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Late-stage ovarian cancer shows promise in two-drug phase I trial
Date:6/9/2010

e, and neutropenia (reduced white blood cell count).

Encouraged by the results of the phase I trial, which determined the safety of two different dosing regimens, a phase II trial is now under way with 17 patients already enrolled. Phase II trials are primarily focused on assessing the effectiveness of a drug or treatment protocol.

The study's other co-principal investigator, Kenneth Nephew, geneticist in the IU Medical Sciences Program-Bloomington, led the report's biochemical and DNA analysis.

In a bid to resensitize patients to carboplatin, Nephew and Matei and co-investigator Jeanne M. Schilder, M.D., associate professor of obstetrics and gynecology in the Division of Gynecologic Oncology at the IU School of Medicine, turned to the DNA demethylating agent, decitabine.

Why trial patients were responsive to the combination of decitabine and carboplatin is not yet known, but based on the literature and an analysis of biopsy tissue and blood samples, Nephew and Matei suspect decitabine reactivates tumor suppression genes that are turned off in ovarian cancer cells.

One of the hallmarks of ovarian cancer is the aberrant methylation of cytosine, one of DNA's four nitrogenous bases. Methylation prevents DNA readers from expressing genes. Some of the silenced genes won't be terribly important, but some, like tumor suppression genes, are. Decitabine is a known methylation inhibitor that can help return tumor suppression genes to an active state, and also improve cells' susceptibility to anti-cancer drugs like carboplatin.

"Our hypothesis is that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments," Nephew said. "By keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages."

The researchers also reported that deci
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Contact: Mary L. Hardin
mhardin@iupui.edu
317-274-7722
Indiana University School of Medicine
Source:Eurekalert

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