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

Abstract

Summary

1. The adenine analog 6-mercaptopurine has been 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 as measured by the criterion of leukemic death. 2. A resistant subline of leukemia L 1210 has been developed by consecutive passage of leukemic cells in DBA/2 strain mice receiving daily injections of 6-mercaptopurine. Resistant leukemic cells grow optimally either in the presence or absence of the antagonist. 3. 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. 4. An increased sensitivity to the folic acid antagonist, 4-amino-N¹⁰ methyl PGA (A-methopterin) is a characteristic of the resistant variant as well as of 2 other variant lines developed through the use of 8-Azaguanine. 5. Attempts to reverse the anti-leukemic activity of 6-mercaptopurine by the physiologic purines adenine, guanine, xanthine, and hypoxanthine have been relatively unsuccessful.