Use of nucleoside kinase-deficient mouse leukemia L1210 cell lines to determine metabolic routes of activation of antitumor nucleoside analogs.

Mouse leukemia L1210 cell lines that were selected for resistance to deoxyguanosine (dGuo-R) or lacked adenosine kinase activity (ED2) were used to evaluate the nature of the nucleoside kinase that was required to phosphorylate nucleoside analogs to their respective active nucleotide form. The dGuo-R cells had reduced levels of kinase activity toward araC, dGuo and 2-CldAdo as substrates with essentially no loss of activity toward dCyd. This cell line showed resistance to dGuo, araC, araG, FdAdo, and Fara A but not to dAdo or araA. The ED2 cell line was resistant to pyrazofurin and 6-methylmercaptopurine riboside and to araA/EHNA but not to 2-CldAdo or 2-Cl-2'-FaraA. The study of the effects of newer nucleoside analogs such as dFdCyd, MdAdo, MdCyd and MdGuo in these cell lines showed that some of these agents are primarily phosphorylated by deoxyribonucleoside kinase (dFdCyd) or by adenosine kinase (MdAdo) or in some instances by multiple kinases (FaraA). These cell lines will be useful in defining the nature of the kinase(s) responsible for activating new nucleoside analogs and defining cross-resistance patterns.