Cellular studies of multidrug resistance mainly involve highly drug resistant sublines, the majority of which have increased expression of MRP1 or P-glycoprotein. Other ABC transporter proteins have also been associated with resistance in highly drug resistant cells. Our studies of drug and radiation resistance have concentrated on low but clinically relevant levels of drug resistance and the cellular response to treatment.

We have established some unique cell sublines that are resistant to chemotherapy. The majority of drug resistant cancer cells have classically been developed in laboratories by continually growing the cancer cells in culture media containing a drug. When normal growth is resumed in the presence of the drug, the drug level is increased and this process is repeated until it produces cancer cells capable of growing in high concentrations of drug. Often these resistant cells are unstable and require continual drug treatment to maintain their resistance, they are highly drug resistant and although they are multidrug resistant, they usually only rely on one resistance mechanism.

In contrast, we have treated cancer cells with low but clinically relevant levels of chemotherapeutic drugs and cells have been treated for 18 hours rather than continually as this approximates a cancer’s exposure to drug during chemotherapy. Several human leukaemia and small cell lung cancer cell lines have been treated in this way and all developed significant but relatively low levels (2 to 10-fold) of resistance to a range of drugs normally associated with multidrug resistance and they have increased levels of MRP1. However they are also resistant to chlorambucil, cisplatin and methotrexate, drugs that are not associated with MRP1 or P-glycoprotein expression. These sublines also showed increased resistance to radiation treatment. Resistance is stable and does not require any further treatment. We have called this type broad drug resistance, extended-multidrug resistance.

As well as having increased levels of MRP1, some resistant cells also have increased amounts of a related protein known as MRP2. These cells are currently being investigated for other known mechanisms of drug resistance. They are also being investigated for other molecular changes associated with this resistance as this will provide clues to how sensitive cancer cells react to drug treatment and become resistant. Unlike the majority of the resistant cancer cells developed in the classical way, our cellular models of drug resistance show many similarities to the drug resistance encountered in the treatment of cancer as outlined in the accompanying table.