Drug resistance

Some tumours are inherently resistant to anthracyclines whereas others initially respond but later become resistant.

The MDR1 gene codes for a P-170 glycoprotein (Pgp) that is a naturally occurring cell-surface pump. Its physiological function appears to be a protective mechanism, expelling toxic substances from the cell. Cell lines resistant to anthracyclines often have increased expression of Pgp and sensitivity can be restored by the addition of Pgp inhibitors such as verapamil or cyclosporin A. The importance of Pgp in the clinic is less clear. Though expression is increased in some human cancers before treatment or at relapse, attempts to manipulate Pgp have had limited success. It can be difficult to achieve potentially effective plasma levels of Pgp modulators without causing side-effects. Cyclosporin A and other modulators can also influence anthracycline pharmacokinetics, directly increasing exposure to the cytotoxic. To date, modulation of Pgp has shown most promise for patients with haematological malignancies. There remains a need for specific, well-tolerated inhibitors of Pgp.

A second efflux pump associated with expression of multi-drug resistance-associated protein (MRP) gene has been implicated in anthracycline resistance in the lab.

Reduced activity of the target enzyme topoisomerase II has also been associated with in vitro anthracycline resistance.

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