DIFFERING PATTERNS OF CROSS-RESISTANCE RESULTING FROM EXPOSURES TO SPECIFIC ANTITUMOR DRUGS OR TO RADIATION IN-VITRO

This article reviews the patterns of cross-resistance identified in various P-glycoprotein-mediated and non-P-glycoprotein-mediated drug resistant mammalian tumour cell lines. The differing patterns of cross-resistance and the variable levels of resistance expressed are summarised and discussed. Although the mechanism by which P-glycoprotein can recognise and transport a large group of structurally-unrelated substrates remains to be defined, the recent evidence indicating that membrane associated domains participate in substrate recognition and binding is summarised, and other possible explanations for these variable cross-resistance patterns are considered. Amongst the non-P-glycoprotein-overexpressing multidrug resistant cell lines, two subsets are clearly identifiable, one lacking and the other expressing cross-resistance to the Vinca alkaloids. Resistance mechanisms implicated in these various sublines and possible explanations for their differing levels and patterns of cross-resistance are summarised. Clinical resistance is identified in patients following treatment not only with antitumour drugs, but also after radiotherapy. Experimental data providing a biological basis for this observation are summarised. A distinctive multiple drug resistance phenotype has been identified in tumour cells following exposure in vitro to fractionated X-irradiation characterised by: the expression of resistance to the Vinca alkaloids and the epipodophyllotoxins but not the anthracyclines and overexpression of P-glycoprotein which is post-translationally regulated, but without any concomitant overexpression of P-glycoprotein mRNA. Finally, the possible clinical relevance of these variable patterns of cross-resistance to the antitumour drugs commonly used in the clinic is considered.