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Updated: Jun 22, 2026
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Decitabine effect on tumor global DNA methylation and other parameters in a phase I trial in refractory solid tumors
David J Stewart1, Jean-Pierre Issa, Razelle Kurzrock
1M. D. Anderson Cancer Center, Houston, Texas, USA. dstewart@mdanderson.org
Purpose:
By hypomethylating genes, decitabine may up-regulate factors required for chemotherapeutic cytotoxicity. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1.
Experimental Design:
Thirty-one patients with refractory malignancies received decitabine 2.5 to 10 mg/m(2) on days 1 to 5, and 8 to 12 or 15 to 20 mg/m(2) on days 1 to 5. Tumor was assessed for DNA methylation (by LINE assays), apoptosis, necrosis, mitoses, Ki67, DNA methyltransferase (DNMT1), CTR1, and p16.
Results:
Febrile neutropenia was dose limiting. One thymoma patient responded. Decitabine decreased tumor DNA methylation (from median 51.2% predecitabine to 43.7% postdecitabine; P = 0.01, with effects at all doses) and in peripheral blood mononuclear cells (from 65.3-56.0%). There was no correlation between tumor and peripheral blood mononuclear cells. Patients starting decitabine < or =3 versus >3 months after last prior cytotoxic or targeted therapy had lower predecitabine tumor CTR1 scores (P = 0.02), higher p16 (P = 0.04), and trends (P = 0.07) toward higher tumor methylation and apoptosis. Decitabine decreased tumor DNMT1 for scores initially >0 (P = 0.04). Decitabine increased tumor apoptosis (P < 0.05), mitoses (if initially low, P = 0.02), and CTR1 (if initially low, P = 0.025, or if < or =3 months from last prior therapy, P = 0.04). Tumor CTR1 scores correlated inversely with methylation (r = -0.41, P = 0.005), but CTR1 promoter was not hypermethylated. Only three patients had tumor p16 promoter hypermethylation. P16 scores did not increase. Higher blood pressure correlated with lower tumor necrosis (P = 0.03) and a trend toward greater DNA demethylation (P = 0.10).
Conclusions:
Exposure to various cytotoxic and targeted agents might generate broad pleiotropic resistance by reducing CTR1 and other transporters. Decitabine decreases DNA methylation and augments CTR1 expression through methylation-independent mechanisms.
Insights
Decitabine reduces DNA methylation and increases CTR1 transporter expression in refractory malignancies. This epigenetic modification may overcome platinum resistance by enhancing chemotherapy efficacy.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Platinum-resistant cancers often exhibit reduced expression of the CTR1 transporter, which is crucial for platinum drug uptake.
- Decitabine, a hypomethylating agent, may restore sensitivity to chemotherapy by up-regulating essential factors.
Purpose of the Study:
- To investigate the effects of decitabine on DNA methylation, CTR1 expression, and other markers in patients with refractory malignancies.
- To explore the potential of decitabine in overcoming chemoresistance.
Main Methods:
- A phase I/II study administering decitabine to 31 patients with refractory malignancies.
- Assessment of tumor DNA methylation, apoptosis, necrosis, mitoses, Ki67, DNMT1, CTR1, and p16 expression.
- Dose-escalation to determine the maximum tolerated dose.
Main Results:
- Decitabine significantly decreased tumor DNA methylation across all doses.
- Increased tumor apoptosis, mitoses, and CTR1 expression were observed, particularly in patients treated within 3 months of prior therapy.
- Tumor CTR1 expression inversely correlated with DNA methylation, but not through promoter hypermethylation.
Conclusions:
- Decitabine effectively reduces DNA methylation and can augment CTR1 expression via methylation-independent mechanisms.
- These findings suggest decitabine's potential to re-sensitize platinum-resistant tumors to chemotherapy.
- Prior exposure to cytotoxic agents may influence treatment response and CTR1 expression.
