Faculty Collaboration Database

Decitabine effect on tumor global DNA methylation and other parameters in a phase I trial in refractory solid tumors and lymphomas. Clin Cancer Res 2009 Jun 01;15(11):3881-8

Date

05/28/2009

Pubmed ID

19470736

DOI

10.1158/1078-0432.CCR-08-2196

Scopus ID

2-s2.0-66649105473 (requires institutional sign-in at Scopus site)   116 Citations

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/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.

Author List

Stewart DJ, Issa JP, Kurzrock R, Nunez MI, Jelinek J, Hong D, Oki Y, Guo Z, Gupta S, Wistuba II

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antimetabolites, Antineoplastic
Apoptosis
Azacitidine
Blood Pressure
Cation Transport Proteins
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
DNA Modification Methylases
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Humans
Hydrogen-Ion Concentration
In Situ Nick-End Labeling
Ki-67 Antigen
Leukocytes, Mononuclear
Lymphoma
Male
Middle Aged
Neoplasms
Sex Factors
Treatment Outcome
Young Adult