Multidrug resistance in solid tumours

Introduction: Most cancers show heterogeneity of response to chemotherapy. This may be due in part to the differential expression of drug resistance proteins and the molecular targets of the drugs concerned. Methods: An ex vivo ATP-based Tumour Chemosensitivity Assay (ATP-TCA), immunohistochemistry and quantitative RT-PCR have been used to assess the chemosensitivity and resistance of a variety of solid tumours and cell lines. Results: (a) Melanoma cell lines showed higher chemosensitivity than tumour-derived cells, partially reversible by lowering the serum concentration, and hence the proliferation rate of the cells. (b) Studies of retinoblastoma samples confirmed that this malignancy is susceptible to cytotoxic drugs of all types, though multidrug resistance may occur in some cases. (c) The ATP-TCA was used to study the activity of high-dose doxorubicin in combination with other cytotoxic agents in ovarian adenocarcinoma samples. The combination of liposomal doxorubicin + vinorelbine was selected for further development. (d) A number of experimental drugs with varying sensitivity to resistance mechanisms were also assessed. One drug, XR5944, has entered phase I/II clinical trials during the course of this project, and the data have provided clinical indications. (e) An inhibitor of multi-drug resistance, tariquidar, has been tested in combination with doxorubicin, vinorelbine or paclitaxel, and has been shown to reverse this resistance. (f) Molecular studies have determined the expression of topoisomerases and drug transporters in tumour cells before and after exposure to chemotherapeutic agents. P-gp expression has been found to be a determinant of sensitivity to a certain number of drugs. Conclusion: The results suggest that drug resistance contributes to heterogeneity of chemosensitivity in many solid tumour types, as well as other mechanisms. Reversal of such resistance may benefit a subset of patients undergoing chemotherapy.