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• W2122626320 abstract "Phase I/II trials using Ad.Egr-TNF.11D, a replication defective adenoviral vector with a radioinducible promoter that expresses tumor necrosis factor α (TNF-α), in soft-tissue sarcomas and esophageal and pancreatic cancers have been promising. We examined the ability of the radiosensitizer chelerythrine chloride, a beniophenanthridine alkaloid that increases tumor cell apoptosis through BH3 antagonism and ceramide production, to induce Ad.Egr-TNF.11D transcription and translation to increase tumor curability in prostate (PC-3) and head and neck (SQ-20B) human tumor lines. The Ad.Egr-TNF was engineered by ligating elements of the Egr-1 gene promoter upstream of a cDNA encoding human TNF-α (1). The SQ-20B and PC-3 cells were infected with Ad.Egr-TNF for 3 hours before chelerythrine (1–5 uM) was added. The TNF-α production was assayed after 12–20 hours using a human TNF-α Elisa assay in quadruplicate and normalized to cell viability via MTS assay. The RT-PCR examined the ability of chelerythrine (1–5 uM) to induce transcription of vector TNF-α in SQ-20B in vitro. In vivo, hind limb xenografts were grown with PC-3 or SQ-20B cells. The 109 PFU of Ad.EGR-TNF were injected after tumors were ≥1 cm3. Ten mice were injected i.p. (5 mg/kg) with chelerythrine 18 hours later and again on Day 2. The PC-3 tumors were harvested on Day 3 to assay for TNF-α protein, while SQ-20B tumors were grown for 4 weeks and fractional tumor volume was calculated. Chelerythrine-induced a statistically significant (p < 0.05) increase in TNF-α protein in PC-3 and SQ-20B cells 12–20 hours after drug administration in vitro. The RT-PCR showed maximal TNF-α induction 2.5 hours after drug dosing with fold changes of 4.5 (1 uM) and 8 (5 uM) over vector treated controls. In vivo, PC-3 tumors treated with the vector and IP chelerythrine grew poorly and showed a 3.5-fold increase in TNF-α protein over vector treated controls. Animals receiving the combined modality therapy of vector and IP chelerythrine showed a 25-fold decrease in fractional SQ-20B tumor volume when compared to virus alone at 4 weeks. These data show the small molecule chelerythrine can induce Ad.Egr-TNF transcription and protein production that exceeds treatment with radiation (RT) in vitro and in vivo. Chelerythrine showed substantial tumor volume reduction in vivo, on par, or greater than combination with RT. Current studies are investigating the in vivo mechanisms through which this multi-agent therapy may enhance tumor curability and if these can be combined with RT as trimodality therapy." @default.
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• W2122626320 date "2009-11-01" @default.
• W2122626320 modified "2023-10-17" @default.
• W2122626320 title "Induction of EGR-TNF Radioinducible virus through BH3 Domain Antagonism with Chelerythrine Chloride" @default.
• W2122626320 doi "https://doi.org/10.1016/j.ijrobp.2009.07.228" @default.
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