Effects of combinations of azaserine and of 6-diazo-5-oxo-L-norleucine with purine analogs and other antimetabolites on the growth of two mouse mammary carcinomas.

The study of combinations of anticancer chemi cals has for its objective the selection of combina tions which would produce synergistic therapeutic effects in animal and human tumors without an in creased toxicity to the host. It could be expected, also, that, when two or more anticancer chemicals are used simultaneously for the treatment of tu mors, there will be less chance for appearance of mutant forms of tumor cells, resistant to the com bination of carcinostatic agents used for the treat ment, since the probability of formation of double or multiple mutants is extremely low (10, 11). Three main biochemical approaches have been utilized for the combination chemotherapy of tu mors: 1. Chemicals which can depress the concentra tion of a metabolite in the tumor have been used. It was hoped in this way to make the tumor more susceptible to an antagonist of the same metabolite (17-19). 2. Two or more steps along a metabolic se quence leading to the formation of an essential metabolite may be blocked by the use of combina tions of appropriate inhibitors—sequential blocking (16). 3. Simultaneous blocking of two or more paral lel pathways concerned with the formation of the same metabolite can be produced by combinations of inhibitors—concurrent blocking (22). Significant synergistic therapeutic effects have been observed after the treatment of animal tu mors with combinations of certain inhibitors of the de novo biosynthesis of purines (antifolics, azaserine,1 DON2) and of analogs of natural purines (e.g., 8-azaguanine, 6-mercaptopurine) presum ably interfering with the de novo biosynthesis of purines and with the utilization of preformed pu-