化合物信息

Description

Ovarian cancer,Myelodysplastic syndromes

Description

Decitabine is a potent inhibitor of DNA methylation with IC50 of 438 nM and 4.38 nM in HL-60 and KG1a cells, respectively.

Targets

IC₅₀

In Vitro

Decitabine inhibits cell growth in a dose and time-dependent manner with IC50 of approximately 438 nM and 43.8 nM for 72 hours and 96 hours exposure in HL-60 and KG1a leukemic cells, respectively. ^[1] A recent study shows that Decitabine exhibits high anti-proliferative and pro-apoptotic activity against anaplastic large cell lymphoma (ALCL), and inhibits [³H]–thymidine uptake in KARPAS-299 cells with EC50 of 0.49 μM. ^[2]

In Vivo

In a ALK+ KARPAS-299 murine xenograft model, Decitabine at a dose of 2.5 mg/kg causes increased apoptosis and reduced proliferation of tumor cells, and also results in demethylation of tumor suppressor p16INK4A. ^[2]

Clinical Trials

Decitabine is currently in Phase I clinical trials in patients with Higher-risk MDS and MDS/AML Receiving Allogeneic Stem Cell Transplantation.

Features

Description

Combination of Decitabine (100 ng/mL) and Trichostatin A (TSA) (3 ng/mL), a potent inhibitor of histone deacetylase, shows an additive effect on the DNA synthesis inhibition in both HL-60 and KG1a leukemic cell lines. Combination of Decitabine and TSA leads to greater growth inhibition of HL-60 and KG1a leukemic cells than either agent alone. ^[1] Combination treatment of Decitabine and Dasatinib is currently in Phase I clinical trials in patients with Accelerated or Blastic Phase Chronic Myelogenous Leukemia.

DNA synthesis assay

The rate of DNA synthesis is measured by the incorporation of radioactive thymidine into DNA. HL-60 and KG1a cells are suspended in 2 mL RPMI medium containing 10% fetal serum in 6-well (35 mm diameter) dishes and incubated with different concentrations of corresponding drugs for 48 hours (drugs are added simultaneously). At 48 hours, 0.5 μCi [³H] thymidine (6.7 Ci/mmol) is added to each well and incubated for an additional 24 hours. The cells are placed on GF/C glass fiber filters (2.4 cm diameter), washed with cold 0.9% NaCl, 5% cold trichloroacetic acid and ethanol. The filters containing the DNA are then dried, placed in EcoLite scintillation liquid (ICN) and the radioactivity measured using Beckman LS 6000IC scintillation counter. The IC50 is defined as the concentration of drug that inhibits 50% of the DNA synthesis of the leukemic cell lines from the dose–response curve.

Cell Lines

HL-60 and KG1a

Concentrations

0-500 nM

Incubation Time

96 hours

Methods

For the growth inhibition assay, cells in log phase are placed in 5 mL of medium. Different concentrations of Decitabine are added to the medium simultaneously. Cell counts are performed at the indicated times using a model ZM Coulter Counter. The concentration that produces 50% inhibition of growth (IC50) is determined from the growth curves of the drug treated leukemic cell lines.

Animal Models

KARPAS-299 human cells are inoculated subcutaneously into the right and left flanks of the mice.

Formulation

Decitabine is dissolved in sterile PBS .

Doses

≤2.5 mg/kg

Administration

Administered via i.p.