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

Our plain-English summary of 6-thioguanine: a drug with unrealized potential for cancer therapy, by P.N. Munshi, M. Lubin, J.R. Bertino (The Oncologist, 2014).

The study

• Authors: P.N. Munshi, M. Lubin, J.R. Bertino
• Journal: The Oncologist
• Published: 2014;19(7):760-5
• Type of article: Review
• Cited by: 65 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

©AlphaMed Press.

In plain English

This article was a review, not a new study of patients. The authors reviewed published work on 6-thioguanine (6-TG), a cancer drug first used in the 1950s. They compared it with 6-mercaptopurine and summarized its metabolism, dosing and earlier trials. The article did not study asbestos exposure. Earlier single-drug trials in solid tumors, which the authors listed in a table, showed minimal anti-tumor effects, except possibly in breast cancer. The review focused on tumors that lack an enzyme called MTAP. A table adapted from earlier work listed this deficiency in 80% of mesothelioma. The authors described a proposed approach in which a natural compound, MTA, is given before high-dose 6-TG to protect normal tissues. They cited animal and laboratory studies supporting it, including one that tested pairs of cell lines, among them mesothelioma, and reported a large increase in the drug's therapeutic index. The MTA and 6-TG combination had not been tested in humans, and its best dose schedule had not been defined. The authors concluded that the method deserves a clinical trial.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published studies on 6-thioguanine
• Who was studied: No new patients were studied. The authors reviewed earlier human trials of 6-TG in leukemias, lymphomas, multiple myeloma and solid tumors, along with published animal and laboratory studies.
• Exposure: Not asbestos. The exposure was the drug 6-thioguanine, given alone, after pretreatment with methylthioadenosine (MTA), or combined with other drugs such as methotrexate or pralatrexate.
• Main results:
  • In earlier single-agent trials of 6-TG in solid tumors summarized by the authors, minimal anti-tumor effects were observed, except possibly in breast cancer.
  • In an earlier high-dose study of 6-TG in multiple myeloma cited by the authors, 3 of 32 patients were clinically improved, with one partial response.
  • Table 1, adapted from an earlier paper, listed MTAP deficiency in 80% of mesothelioma, citing a separate study. It also listed 50% for pancreatic cancer and 30% for non-small cell lung cancer, sarcoma and glioblastoma.
  • In mouse xenograft experiments cited by the authors, MTA plus 6-TG caused complete regression of MTAP-deficient CCRF-CEM human lymphoma/leukemia tumors, although the tumors later regrew.
  • An in vitro study by Kruger and colleagues, cited by the authors, reported that MTA plus 6-TG greatly increased the therapeutic index of 6-TG in paired cell lines with and without MTAP, including mesothelioma, osteosarcoma and mouse embryo fibroblasts.
  • The authors stated that the relationship between MTAP deficiency and response to 6-TG had not been tested in the clinic.
• The authors' conclusion: The authors concluded that MTAP deficiency is common in many tumors with a dismal prognosis, and that the proposed MTA/6-TG method deserves a clinical trial.
• Limitations the authors state:
  • The authors stated that the MTA/6-TG dose schedule had not been tested in humans.
  • The authors stated that the optimal dose schedule of 6-TG, alone or in combination, had not been adequately defined.
  • The authors noted that earlier solid-tumor studies lacked information on tumor MTAP status.
  • The authors noted that the optimal dosage and schedule for in vivo experiments with the MTA/6-TG method have barely been explored.

Topics

Medical terms in this study, explained in our Lexicon: Homozygous Deletion, MTAP, CDKN2A, Mesothelioma, Sarcoma, Squamous Cell Carcinoma, Carcinoma, Clinical Trial.

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