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Tang BQ , Testa JR , Kruger WD
Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells
Cancer Biology & Therapy. 2012 Sep;13(11) :1082-1090
PMID: WOS:000308694300013 PMCID: PMC3461818
AbstractMethylthioadenosine phosphorylase (MTAP), a key enzyme in the catabolism of 5'-deoxy-5'-methylthioadenosine (MTA), catalyzes the formation of adenine and 5-methylthioribose-1-phosphate. MTAP is expressed in all cells throughout the body, but a significant percentage of human tumors have lost MTAP expression, thereby making MTAP-loss a potential therapeutic target. Here, we have tested an MTAP-targeting strategy based on the idea that MTAP-expressing cells can be protected from toxic purine and uracil analogs by addition of MTA, but MTAP-deleted tumor cells cannot. Addition of as little as 10 mu M MTA could entirely protect isogenic MTAP(+), but not MTAP(-), HT1080 cells from toxicity caused by the chemotherapy agents 6-thioguanine (6TG) or 5-fluorouracil (5FU). Inhibitor studies showed that MTA protection requires functional MTAP activity. Addition of adenine protected both MTAP(+) and MTAP(-) cells from 6TG and 5FU, consistent with the idea that adenine produced from the MTAP reaction competes with 6TG and 5FU for a rate limiting pool of phosphoribosyl-1-pyrophosphate (PRPP), which is required for the conversion of purine and uracil bases into nucleotides. Extracellular MTA can also protect mouse mesothelioma cells from killing by 6-TG or the drug L-alanosine in an MTAP dependent manner. In addition, MTA can protect non-transformed MTAP(+) mouse embryo fibroblasts from 6TG toxicity. Taken together, our data suggest that the addition of MTA to anti-purine-based chemotherapy may greatly increase the therapeutic index of this class of drugs if used specifically to treat MTAP(-) tumors.
NotesTang, Baiqing Testa, Joseph R. Kruger, Warren D. Nih [ca06927, ca131024]; [ca-114047] This research was supported by CA06927 and CA131024 from the NIH and an appropriation from the Commonwealth of Pennsylvania. J.R.T. was supported in part by CA-114047. We thank Fang Jin in the FCCC Tissue Culture Facility for the preparation of the MEF lines used in this study and Deborah Altomare for assistance with the culture and expansion of mouse mesothelioma cell lines. We thank Dr Schramm and Dr Carson for providing drugs used in the study. We also thank Martin and Adam Lubin for critical reading of the manuscript. 34 Landes bioscience Austin 004pt