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

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 Transcription gene encoding death receptor 5 (DR5) response HDACI phenylbutyrate (PB, Kroll unpublished).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