DNA Methyltransferase

DNA methyltransferase 1 (DNA MeTase) is the major DNA-methylating enzyme and methylates cytosine bases at a CpG dinucleotide site. Unmethylated CpG regions are associated with transcriptionally active DNA, whereas hypermethylated DNA is linked with gene silencing. In tumor cells, the patterns of DNA methylation are altered and hypermethylation of tumor suppressor genes that affect cell-cycle regulation is a common event (99). Researchers at MethylGene screened a series of second-generation mixed backbone oligonucleotides, with the same chemical modifications as GEMĀ®231 to identify AS-ODNs with inhibitory activities to DNA MeTase mRNA expression. MG88 (targeting the 5' region) and MG98 (targeting the 3'-UTR) were found to be the most potent AS-ODNs with IC50 concentrations of 40 and 45 nM, respectively (100). Following the observations of tumor growth delays or regressions in xenografted tumors together with an acceptable safety profile in primates (101), MG98 was entered into phase I studies. In the first phase I study, MG98 (40-240 mg/m2/d) was administered to 14 patients as a continuous iv infusion for 3 wk with 1 wk of rest between cycles (102). DLTs resulting from this schedule were defined as transaminitis, fatigue, and throm-bocytopenia. A transient decrease in MeTase was observed in 7 of 10 patients evaluated. In the second phase I study, MG98 (40-480 mg/m2) was administered to 19 patients with solid tumors by twice weekly 2-h infusions for 3 wk followed by 1 wk of rest between cycles (103). An increase in aPTT was seen shortly after the infusions, similar to the observations of others using 2-h infusion schedules of AS-ODNs. Other mild toxicities experienced were fatigue, fever, nausea, anorexia, anemia, transaminitis, and thrombocytopenia, while the DLTs were defined as rigors and fatigue (two of three patients) at the highest dose of 480 mg/m2. Inhibition of MeTase mRNA was recorded in two of nine patients evaluated, and there was one partial response of more than six cycles of treatment duration in one patient with renal cell carcinoma. Using this 2-h infusion schedule, MG98 has entered into phase II studies for meta-static head and neck cancer at 240 mg/m2, and for advanced renal cell carcinoma at 360 mg/m2, and MethylGene and MGI Pharama have initiated a third trial against myelodysplastic syndrome/AML.

0 0

Post a comment