Selective inhibition of DNA methyltransferase enzymes as a novel strategy for cancer treatment.
A common event in the development of human neoplasia is the loss of growth regulatory tumor suppressor functions. Methylation of 5'-CpG islands of tumor suppressor genes and elevated levels of the DNA-(cytosine-5)-methyltransferase enzymes (DNMT1, 3A and 3B) are also prevalent features of human neoplasia. However, direct evidence that elevated DNMT enzyme levels alter gene expression and influence oncogenesis has been difficult to obtain due to the lack of specific DNMT inhibitors. We have developed potent and selective antisense inhibitors of the known DNA methyltransferases. MG-98, a second-generation DNMT1-specific antisense inhibitor currently in phase II clinical trials, reactivates silenced tumor suppressor genes and inhibits the growth of cancer cells in vitro and in preclinical in vivo models. Here, we will review the discovery and development of MG-98 as a cancer therapeutic.
Reid
Gregory K
GK
MethylGene Inc, Montreal, Québec, Canada. reidg@methylgene.com
Besterman
Jeffrey M
JM
MacLeod
A Robert
AR
D002986:Clinical Trials as Topic; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017384:Sequence Deletion; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D015254:DNA Modification Methylases