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- W1514896838 abstract "Top of pageAbstractGene attenuated replication competent adenoviruses are being developed as novel anti-tumor therapeutics. Clinical trials with the ONYX-015 (E1B 55kDa-deleted) adenovirus in combination with chemotherapeutic agents, cisplatin or 5-FU, have demonstrated a synergistically lethal effect. All replicating adenoviruses used in combination therapy to date have their E1B 19kDa gene in tact. The E1B 19kDa functions as an anti-apoptotic agent. Due to cell death induced by the apoptotic pathway, the E1B 19kDa gene may interfere with the mode of action of chemotherapeutic agents, underestimating the value of these combination studies. For the aim of improving adenoviral vectors for cancer gene therapy, we generated adenoviral vectors with different combination of E1B 19kDa and E1B 55kDa genes and investigated the possibility of enhanced oncolytic and replication ability of these adenoviruses (Ad-ΔE1B55, Ad-ΔE1B19/55) combined with various chemotherapeutic agents. The in vitro efficacy of adenovirus and chemotherapeutic agents (taxol, cisplatin, 5-FU, adriamycin) has been evaluated by comparison of CPE assay and MTT assay. Our results show that the degree of cytopathic effect of Ad-ΔE1B19/55 was higher than that of Ad-ΔE1B55. Furthermore, compared with a virus-only treatment, combination therapy with Ad-ΔE1B19/55 and chemotherapeutic agents led to improved cytopathic effect compared to combination therapy with Ad-ΔE1B55 and chemotherapeutic agents. PI staining and TUNEL assay also revealed that combination therapy with Ad-ΔE1B19/55 and chemotherapeutic agents caused greater induction of apoptosis compared to that with Ad-ΔE1B55 and chemotherapeutic agents. Through limiting titration experiments, the total yield of adenovirus was shown to be higher when the adenovirus was treated in combination with paclitaxel compared to virus-only treatment. In contrast, the total yield of adenovirus was shown to be lower or equal when the adenovirus was treated in combination with cisplatin, 5-FU, or adriamycin compared to virus-only treatment. E1B-mutant replication competent adenovirus combined with paclitaxel exhibited superior anti-tumor effect in C33A cervical xenograft tumor in vivo compared to individual treatments of the adenovirus or paclitaxel.Taken together, the E1B 19kDa-deleted (Ad-ΔE1B19/55) replication competent adenovirus may serve as an enhanced vector for anticancer gene therapy, especially when applied in combination with apoptotic chemotherapeutic agents such as paclitaxel." @default.
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- W1514896838 date "2004-05-01" @default.
- W1514896838 modified "2023-09-25" @default.
- W1514896838 title "E1B-Mutant Replication Competent Adenovirus Combined with Chemotherapeutic Agents Shows Increased Anti-Tumor Effect" @default.
- W1514896838 doi "https://doi.org/10.1016/j.ymthe.2004.06.888" @default.
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