Modulation of daunorubicin toxicity by liposomal encapsulation and use of specific inhibitors in vitro

Anthracyclines serve as a valuable tool in chemotherapy, but their usefulne ss is often limited by the occurrence of resistance mechanisms in tumor cel ls. Resistance of tumor cells is a multifactorial event. where several mech anisms act concurrently, including drug efflux and enzymatic drug inactivat ion. Liposomal encapsulation of anthracyclines has been discussed as a succ essful regimen to overcome drug resistance. Our investigations were carried out on a daunorubicin (DRC) sensitive breast cancer cell line and two DRC resistant sublines generated thereof. In all three cell lines, the extent o f DRC detoxification via carbonyl reduction to daunorubicinol (DRCOL) was d etermined. In addition. rutin. the most effective inhibitor of carbonyl red ucing enzymes, was tested to affect DRCOL formation. DRC TC,,, values were determined in relation to several combinations of DRC administration, (a) l iposomal encapsulated DRC. (b) addition of verapamil (inhibitor of drug eff lux), (c) addition of rutin (inhibitor of DRC carbonyl reduction). We could show that DRC sensitive and resistant breast cancer cell lines are able to catalyze DRC detoxification via carbonyl reduction to DRCOL. Rutin was sho wn to inhibit this reaction. but could not serve as an enhancer of DRC toxi city in MTT tests. Verapamil was effective only in resistant cells due to t he overexpression of P-glycoprotein 170. Liposomal encapsulation of DRC did not show the expected increase in DRC toxicity in the present tumor cell m odel. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.