Circumventing drug resistance : Studies exploring the expediency of a total cell kill chemoresistance assay

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Cellular resistance to anti-cancer drugs is considered to be the major cause of treatment failure in clinical practice. The present studies have therefore focused on ways to circumvent resistance as evaluated by an in vitro chemoresistance assay.Based on a meta-analysis of all retrievable published studies conducted with Total Cell Kill (TCK) assays since 1983, it is concluded that individualised utilisation of presently available anti-cancer drugs guided by a TCK assay, despite numerous identified theoretical obstacles, is likely to improve treatment outcome in individual patients. The cumulated experience with licensed anticancer drugs also indicates that TCK assays are feasible tools for the rational development of new cytotoxic drugs.The expediency of TCK assays in drug development was therefore exemplified, starting with a serendipity finding as regards a licensed medicinal product, Cyclosporin A (CSA). The cytotoxicity profile of CSA in vitro was shown to be compatible with a relatively pronounced effect on tumour cells from patients with chronic lymphocytic leukaemia (CLL). Relevant clinical anti-tumoural activity of CSA in a single patientwith CLL failing conventional therapy is possible to interpret as supportive of the assay findings. There are, however, alternative explanations of the observed in vivo activity warranting further preclinical exploration. Calcein AM, a probe used for, e.g., detection of P-glycoprotein (Pgp) meditated drug efflux, was then demonstrated to pose cytotoxic activity of clinical interest due to a low degree of cross-resistance with available anti-cancer drugs. This activity pattern in fresh tumour samples is interpreted as indicative of novel mechanisms of action, and studies are presently ongoing aiming at identification and characterisation of likely targets.A major role of Pgp for the development of clinical multi-drug resistance (MDR) has been implicated. The tentative role of the Pgp modulating substance PSC833 (PSC) was investigated in cell lines, in an in vitro phase II trial, and finally in a clinical phase I/II study in acute myelocytic leukaemia (AML). Available data indicate that PSC is an effective modulator of Pgp mediated resistance at clinically achievable concentrations. The proportion of patients likely to benefit from therapy with MDR modulating agents is not, however, known. The seemingly low clinical response rate in this phase I/II study in combination with pharmacological activity of PSC detectable in vitro in a relatively small subgroup of patients indicates that Pgp mediated drug resistance is of no major importance in patients with advanced AML.

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