Abstract
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.
Highlights
Cisplatin (CDDP) is an important anti-cancer drug for the treatment of many solid tumours, but its efficiency is low in human colon cancer (Durant, 1980)
Potentiation of CDDP accumulation and cytotoxicity by Amphotericin B (AmB) determined in serum-free medium
The effect of AmB on CDDP, L-OHP and Carbo-P cellular accumulation was first studied in HT 29 cells in the presence of serum-free Ham FIO medium (Figure 1)
Summary
Cisplatin (cis-diamminedichloroplatinum, CDDP) was purchased as a formulation for clinical use from Roger Bellon laboratories (Neuilly, France). Carboplatin (Carbo-P) was provided by Bristol-Myers Laboratories (Paris, France) and oxaloplatin (L-OHP) by Debiopharm Amphotericin B (AmB) was supplied as a commercially available formulation for intravenous administration 7 Bd Jeanne d'Arc, 21033 Dijon Cedex, France. 38 mg of sodium deoxycholate, 10 mg of disodium phosphate and 0.9 mg of monosodium phosphate. Sodium deoxycholate allows the formation of a colloidal dispersion of AmB with an enhanced solubility. Deoxycholate is a bile salt with lipophilic properties but, used alone, it did not potentiate CDDP accumulation and cytotoxicity (data not shown).
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