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.