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Oncologist. 2014 Jul;19(7):760-5. doi: 10.1634/theoncologist.2014-0178. Epub 2014 Jun 13.

6-thioguanine: a drug with unrealized potential for cancer therapy.

Author information

1
Rutgers Robert Wood Johnson University Hospital and 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; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
2
Rutgers Robert Wood Johnson University Hospital and 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; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA bertinoj@cinj.rutgers.edu.

Abstract

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.

KEYWORDS:

6-thioguanine; Chemotherapy; Denovo purine synthesis; Folate antagonists

PMID:
24928612
PMCID:
PMC4077447
DOI:
10.1634/theoncologist.2014-0178
[Indexed for MEDLINE]
Free PMC Article

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