Resistance to 9-beta-D-arabinofuranosyladenine in murine tumor cells

Two lines of the 6C3HED (Gardner lymphosarcoma), 6C3HED-LeP and 6C3HED-ADL, were studied. The former is exquisitely sensitive to 9-beta-D-arabinofuranosyladenine (ara-A) and the latter is resistant. Cytological examinations and strain specificity tests indicated that they are both 6C3HED. DNA synthesis in the sensitive line was found to be more sensitive to ara-A in whole-cell incubations than it was in the resistant line. In cell-free extracts, the DNA synthesis of the sensitive line showed greater inhibition by 9-beta-D-arabinofuranosyladenine 5'-triphosphate. Lower ability to form 9-beta-D-arabinofuranosyladenine 5'-triphosphate or to allow access to the intracellular space was eliminated as an explanation for the resistance. Cells from an ara-A-resistant human leukemia were tested, and the DNA synthesis of the cells, in either whole cells or cell-free extract, was unaffected by ara-A or 9-beta-D-arabinofuranosyladenine 5'-triphosphate, respectively. This suggests that resistance has emerged by reason of change in the DNA polymerase(s) and that the finding may be important in the clinical use of ara-A.