Assem M, Bonvalot S, Beltramo J L, Garrido C, Dimanche-Boitrel M T, Genne P, Rebibou J M, Caillot D, Chauffert B
INSERM U252, Faculté de Médecine, Dijon, France.
Br J Cancer. 1994 Oct;70(4):631-5. doi: 10.1038/bjc.1994.362.
Inherent resistance of colon cancer cells to cis-diamminedichloroplatinum(II) (CDDP) is partly attributed to reduced drug penetration through plasma membrane. Amphotericin B (AmB), a polyene antifungal antibiotic, has been shown to increase CDDP penetration and cytotoxicity on several non-digestive cancer cell lines. We demonstrated here that AmB dramatically increases the penetration of CDDP, and to a lesser extent that of carboplatin (Carbo-P) and oxaloplatin (L-OHP), in the primary resistant HT 29 human colon cancer cells when drug incubation is performed in serum-free medium. The cytotoxicity of CDDP but not that of Carbo-P and L-OHP was increased by AmB. However, AmB-induced potentiation of CDDP penetration and toxicity was almost completely abolished when cell incubation was performed in presence of human serum. We investigated whether the dilution of human serum by a high osmotic power gelatine solution (Lomol) could restore the positive effect of AmB on CDDP accumulation in HT 29 cells. Incubation of cells with CDDP and AmB in pure Lomol resulted in a 6-fold increase in platinum cellular content. However, addition of serum (25%) in Lomol solution reduced to only 2-fold the increase in platinum cellular content provoked by AmB. These disappointing results show that AmB is probably uninteresting as a modulator of CDDP resistance in clinical practice. The use of haemodilution to restore the positive AmB effect on platinum cellular accumulation cannot be warranted.
结肠癌细胞对顺二氨二氯铂（II）（CDDP）的内在抗性部分归因于药物通过质膜的渗透减少。两性霉素B（AmB）是一种多烯类抗真菌抗生素，已被证明可增加CDDP在几种非消化性癌细胞系中的渗透和细胞毒性。我们在此证明，当在无血清培养基中进行药物孵育时，AmB可显著增加原发性耐药HT 29人结肠癌细胞中CDDP的渗透，对卡铂（Carbo-P）和奥沙利铂（L-OHP）的渗透增加程度较小。AmB增加了CDDP的细胞毒性，但未增加Carbo-P和L-OHP的细胞毒性。然而，当在人血清存在下进行细胞孵育时，AmB诱导的CDDP渗透和毒性增强几乎完全被消除。我们研究了高渗力明胶溶液（Lomol）对人血清的稀释是否能恢复AmB对HT 29细胞中CDDP积累的积极作用。在纯Lomol中用CDDP和AmB孵育细胞导致铂细胞含量增加6倍。然而，在Lomol溶液中加入血清（25%）后，AmB引起的铂细胞含量增加仅降至2倍。这些令人失望的结果表明，在临床实践中，AmB作为CDDP抗性调节剂可能并不理想。不能保证使用血液稀释来恢复AmB对铂细胞积累的积极作用。
