Arrest of Trypanosoma brucei rhodesiense and T. brucei brucei in the S-phase of the cell cycle by (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA).
African trypanosomes are incapable of purine de novo synthesis. They use salvage pathways to meet their purine requirements. Therefore, purine analogues appear as potential candidates to interfere in trypanosome metabolism. The acyclic adenosine analogue (S)-9-(-3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA) expressed antitrypanosomal activity in vitro and vivo. When exposed to 20 microM (S)-HPMPA, trypanosomes were arrested in the S-phase of the cell cycle and were unable to enter G2-phase. Thymidine uptake and incorporation was inhibited almost completely. Only nuclear DNA replication was inhibited, while mitochondrial DNA replication and kinetoplast division was not inhibited. The antitrypanosomal effect was reversible when cells were exposed for 12 h. As a control, aphidicolin arrested trypanosomes in the G1-phase of the cell cycle at a concentration of 30 microM. At 20 microM (S)-HPMPA, glycolysis was not effected, while leucine and adenine uptake were reduced with prolonged exposure.
Kaminsky
R
R
Swiss Tropical Institute, Basel. kaminsky@ubaclu.unibas.ch
Nickel
B
B
Holý
A
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D018105:DNA, Kinetoplast / Q000302:isolation & purification; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011773:Pyruvates / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000472:pathogenicity
D018105:DNA, Kinetoplast; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011773:Pyruvates; D014344:Trypanocidal Agents; D016590:Aphidicolin; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D013936:Thymidine