DNA MethyltransferaseMG

Hypermethylation by the enzyme DNA methyltransferase has been postulated to inactivate tumor suppressor genes, resulting in neoplastic transformation and tumorigenesis. Agents that prevent or reverse DNA methylation might therefore restore normal growth control to cancer cells. MG 98 is a phos-

phorothioate AS-ODN that is a highly specific inhibitor of translation of the mRNA for human DNA methyltransferase with IC50 values of 50-70 nM in cell lines. Tumor growth delay and regression were observed with MG 98 in human lung and colon cancer xenografts. A phase I study examined MG 98 administered as a continuous 21-d iv infusion every 4 wk. At an interim report, nine patients with solid cancers received 10 courses at doses up to 240 mg/m2/d. Dose-limiting grade 3 drug-related elevation of transaminases was encountered in two of two patients at the 240 mg/m2/d dose level. Other toxicities were minimal. Biologically relevant concentrations for the inhibition of human DNA methyltransferase mRNA were achievable at the lowest dose level evaluated (40 mg/m2/d) (48).

Phase II trials are currently being conducted in patients with head and neck as well as metastatic renal cancer. A third phase II trial will analyze MG 98 in patients with myelodysplastic syndrome and AML. The studies aim to evaluate the clinical efficacy as well as the effects of MG 98 both on the methylation status of potential tumor suppressor genes and on suppression of DNA methyltransferase 1 (MeTase) mRNA levels in primary tumor biopsy samples.

0 0

Post a comment