Resistance in Leukemic Cells to an Adenine Antagonist, 6-Mercaptopurine

Abstract

In mice the adenine analog 6-mercaptopurine was shown to inhibit leukemic-cell growth of the acute lymphocytic leukemia L 1210 in a definite, regular, and reproducible manner. Lower dosage levels of this compound appear to be as effective as higher (near-MTD) levels (measured by the criterion of leukemic death). A resistant subline of leukemia L 1210 was developed by con secutive passage of leukemic cells in DBA/2 strain mice re ceiving daily injns. of 6-mercaptopurine. Resistant leukemic cells grow optimally either in the presence or absence of the antagonist. Resistance to 6-mercaptopurine is accompanied by resistance to all other purine analogs tested (8-azaguanine, 8-azaxanthine, 2,6-diaminopurine, and thioguanine), some of which are moderate anti-leukemic agents in the sensitive line of this transplantable leukemia. An increased sensitivity to the folic acid antagonist, 4-amino-N10 methyl PGA (A-methop-terin) is a characteristic of the resistant variant as well as of 2 other variant lines developed through the use of 8-azaguanine. Attempts to reverse the anti-leukemic activity of 6-mercaptopurine by the physiological purines adenine, guanine, xanthine, and hypoxanthine were relatively unsuccessful.