Drug Resistance

Resistance to a chemotherapy agent may be present at the outset (primary resistance), or may develop with repeated drug exposure (acquired resistance). Increasing dosage is limited by toxicity, e.g. to bone marrow, which does not become tolerant. Therefore combination chemotherapy is more commonly used in an attempt to overcome the problems of resistance rendering a tumour unresponsive.

Multiple drug resistance (MDR) of a cancer is not uncommon. MDR is most frequently due to increased expression of an ATP-dependent membrane efflux pump called P-glycoprotein (Pgp) which is a member of a class of membrane proteins called the ATP-binding cassette superfamily. Pgp is a protective mechanism possessed by many normal cells against environmental toxins and has broad specificity for hydrophobic compounds. Long-lived cells such as the haemopoietic stem cell, cells on excretory surfaces such as biliary hepatocytes, proximal renal tubule and intestinal cells and the cells of the blood-brain barrier all have high expression of Pgp and the protein is clearly an important protective mechanism for both individual cells and organisms. Pgp can be blocked by a number of agents including immunosuppressants (ciclosporin) and calcium channel blockers (verapamil and nifedipine). The MDR phenomenon illustrates how tumour cells adapt and enhance normal cell mechanisms to deal with the effects of chemotherapy and how repeated cycles of chemotherapy select out a population of cells which have developed adaptive survival mechanisms e.g. in myeloma where MDR proteins are rare at diagnosis but common at progression.

Cytotoxic drugs vary in their capacity to stimulate P-glycoprotein and some, e.g. cisplatin, do not induce this type of resistance.

In those tumours where cures can be achieved by chemotherapy (acute lymphoblastic leukaemia in childhood, Hodgkin's lymphoma, choriocarcinoma) it is essential that optimal doses of chemotherapy be administered and dose intensity maintained in order to avoid the emergence of chemoresistance.

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