Date of Award

Fall 1995

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

George L. Wright, Jr.

Committee Member

Laura K. Moen

Committee Member

Kenneth Somers

Committee Member

William Wasilenko

Abstract

Prostate cancer is the most common malignancy and the second leading cause of cancer death in males in the United States. Additionally, the number of deaths attributed to prostate cancer is increasing at a rate of approximately 8% a year. Development of new diagnostic and therapy strategies are needed in order to improve the life expectancy of patients with this disease. One tool which may allow for improvements in prostate cancer diagnosis and therapy is the monoclonal antibody (MAb) 7E11-C5.3 which was first described in 1987. Since then, the antigen recognized by MAb 7E11-C5.3 has been named the prostate specific membrane antigen or PSMA. Antibody-radionuclide conjugates of 7E11-C5.3 have been successfully used to localize metastatic disease in vivo and treat human prostate tumors in nude mice suggesting that PSMA may have promise as an important new diagnostic and therapeutic tool for prostate cancer. Many questions remain to be answered however, regarding the basic biology of MAb 7E11-C5.3 and PSMA before the true potential of this new marker is known. The present study has attempted to answer these questions utilizing a comprehensive characterization of PSMA at the biochemical, physical and molecular level. PSMA was found to be localized at the inner face of the plasma membrane and within mitochondria in LNCaP cells. The MAb 7E11-C5.3 epitope was determined to consist of only the peptide backbone of PSMA and localized to the intracellular domain with a minimal reactive peptide of 6 amino acids (MWNLLH). PSMA was detected in normal, benign and malignant prostate tissues as well as normal small intestine, brain and salivary gland indicating that this marker is not as specific as once thought. Additionally, PSMA was detected in seminal fluid but not in serum using MAb 7E11-C5.3. Finally, the promoter of the PSMA gene was cloned upstream of a reporter gene construct which was expressed in androgen and androgen receptor free conditions indicating that the regulation of PSMA is markedly different from that of the prostate specific antigen (PSA). This study has provided a solid foundation on which to build a more thorough understanding of MAb 7E11-C5.3 based imaging and therapy applications and continues to suggest that PSMA is a novel and important new prostate biomarker.

Comments

A Dissertation Submitted to the Faculties of Eastern Virginia Medical School and Old Dominion University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/3s95-dd92

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