Multidrug Resistance Is a Component of V79 Cell Resistance to the Alkylating Agent Adozelesin

Abstract Adozelesin is a highly potent alkylating agent which has entered clinical trials based on its unique mechanism of action and broad-spectrum anti-tumor activity in vivo . V79 cells resistant to adozelesin (V79/Ado R ) were not resistant to the alkylating agent cisplatin but showed the phenotypic and genotypic characteristics of multidrug resistance. Thus V79/Ado R was cross-resistant to several structurally and functionally unrelated drugs, resistance was reversed by verapamil, and the resistant cell line expressed mdr mRNA and p170 glycoprotein. Also, adozelesin uptake and the amount of drug alkylated to DNA was much lower in the resistant cell line as compared to the sensitive parent. However, even with the same amount of drug bound to DNA (10 fmol/µg DNA) the survival of V79/S (≃15% survival) was much lower than that of V79/Ado R (≃80%). Therefore the resistance of V79/Ado R cannot be explained solely by the multidrug resistance mechanism ( i.e. , lower drug uptake and less drug alkylation to DNA), which suggests that multiple mechanisms may account for resistance to adozelesin. V79/Ado R showed different levels of cross-resistance to several adozelesin analogues. The analogues could be divided into 2 groups; those with very low partition coefficients (log P P > 2.4) were cross-resistant to adozelesin.