An Innovative Strategy for the Prevention and Treatment of Metastatic Prostate Cancer: Modified Tetracycline as Chemotherapeutics
Abstract
In this second year (months 12-24) of the Phase II of the project, the molecular basis of chemoresistance in prostate tumor cells, acquired due to their interaction with stromal cells was explored. Both biochemical and molecular biological approaches using quantitative mRNA expression analysis by cDNA Microarray, Quantikine mRNA ELISA, and stable transfection with anti-sense cDNA were undertaken to analyze the role of three pro-inflammatory cytokines in the modulation of tumor cells' response to chemotherapeutic drugs. These studies revealed that in addition to chemodrugs induced increase in the expression levels of three cytokines IL-8, IL-6 and IL-8, cyclooxygenase-II (cox-2), the key enzyme in the classical inflammatory response, in also highly elevated. Inhibition of the expression of IL-1beta, IL-6 and IL-8, not only increased response chemotherapy drug-induced cytotoxicity and apoptosis but also showed an interlinking relationship between the three cytokines. Inhibition of COX-2 by specific inhibitors such as Celecoxib or NS 398 also induced apoptosis mediated cytotoxicity in CaP cells. A combination of COX-2 inhibition and CMT-3 revealed synergistic increase in cytotoxicity and apoptosis. Furthermore, a combined treatment modality, using Celecoxib and CMT-3, in mice bearing human tumor xenografts produced an increased tumor growth delay, without any adverse effect on the host, suggesting increased efficacy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2002
- Accession Number
- ADA427704
Entities
People
- Balakrishna L. Lokeshwar
Organizations
- University of Miami