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Experimental Therapeutics |
Calydon, Inc., Sunnyvale, California 94089
Human glandular kallikrein (hK2) and prostate-specific antigen (PSA) are related members of the human kallikrein gene family. The genes for hK2 and PSA are expressed predominately in the prostate, are transcriptionally up-regulated by androgens, and share 78% homology. Previously, one functional androgen response element was identified within the proximal promoter (-324 to +33 relative to the cap site) of the hK2 gene. To detect additional upstream regulatory elements, the 12.3 kbp between the PSA gene and 5' to the hK2 gene were amplified by PCR and linked to a promoterless firefly luciferase reporter gene. Transient transfection experiments showed an androgen-dependent enhancer, located between -3.4 and -5.2 kb upstream of the transcription start site of the hK2 gene. This hK2 enhancer increased luciferase expression 100-fold in the presence of the testosterone analogue R1881. The hK2 enhancer contains an androgen response element that lost activity when mutated. The hK2 enhancer/promoter demonstrated activity in PSA(+) LNCaP cells whereas the enhancer/promoter was inactive in PSA(-) 293, A549, HBL100, HUH-7, LoVo, MCF-7, OVCAR-3, and PC-3 cells.
Insertion of the hK2 enhancer/promoter into adenovirus to drive the E1A genes of adenovirus type 5 (Ad5) created an attenuated replication competent adenovirus variant Calydon virus (CV) 763, which replicates similarly to wild-type adenovirus in prostate tumor cells but is attenuated in nonprostate tumor cells. In addition, CV764, an adenovirus variant containing the previously cloned prostate-specific enhancer (to drive the Ad5 E1A genes) and the hK2 enhancer/promoter (to drive the Ad5 E1B genes) was constructed. CV764 is significantly attenuated and has a high therapeutic index with a cell specificity of 10,000:1 for PSA(+) LNCaP cells, compared to ovarian cancer OVCAR-3 cells and SK-OV-3 cells and PA-1 cells. CV764 is also highly attenuated in primary human microvascular endothelial cells.
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