpose T. b. brucei AnTat1.1 and Lister 427 were incubated with low concentrations (1 LD50 or higher doses) of cordycepin for 72 h at 37°C. Parasites surviving the highest concentrations of cordycepin, were then further cultured for 3 days with similar or higher concentrations of cordycepin. This procedure was repeated for four months, after which a 40–60 fold increased resistance to cordycepin, compared to the parental strain was achieved (Figure 8A, F).

Bottom Line: Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment.Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites.Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.

ABSTRACT

Background: There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).

Methodology/principal findings: Cordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug.

Conclusions/significance: Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

No MeSH data available.


Related in: MedlinePlus