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Clinical Cancer Research
Year: 2009  |  Volume: 15  |  Issue: 11  |  Page No.: 3881 - 3888

Decitabine Effect on Tumor Global DNA Methylation and Other Parameters in a Phase I Trial in Refractory Solid Tumors and Lymphomas

D. J Stewart, J. P Issa, R Kurzrock, M. I Nunez, J Jelinek, D Hong, Y Oki, Z Guo, S Gupta and I. I. Wistuba    

Abstract:

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/m2 on days 1 to 5, and 8 to 12 or 15 to 20 mg/m2 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 ≤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 ≤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.

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