Success of cancer treatment is often hampered by the emergence of multidrug resistance
(MDR) mediated by P-glycoprotein (ABCB1/Pgp). Doxorubicin (DOX) is recognized by Pgp
and therefore it can induce therapy resistance in breast cancer patients. In this
study our aim was to evaluate the susceptibility of the pegylated liposomal formulation
of doxorubicin (PLD/Doxil(R)/Caelyx(R)) to MDR. We show that cells selected to be
resistant to DOX are cross-resistant to PLD and PLD is also ineffective in an allograft
model of doxorubicin-resistant mouse B-cell leukemia. In contrast, PLD was far more
efficient than DOX as reflected by a significant increase of both relapse-free and
overall survival of Brca1-/-;p53-/- mammary tumor bearing mice. Increased survival
could be explained by the delayed onset of drug resistance. Consistent with the higher
Pgp levels needed to confer resistance, PLD administration was able to overcome doxorubicin
insensitivity of the mouse mammary tumors. Our results indicate that the favorable
pharmacokinetics achieved with PLD can effectively overcome Pgp-mediated resistance,
suggesting that PLD therapy could be a promising strategy for the treatment of therapy-resistant
breast cancer patients.
