The design of cancer chemotherapy: metabolic modulation and cellular de novo versus salvage metabolism.

Attempts were made to evaluate the degree of utilization of 'salvage' and de novo purine and pyrimidine metabolites by normal and tumor cells. The significance of unique ribonucleotide pools and their ratios were also investigated. The results indicate that while normal bone marrow cells appear to depend almost exclusively on salvage pathways for their nucleic acid synthesis, tumor cells appear to utilize both the de novo and salvage pathways. The degree of dependence of tumor cells on these pathways appears to vary considerably. Utilizing this unique difference between tumor and normal cells, attempts were made to utilize the salvage precursors with the hope of modifying selectively the effects of antimetabolites against tumor cells in vivo. Results indicate that thymidine can potentiate the in vivo toxicity of 1-beta-D-arabinofuranosylcytosine and fluorouracil. The degree of modulation by normal metabolites appears to correlate with the level of circulating salvage metabolites.