{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:49:06Z","timestamp":1780084146727,"version":"3.54.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2014,6,13]],"date-time":"2014-06-13T00:00:00Z","timestamp":1402617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sixty years ago, 6-thioguanine (6-TG) was introduced into the clinic. We suggest its full potential in therapy may not have been reached. In this paper, we contrast 6-TG and the more widely used 6-mercaptopurine; discuss 6-TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6-TG treatment of cancers. We also consider studies that suggest that combinations of 6-TG with other agents may enhance antitumor effects. Although not yet tested in man, 6-TG has recently been proposed to treat a wide variety of cancers with a high frequency of homozygous deletion of the gene for methylthioadenosine phosphorylase (MTAP), often codeleted with the adjacent tumor suppressor CDKN2A (p16). Among the cancers with a high frequency of MTAP deficiency are leukemias, lymphomas, mesothelioma, melanoma, biliary tract cancer, glioblastoma, osteosarcoma, soft tissue sarcoma, neuroendocrine tumors, and lung, pancreatic, and squamous cell carcinomas. The method involves pretreatment with the naturally occurring nucleoside methylthioadenosine (MTA), the substrate for the enzyme MTAP. MTA pretreatment protects normal host tissues, but not MTAP-deficient cancers, from 6-TG toxicity and permits administration of doses of 6-TG that are much higher than can now be safely administered. The combination of MTA\/6-TG has produced substantial shrinkage or slowing of growth in two different xenograft human tumor models: lymphoblastic leukemia and metastatic prostate carcinoma with neuroendocrine features. Further development and a clinical trial of the proposed MTA\/6-TG treatment of MTAP-deficient cancers seem warranted.<\/jats:p>","DOI":"10.1634\/theoncologist.2014-0178","type":"journal-article","created":{"date-parts":[[2014,6,16]],"date-time":"2014-06-16T13:48:09Z","timestamp":1402926489000},"page":"760-765","source":"Crossref","is-referenced-by-count":83,"title":["6-Thioguanine: A Drug With Unrealized Potential for Cancer Therapy"],"prefix":"10.1093","volume":"19","author":[{"given":"Pashna N.","family":"Munshi","sequence":"first","affiliation":[{"name":"Rutgers Robert Wood Johnson University Hospital, The State University of New Jersey, New Brunswick, New Jersey, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lubin","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Bertino","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute of New Jersey, Departments of Pharmacology, Biochemistry, and Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,6,13]]},"reference":[{"key":"2021122308560707200_B1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1182\/blood.V8.11.965.965","article-title":"Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of acute leukemia and allied diseases","volume":"8","author":"Burchenal","year":"1953","journal-title":"Blood"},{"key":"2021122308560707200_B2","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1182\/blood-2009-07-230656","article-title":"Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: Report of the Children's Oncology Group CCG-1952 clinical trial","volume":"115","author":"Stork","year":"2010","journal-title":"Blood"},{"key":"2021122308560707200_B3","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1158\/1535-7163.MCT-10-0798","article-title":"Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers","volume":"10","author":"Coulthard","year":"2011","journal-title":"Mol Cancer Ther"},{"key":"2021122308560707200_B4","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1749-6632.1954.tb40008.x","article-title":"The chemistry and biochemistry of purine analogs","volume":"60","author":"Hitchings","year":"1954","journal-title":"Ann N Y Acad Sci"},{"key":"2021122308560707200_B5","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1016\/0006-2952(85)90230-8","article-title":"Dissimilar actions of 6-mercaptopurine and 6-thioguanine in Chinese hamster ovary cells","volume":"34","author":"Maybaum","year":"1985","journal-title":"Biochem Pharmacol"},{"key":"2021122308560707200_B6","first-page":"2872","article-title":"Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine","volume":"35","author":"Nelson","year":"1975","journal-title":"Cancer Res"},{"key":"2021122308560707200_B7","first-page":"5387","article-title":"6-Thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells","volume":"54","author":"Morgan","year":"1994","journal-title":"Cancer Res"},{"key":"2021122308560707200_B8","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10637-005-4020-8","article-title":"The thiopurines: An update","volume":"23","author":"Coulthard","year":"2005","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1093\/bmb\/ldl020","article-title":"Thiopurines, DNA damage, DNA repair and therapy-related cancer","volume":"79-80","author":"Karran","year":"2006","journal-title":"Br Med Bull"},{"key":"2021122308560707200_B10","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0006-2952(60)90020-4","article-title":"Potentiation of carcinostasis by combinations of thioguanine and 6-mercaptopurine","volume":"5","author":"Henderson","year":"1960","journal-title":"Biochem Pharmacol"},{"key":"2021122308560707200_B11","first-page":"1590","article-title":"Further studies on the mechanism of action of 6-thioguanine","volume":"21","author":"Lepage","year":"1961","journal-title":"Cancer Res"},{"key":"2021122308560707200_B12","first-page":"1627","article-title":"Pharmacology of 6-thioguanine in man","volume":"31","author":"LePage","year":"1971","journal-title":"Cancer Res"},{"key":"2021122308560707200_B13","first-page":"5959","article-title":"Phase I trial of parenteral 6-thioguanine given on 5 consecutive days","volume":"46","author":"Kovach","year":"1986","journal-title":"Cancer Res"},{"key":"2021122308560707200_B14","first-page":"909","article-title":"Phase II trial of iv 6-thioguanine in advanced colorectal carcinoma","volume":"65","author":"Britell","year":"1981","journal-title":"Cancer Treat Rep"},{"key":"2021122308560707200_B15","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1002\/1097-0142(19840615)53:12<2610::AID-CNCR2820531207>3.0.CO;2-9","article-title":"Prospective randomized reappraisal of 5-fluorouracil in metastatic colorectal carcinoma. A comparative trial with 6-thioguanine","volume":"53","author":"Presant","year":"1984","journal-title":"Cancer"},{"key":"2021122308560707200_B16","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/BF00176979","article-title":"Phase II study of intravenous 6-thioguanine in patients with advanced gastric carcinoma","volume":"9","author":"Ajani","year":"1991","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B17","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/BF00183584","article-title":"Phase II study of intravenous 6-thioguanine in patients with advanced carcinoma of the pancreas","volume":"9","author":"Ajani","year":"1991","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/BF00873122","article-title":"Phase II trial of 5 day continuous intravenous infusion of 6-thioguanine in patients with recurrent and metastatic squamous cell carcinoma of the head and neck","volume":"10","author":"Kruter","year":"1992","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B19","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/oxfordjournals.annonc.a058328","article-title":"Intravenous 6-thioguanine or cisplatin, fluorouracil and leucovorin for advanced non-small cell lung cancer: A randomized phase II study of the Cancer and Leukemia Group B","volume":"3","author":"Vokes","year":"1992","journal-title":"Ann Oncol"},{"key":"2021122308560707200_B20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/BF00873917","article-title":"Phase II trial of 6-thioguanine administered as 120 hour continuous infusion for refractory or recurrent small cell lung cancer. A Southwest Oncology Group study","volume":"11","author":"Williamson","year":"1993","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B21","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S1078-1439(96)00073-7","article-title":"A phase II trial of melphalan or thioguanine in the treatment of patients with advanced renal cell cancer","volume":"2","author":"Witte","year":"1996","journal-title":"Urol Oncol"},{"key":"2021122308560707200_B22","first-page":"191","article-title":"Phase II trial of 6-thioguanine in metastatic breast cancer","volume":"64","author":"Pandya","year":"1980","journal-title":"Cancer Treat Rep"},{"key":"2021122308560707200_B23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/00000421-199702000-00015","article-title":"Evaluation of intravenous 6-thioguanine as first-line chemotherapy in women with metastatic breast cancer","volume":"20","author":"Ingle","year":"1997","journal-title":"Am J Clin Oncol"},{"key":"2021122308560707200_B24","first-page":"921","article-title":"Combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas","volume":"39","author":"Kyritsis","year":"1996","journal-title":"Neurosurgery"},{"key":"2021122308560707200_B25","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1080\/08880010390232709","article-title":"Chemotherapy for progressive low-grade gliomas in children older than ten years: The Dana-Farber experience","volume":"20","author":"Heath","year":"2003","journal-title":"Pediatr Hematol Oncol"},{"key":"2021122308560707200_B26","first-page":"59","article-title":"6-Thioguanine (NSC-752)-1 therapy in patients with multiple myeloma","volume":"36","author":"Carbone","year":"1964","journal-title":"Cancer Chemotherapy Rep"},{"issue":"suppl 1","key":"2021122308560707200_B27","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1007\/BF00171990","article-title":"A-phase II study of intravenous 6-thioguanine (NSC-752) in multiple myeloma. A Southwest Oncology Group study","volume":"8","author":"Edelstein","year":"1990","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/1097-0142(19850115)55:2<323::AID-CNCR2820550204>3.0.CO;2-9","article-title":"Pediatric Oncology Group experience with modified LSA2-L2 therapy in 107 children with non-Hodgkin's lymphoma (Burkitt's lymphoma excluded)","volume":"55","author":"Sullivan","year":"1985","journal-title":"Cancer"},{"key":"2021122308560707200_B29","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.clml.2012.07.001","article-title":"Lack of expression of MTAP in uncommon T-cell lymphomas","volume":"12","author":"Bertino","year":"2012","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"2021122308560707200_B30","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1158\/1078-0432.CCR-05-2780","article-title":"Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: Implications for a potential targeted therapy","volume":"12","author":"Marc\u00e9","year":"2006","journal-title":"Clin Cancer Res"},{"key":"2021122308560707200_B31","doi-asserted-by":"crossref","first-page":"627","DOI":"10.4161\/cbt.11.7.14948","article-title":"Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: Current strategies","volume":"11","author":"Bertino","year":"2011","journal-title":"Cancer Biol Ther"},{"key":"2021122308560707200_B32","first-page":"2108","article-title":"Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesothelioma","volume":"9","author":"Illei","year":"2003","journal-title":"Clin Can Res"},{"key":"2021122308560707200_B33","doi-asserted-by":"crossref","first-page":"83","DOI":"10.4161\/cbt.4.1.1380","article-title":"Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: A potential new target for therapy","volume":"4","author":"Hustinx","year":"2005","journal-title":"Cancer Biol Ther"},{"key":"2021122308560707200_B34","first-page":"1098","article-title":"Methylthioadenosine phosphorylase deficiency in human non-small cell lung cancers","volume":"53","author":"Nobori","year":"1993","journal-title":"Cancer Res"},{"key":"2021122308560707200_B35","first-page":"782","article-title":"Methylthioadenosine phosphorylase gene deletions are common in osteosarcoma","volume":"8","author":"Garc\u00eda-Castellano","year":"2002","journal-title":"Clin Cancer Res"},{"key":"2021122308560707200_B36","first-page":"3193","article-title":"Absence of methylthioadenosine phosphorylase in human gliomas","volume":"51","author":"Nobori","year":"1991","journal-title":"Cancer Res"},{"key":"2021122308560707200_B37","doi-asserted-by":"crossref","first-page":"6963","DOI":"10.1158\/1078-0432.CCR-09-1511","article-title":"Homozygous deletion of MTAP gene as a poor prognosticator in gastrointestinal stromal tumors","volume":"15","author":"Huang","year":"2009","journal-title":"Clin Cancer Res"},{"key":"2021122308560707200_B38","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1182\/blood.V88.8.3083.bloodjournal8883083","article-title":"Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: Strategies for enzyme-targeted therapy","volume":"88","author":"Batova","year":"1996","journal-title":"Blood"},{"key":"2021122308560707200_B39","first-page":"881","article-title":"The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951","volume":"91","author":"Mirebeau","year":"2006","journal-title":"Haematologica"},{"key":"2021122308560707200_B40","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1182\/blood.V71.6.1568.1568","article-title":"Methylthioadenosine phosphorylase deficiency in acute leukemia: Pathologic, cytogenetic, and clinical features","volume":"71","author":"Traweek","year":"1988","journal-title":"Blood"},{"key":"2021122308560707200_B41","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/(SICI)1097-0215(19980105)75:1<51::AID-IJC9>3.0.CO;2-0","article-title":"The methylthioadenosine phosphorylase gene is frequently co-deleted with the p16INK4a gene in acute type adult T-cell leukemia","volume":"75","author":"Hori","year":"1998","journal-title":"Int J Cancer"},{"key":"2021122308560707200_B42","doi-asserted-by":"crossref","first-page":"14935","DOI":"10.1073\/pnas.0706546104","article-title":"Targeting the absence: Homozygous DNA deletions as immutable signposts for cancer therapy","volume":"104","author":"Varshavsky","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122308560707200_B43","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0006-2952(85)90044-9","article-title":"5\u2032-Deoxy-5\u2032-methylthioadenosine phosphorylase\u2014III. Role of the enzyme in the metabolism and action of 5\u2032-halogenated adenosine analogs","volume":"34","author":"Savarese","year":"1985","journal-title":"Biochem Pharmacol"},{"key":"2021122308560707200_B44","doi-asserted-by":"crossref","first-page":"e5735","DOI":"10.1371\/journal.pone.0005735","article-title":"Selective killing of tumors deficient in methylthioadenosine phosphorylase: A novel strategy","volume":"4","author":"Lubin","year":"2009","journal-title":"PLoS One"},{"key":"2021122308560707200_B45","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1158\/1535-7163.MCT-11-0826","article-title":"Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target","volume":"11","author":"Collins","year":"2012","journal-title":"Mol Cancer Ther"},{"key":"2021122308560707200_B46","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.4161\/cbt.21115","article-title":"Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells","volume":"13","author":"Tang","year":"2012","journal-title":"Cancer Biol Ther"},{"key":"2021122308560707200_B47","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1182\/blood-2005-06-2430","article-title":"EFA (9-beta-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine","volume":"107","author":"Batova","year":"2006","journal-title":"Blood"},{"key":"2021122308560707200_B48","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10637-008-9160-1","article-title":"A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer","volume":"27","author":"Kindler","year":"2009","journal-title":"Invest New Drugs"},{"key":"2021122308560707200_B49","first-page":"938","article-title":"Inhibition of ascites cell growth by combinations of 6-thioguanine and azaserine","volume":"18","author":"Sartorelli","year":"1958","journal-title":"Cancer Res"},{"key":"2021122308560707200_B50","first-page":"235","article-title":"Combination therapy with thioguanine (NSC-752) and azaserine (NSC-742) for multiple myeloma","volume":"51","author":"Hayes","year":"1967","journal-title":"Cancer Chemother Rep"},{"key":"2021122308560707200_B51","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/bjc.1964.51","article-title":"Toxicity and clinical trial of azaserine and 6-thioguanine in advanced solid malignant neoplasms","volume":"13","author":"Schroeder","year":"1964","journal-title":"Br J Cancer"},{"key":"2021122308560707200_B52","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.1073\/pnas.82.15.4881","article-title":"Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates","volume":"82","author":"Allegra","year":"1985","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122308560707200_B53","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1200\/JCO.1994.12.9.1955","article-title":"Pharmacologic-guided trial of sequential methotrexate and thioguanine in children with advanced malignancies","volume":"12","author":"Tan","year":"1994","journal-title":"J Clin Oncol"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pericles-gcp.literatumonline.com\/doi\/pdf\/10.1634\/theoncologist.2014-0178","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pericles-gcp.literatumonline.com\/doi\/full-xml\/10.1634\/theoncologist.2014-0178","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/19\/7\/760\/41861584\/oncolo_19_7_760.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/19\/7\/760\/41861584\/oncolo_19_7_760.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T08:33:34Z","timestamp":1689323614000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/19\/7\/760\/6399314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,13]]},"references-count":53,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2014,6,13]]},"published-print":{"date-parts":[[2014,7,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2014-0178","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,7,1]]},"published":{"date-parts":[[2014,6,13]]}}}