Accession Number:

ADA409401

Title:

A Biologically-Based Rationale for Combination Chemotherapy of Novel Agents with Doxorubicin in Human Breast Cancer Cell Lines

Descriptive Note:

Final rept. 1 Aug 2001-31 Jul 2002

Corporate Author:

COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO GRANTS AND CONTRACTS

Report Date:

2002-08-01

Pagination or Media Count:

17.0

Abstract:

It is common to treat cancer patients with a cocktail of cytotoxic chemotherapeutic agents designed to eradicate cancer cells without overwhelming healthy cells. Unfortunately, patient toxicity often necessitates reduced dosing at the expense of therapeutic success. Recently, researchers have been interested in identifying nontoxic adjunct therapies which could be used to increase the sensitivity of cancer cells to more commonly used chemotherapeutics, allowing reduced prolonged dosing for greater therapeutic success in the absence of patient toxicity. In pursuit of this goal, much attention has fallen on a group of agents called histone deacetylase inhibtors HDACI. As suggested by their name, these compounds prevent deacetylation of hi stones resulting in a relaxation of the DNA near the hyperacetylated histones. This opening up of DNA appears to facilitate transcription of the DNA and consequent increased expression of a number of genes 1,2 Increased transcription from the topoisomerase II Ct topoil promoter was observed in NIH3T3 cells treated with the HDACI, trichostatin A TSA 3. Topoisomerase poisons such as doxorubicin DOX are commonly used chemotherapeutics. The sensitivity of cells to these compounds is directly proportional the amount of intracellular topoli protein expression 4. Transcription of the gene encoding death receptor 5 DR5 appears to increase in response to the HDACI phenylbutyrate PB, Kroll unpublished. When bound by its ligand, TNFoc related apoptosis inducing ligand TRAIL, DR5 initiates a signaling cascade that causes the cell to undergo apoptosis. Although DR5 is widely expressed, TRAIL killing occurs more readily in tumor cells, perhaps due to a lack of expression of the inhibitory decoy receptor, TRID 5,6 HDACIs may, thus, sensitize cells to doxorubicin anor TRAIL, providing a nontoxic adjunct therapy, which would be expected to work even in advanced breast cancer disease.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE