Comparison of Molecular Strategies for Breast Cancer Virotherapy using Oncolytic Adenovirus.
Hum Gene Ther. 2008 Jun 27;
Authors: Seymour LW, Bazan-Peregrino M, Carlisle R, Hernandez-Alcoceba R, Iggo R, Homicsko K, Hallden G, Mautner V, Shen J, Fisher K
Oncolytic viruses are regulated by the tumour phenotype to replicate and lyse cancer cells selectively. To identify optimal strategies for breast cancer we compared five adenoviruses with distinct regulatory mechanisms: Ad-dl922-947 (targets G1-S checkpoint); Ad-Onyx-015 and Ad-Onyx-017 (target p53/mRNA export); Ad-vKH1 (targets Wnt pathway) and AdEHE2F (targets estrogen receptor/G1-S checkpoint/hypoxic signalling). The quantity of virus required to kill 50% of breast cancer cells after 6 days (EC50, PFU/cell) was measured. The most potent virus was Ad-dl922-947 (EC50 0.01-5.4 in SkBr3, MDA-231, MDA-468, MCF7, ZR75.1), followed by wild type (Ad-WT; EC50 0.3-5.5) and AdEHE2F (EC50 1.4-3.9). Ad-vKH1 (EC50 7.2-72.1), Ad-Onyx-017 (EC50 8.4-167) and Ad-Onyx-015 (EC50 17.7-377) showed less activity. Most viruses showed very limited cytotoxicity in normal human cells, including breast epithelium MCF10A (EC50 >722) and fibroblasts (EC50 >192) and only moderate cytotoxicity in normal microvascular endothelial cells (HMVEC, EC50 42.8-149), except Ad-dl922-947 which was active in HMVEC (EC50 1.6). After injection into MDA-231 xenografts, Ad-WT, AdEHE2F and Ad-dl922-947 showed replication, assessed by hexon staining and quantitative PCR measurement of viral DNA, and significantly inhibited tumour growth leading to extended survival. Following intravenous injection Ad-dl922-947 showed DNA replication (233% of the injected dose was measured in liver after 3 days) while AdEHE2F did not. Overall, AdEHE2F showed the best combination of low toxicity in normal cells and high activity in breast cancer in vitro and in vivo, suggesting that molecular targeting using estrogen reponse elements, hypoxia response elements and dysregulated G1-S checkpoint provides a good strategy for virotherapy of breast cancer.
PMID: 18588425 [PubMed - as supplied by publisher]
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PubMed: Wnt
NCBI: db=PubMed; Term=Wnt
