Basselin M, Lawrence F, Robert-Gero M
Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur Yvette, France.
Parasitol Res. 1997;83(5):413-8. doi: 10.1007/s004360050274.
Pentamidine-resistant clones of Leishmania donovani and L. amazonensis promastigotes were developed by increase of the drug pressure in the culture medium and characterized. The resistant clones could grow in 40 and 20 microM pentamidine as determined for L. donovani and L. amazonensis, respectively, with 50% inhibitory concentrations (IC50 values) being 140 and 60 microM, which were 18 and 75 times higher than those recorded for the parental clones, respectively. Biochemical analysis of the clones showed that the acquired pentamidine resistance was specific (no cross-resistance to unrelated drugs and no reversibility with verapamil) and stable in vitro and in vivo. Pentamidine resistance is related to decreased drug uptake and highly increased efflux in both clones of Leishmania spp., accompanied by an alteration in polyamine carriers. Furthermore, a modification of the uptake of pyrimidine nucleosides and several amino acids by these resistant clones indicates alterations in the surface membrane.
通过提高培养基中的药物压力，培育出了杜氏利什曼原虫和亚马逊利什曼原虫无鞭毛体的喷他脒抗性克隆，并对其进行了表征。对于杜氏利什曼原虫和亚马逊利什曼原虫，抗性克隆分别可以在40和20微摩尔的喷他脒中生长，50%抑制浓度（IC50值）分别为140和60微摩尔，分别比亲本克隆的记录值高18倍和75倍。对这些克隆的生化分析表明，获得的喷他脒抗性具有特异性（对无关药物无交叉抗性，维拉帕米不能使其逆转），并且在体外和体内都很稳定。喷他脒抗性与利什曼原虫两个克隆中药物摄取减少和外排高度增加有关，同时伴随着多胺载体的改变。此外，这些抗性克隆对嘧啶核苷和几种氨基酸摄取的改变表明其表面膜发生了变化。
