Cancer therapy utilizing an adenoviral vector expressing only E1A.
The human adenovirus type 5 (Ad5) early region 1A (E1A) proteins have been shown to have potent antitumor effects, due to their ability to reprogram oncogenic signalling pathways in tumor cells. The success of E1A antitumor therapy in animal models has led to its use in phase I and phase II clinical trials, where liposome-based delivery vehicles are being used to deliver a plasmid encoding E1A. To increase the efficiency of E1A delivery to tumors, we have developed an Ad vector deleted of all viral protein coding sequences (termed helper-dependent Ad vectors, hdAds) with the exception of E1A, designated hdAd-E1A. In culture, this vector mediated high-level expression of E1A gene products. A549 cells, a human lung adenocarcinoma cell line, infected with hdAd-E1A showed a reduced proliferative capacity in adherent culture, and the ability to form colonies in soft agarose was completely abolished. In contrast, A549 infected with an hdAd expressing beta-gal were able to form colonies of a similar size and frequency as uninfected cells. Under serum-depleted conditions, expression of E1A within A549 led to the induction of apoptosis. Finally, A549 cells treated with hdAd-E1A showed approximately 10-fold greater sensitivity to the chemotherapeutic drug cisplatin. Taken together, these data indicate that the use of hdAd provides a simple and effective method to deliver E1A to cancer cells, and results in reduction in the tumorigenic potential of the cells, as well as increasing the cells sensitivity to anticancer drugs.
Hubberstey
Andrew V
AV
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada.
Pavliv
Marta
M
Parks
Robin J
RJ
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D003673:Defective Viruses; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005814:Genes, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D002945:Cisplatin