Novel treatment for prostate cancer using 5[alpha]-reductase inhibitor type II and ER[alpha] blocker.
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Issue Date
2013
Authors
Hariri, Waseem Abdulrahman '13
Degree
MS in Biotechnology
Advisor
Mousa, Shaker
Committee Members
Thangirala, Sudha
Mukhtar, Hasan
Mian, Badar
Mukhtar, Hasan
Mian, Badar
Journal Title
Journal ISSN
Volume Title
Abstract
Prostate cancer (PCa) is the most frequently diagnosed malignancy in American men. Studies have shown that high levels of androgen hormones are responsible for the development of PCa, but the high levels do not explain the relationship between the increased incidence of PCa with age because the levels of androgen hormones decline with age. It has been hypothesized that Dihydrotestosterone (DHT) binds to intracellular androgen receptor, it prevents the apoptotic signaling pathway. Studies have shown that estrogen hormone in the form of 17β-estradiol (E2) plays a role in the pathogenesis of PCa through estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). ERα is found much more in cancerous prostate cells and acts as an oncogene, while ERβ is found in normal prostate tissue and acts as a suppressor gene. We propose that targeting ERα by using an ERα blocker like Toremifene and blocking the effect of DHT by 5α-reductase type II inhibitor Finasteride we will maximize the therapeutic results for PCa and reduce the tumorigenicity. We also propose that by encapsulating these drugs inside nanoparticles (NPs) and conjugating NPs with prostate specific membrane antigen (PSMA) we will enhance the targeting therapy and prevent unwanted side effects. In our proposed studies, we tested the effects of our chosen drugs on the growth and differentiation of a prostate cancer cell line (PC3M-Lucciferase transfected) in vitro and in vivo using male nude mice. In our studies, different techniques were used including flow cytometry, MTT assay, and LC/MS and histopathology analysis. Finasteride did not show a significant reduction in tumor growth; however, Toremifene showed a very significant reduction in tumor growth both in vitro and in vivo. The nano-encapsulated Toremifene conjugated with anti-PSMA antibody showed more significant reduction on the tumor growth in vitro and in vivo more than the free Toremifene. We conclude that NP-Toremifene with PSMA is a promising method to treat PCa.
Citation
Hariri, Waseem Abdulrahman. "Novel Treatment for Prostate Cancer Using 5[Alpha]-Reductase Inhibitor Type II and ER[Alpha] Blocker." Albany College of Pharmacy and Health Sciences, New York, Proquest/UMI, 2013.
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