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

摘要

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of the gene encoding death receptor 5 (DR5) appears to increase in response to the HDACI phenylbutyrate (PB, Kroll unpublished).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 an&or TRAIL, providing a nontoxic adjunct therapy, which would be expected to work even in advanced breast cancer disease.