title: Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells.
abstract: Methylthioadenosine 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 μM 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.
authors: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Baiqing
authors: B
authors: Tang
authors: Joseph R
authors: JR
authors: Testa
authors: Warren D
authors: WD
authors: Kruger
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism*; D013866:Thioguanine / Q000494:pharmacology*; D013872:Thionucleosides / Q000494:pharmacology
chemical_list: C116879:5'-deoxy-5'-trifluoromethylthioadenosine; D013872:Thionucleosides; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D013866:Thioguanine; D000241:Adenosine; D005472:Fluorouracil