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Cellular ATP Depletion by LY309887 as a Predictor of Growth Inhibition in Human Tumor Cell Lines¹

Cancer Research Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom [X. L., J. E., N. J. C., A. V. B., D. R. N], and Lilly Research Laboratories, Indianapolis, Indiana 46285 [V. J. C]

The antifolate LY309887 is a specific glycinamide ribonucleotide formyltransferase inhibitor that blocks de novo purine synthesis and produces a depletion of purine nucleotides. The activity of LY309887 in six human tumor cell lines has been examined by growth inhibition and clonogenic assay after continuous exposure for three cell doubling times and by ATP depletion at 24 h. Three cell lines (CCRF-CEM, MCF7, and GC3) were sensitive to LY309887-induced growth inhibition (IC₅₀: 5.6–8.1 nM), whereas the other cell lines (COR-L23, T-47D, and A549) were comparatively resistant (IC₅₀: 36–55 nM). Sensitivity to LY309887 cytotoxicity was consistent with sensitivity to growth inhibition in four of five cell lines tested (MCF7/GC3: 0.01% survival and COR-L23/T-47D: 1–5% survival at 100 nM LY309887). LY309887-induced ATP depletion was measured by luciferase-based ATP assay and confirmed by high performance liquid chromatography measurements. There was a linear relationship between ATP depletion and growth inhibition when data were analyzed for all six cell lines (r² = 0.93; P < 0.0001). Depletion of 24-h cellular ATP concentrations to <1 mM was associated with both cell growth inhibition and cytotoxicity in all cell lines studied. In conclusion, cellular ATP depletion induced by LY309887 can be used to predict growth inhibition and cytotoxicity in human tumor cells.