1. The effects of added 6-mercaptopurine (6-MP) on the in vitro incorporation of radioformate (C14) into the leukocyte nucleic acid purines and thymine of six cases of acute myeloblastic leukemia (AML) and four cases of acute lymphoblastic leukemia (ALL) have been compared with the patients’ clinical response to 6-MP.
2. In seven cases subsequent therapy with 6-MP produced leukopenia. Of these, in vitro 6-MP diminished leukocyte C14 incorporation into the nucleic acid purines in three cases of AML, had no effect in two cases of AML and one case of ALL, and enhanced C14 incorporation into the leukocyte purines of a second case of ALL. Thymine synthesis was slightly diminished by 6-MP in the AML leukocytes in which purine synthesis was inhibited, and in one drugsensitive ALL leukocyte population in which purine synthesis was slightly increased by the analog. Thus, no regular and consistent relationship between the antileukemic effect of the drug and suppression of purine or thymine synthesis by 6-MP in vitro could be demonstrated.
3. Studies of the leukocytes of two cases of drug-resistant ALL yielded results similar to those observed in presumably drug-sensitive ALL cells.
4. The leukocytes of two cases of AML with acquired drug-resistance showed an increased capacity for in vitro RNA purine synthesis; in the one case in which studies before and after the development of resistance were possible, this property was apparently acquired during therapy. This suggests that an increase in purine biosynthetic enzyme reserves may be a mechanism of 6-MP-resistance in some human leukemias.