Circulating cell-free DNA: a novel biomarker for response to therapy in ovarian carcinoma. Academic Article uri icon

Overview

abstract

  • INTRODUCTION: Cell-free DNA (CFDNA) is a reflection of both normal and tumor-derived DNA released into the circulation through cellular necrosis and apoptosis. We sought to determine whether tumor-specific plasma DNA could be used as a biomarker for tumor burden and response to therapy in an orthotopic ovarian cancer model. METHODS: Female nude mice injected intraperitoneally with HeyA8 ovarian cancer cells were treated with either docetaxel alone or in combination with anti-angiogenic agents (AEE788-dual VEGFR and EGFR antagonist or EA5-monoclonal antibody against ephrin A2). Following DNA extraction from plasma, quantification of tumor-specific DNA was performed by real-time PCR using human specific beta-actin primers. The number of genome equivalents (GE/ml) were determined from a standard curve. Apoptosis was assessed by TUNEL staining of treated tumors. RESULTS: The levels of tumor-specific DNA in plasma increased progressively with increasing tumor burden (R2=0.8, p<0.01). Additionally, tumor-specific plasma DNA levels varied following treatment with chemotherapy. In mice with established tumors (19 days following tumor injection), tumor-specific plasma DNA levels increased by 63% at 24 hours following a single dose of docetaxel (15 mg/kg), and then declined to 20% below baseline at 72 hours and were 83% lower than baseline 10 days following therapy. In addition, docetaxel treatment resulted in a significant increase in the apoptotic index at 24 hours (p<0.01). Moreover, in two separate therapy experiments using a combination of cytotoxic chemotherapy with anti-angiogenic agents, tumor-specific plasma DNA levels were significantly higher in mice treated with vehicle compared to the treatment groups. The correlation between tumor weight and tumor-specific DNA in these experiments was 0.71-0.76 (p<0.01). CONCLUSIONS: Our results indicate that tumor-specific CFDNA levels correlate with increasing tumor burden and decline following therapy. Thus, tumor-specific DNA may be a useful surrogate biomarker of therapeutic response and should be evaluated in future clinical trials.

authors

  • Kamat, Aparna A.
  • Bischoff, Farideh Z
  • Dang, Dianne
  • Baldwin, Matthew F
  • Han, Liz Y
  • Lin, Yvonne G
  • Merritt, William M
  • Landen, Charles N
  • Lu, Chunhua
  • Gershenson, David M
  • Simpson, Joe L
  • Sood, Anil K

publication date

  • October 26, 2006

Research

keywords

  • DNA, Neoplasm
  • Ovarian Neoplasms

Identity

Scopus Document Identifier

  • 33751074674

Digital Object Identifier (DOI)

  • 10.4161/cbt.5.10.3240

PubMed ID

  • 16969071

Additional Document Info

volume

  • 5

issue

  • 10