జీవక్రియ: ఓపెన్ యాక్సెస్

Enhanced Delivery of Chemotherapeutic Alkylating Agents into Prostate Cancer Cells Employing the Androgen Receptor as Delivery Vehicle

Abstract

Marvin Rubenstein, Courtney MP Hollowell and Patrick Guinan

Effective chemotherapy for tumors, particularly those of disseminated prostate cancer, is limited by the inability of effective agents to distinguish between tumor and non-tumor cells, their inability to be delivered in sufficient dosage to susceptible targets (within tumor cells and organelles) and the development of tumor resistance. Overall chemotherapy for prostate cancer is relatively ineffective, providing only months of additional survival time for recurrent disease. While most recurrent and advanced stage tumors are resistant to chemotherapy, there may be a window of opportunity when new types of innovative therapy can be employed. Until proven, this approach could be employed either as adjuvant treatment for localized disease primarily treated by surgery or radiation; or for advanced cases, in combination with traditional chemotherapy protocols which currently provide only a limited improvement in survival. The innovative therapy being proposed here employs the tumors' endogenous androgen receptor (AR) not only as a tumor specific marker for identification and specificity, but also as a delivery vehicle. By coupling the DNA cross linking chemotherapeutic cyclophosphamide (Cytoxan) to an androgen receptor ligand (AR agonist; R1881) cytotoxic chemotherapy can be delivered not only specifically to those cells which express AR but also, through the natural intracellular transit of this activated receptor, specifically direct the drug into the nucleus and transcriptionally active DNA sites. When localized, opposing DNA strands would be cross linked preventing DNA transcription and replication, leading to cell death. Normal androgen activation (provided by the R1881 agonist) mediated via the bound receptor would make the cell even more susceptible to Cytoxan action. An in vitro assay to determine any enhanced activity of Cytoxan combined with R1881 vs Cytoxan alone is easily performed and described.