Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1519176 (PSA)
 5,490 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy for breast cancer initially involves local or systemic delivery. Local delivery may be intrapleural or via direct injection to lesions. However, systemic delivery remains the greatest challenge with targeting, although methods using antibodies or growth factor receptor ligands have been demonstrated in preclinical models. This review focuses on the next step of using tissue-specific promoters such as Muc-1, CEA, PSA, HER-2, Myc, L-plastin and secretory leukoproteinase inhibitor promoters. All of these have demonstrated differential upregulation in breast cancer and additional specificity may be obtained by using physiological stimuli that are more frequently expressed in cancers, such as glucose regulated promoters and hypoxia response elements or radiation inducible elements. Amongst the later are the EGR-1, p21 and tissue type plaminogen activator promoters. Potential therapy genes include the prodrug activation system 5-fluorocytosine and other analogues of antimetabolites, but all of these need gap junctions to transfer the phosphorylated metabolites. Other approaches involving more freely diffusible products include cyclophosphamide, ifosfamide and thymidine phosphorylase to activate 5-deoxy-5-fluoruridine to fluorouracil. The bystander effect is important both for cell killing and for immunological and antivascular effects. Breast cancer is one type of tumour where a major clinical research effort is underway using local delivery methods. For prodrug activation systems, the use of human enzymes is desirable to prevent an immunological response that would eventually eliminate cells producing the prodrug activation system. The use of alkylating agents has an advantage over antimetabolites in that they are cytotoxic to cycling and noncycling cells, and the cytotoxic products can diffuse across cell membranes without the need for gap junctions. They also have a much steeper dose response curve than antimetabolites.
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PMID:Molecular chemotherapy for breast cancer. 1008 62

Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.
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PMID:Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling. 2168 Nov 93