COMPARATIVE-STUDY OF INTRACELLULAR CALCIUM AND ADENOSINE 3',5'-CYCLIC-MONOPHOSPHATE LEVELS IN HUMAN BREAST-CARCINOMA CELLS SENSITIVE OR RESISTANT TO ADRIAMYCIN(R) - CONTRIBUTION TO REVERSION OF CHEMORESISTANCE

Multidrug resistance (MDR) corresponds to the cross-over resistance of tumour cells to structurally unrelated cytotoxic chemotherapeutic dru gs. One of the mechanisms causing this resistance is the enhanced expr ession of a transmembrane drug efflux pump P-glycoprotein (P-170). Rev ersal of P-glycoprotein-associated MDR has received much attention in recent years. In experimental cell lines, P-170 and the glutathione re dox cycle seem to contribute to this phenomenon; P-170 may be inactiva ted by calcium and calmodulin antagonists and the glutathione redox cy cle altered by buthionine sulphoximine (BSO). Treatment of human MCF-7 breast cancer cells with chemosensitizers (CS), such as verapamil, tr ifluoperazine or BSO, for 72 hr resulted in an enhanced sensitization of cells to Adriamycin, trifluoperazine being the most potent compound in the reversion of chemoresistance. In these Adriamycin sensitive or resistant cells, treated or not by the CS, the possible role of calci um and cyclic adenosine monophosphate (cAMP) in mediating the reversio n of chemoresistance to Adriamycin was investigated. It was found that intracellular calcium was approximately 2-fold higher in resistant th an in sensitive cells, the opposite was true for cAMP. Modifications i n calcium and cAMP levels were observed in MCF-7 resistant cells after treatment with verapamil and BSO; triffuoperazine had no effect on th ese two parameters. These results seemed to rule out any implication o f calcium and cAMP levels in the contribution of these three chemosens itizers in the mechanisms of reversion of chemoresistance to Adriamyci n.