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发布于:2019-5-24 09:24:30  访问:34 次 回复:0 篇
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As shown in Supplementary Figure S2, the cytotoxicity of Ad11-Ad5-EP was significantly increased compared to Ad11 in all the nine humanNovel Adenovirus 11 Mutant for Cancer Therapy?The American Society of Gene Cell Therapyab1,000 800 600 400 200 0 0 10 20 Days Injections 30 40 50 Free of progression PBS Ad5 Ad11 Ad11-Ad5-P Ad11-Ad5-EP100 80 60 40 20 0 PBS Ad5 Ad11 Ad11-Ad5-P Ad11-Ad5-EP 0 10 20 30 Days 40 50Tumor size (mm3)Injectionsc1,000 Arbitrary units/total DNA Ad5 Ad11 Ad11-Ad5-P Ad11-Ad5-EPd10,00,000 100,000 10,000 1,000 100 10 1 48 72 Time (hours)PFU/ng of total DNAAd5 Ad11 Ad11-Ad5-P Ad11-Ad5-EP72 Time (hours)Figure 7 Antitumoral efficacies of adenovirus serotype 5 (Ad5), Ad11, Ad11-Ad5-P, and Ad11-Ad5-eP in a MIA Paca-2 subcutaneous xenograft model. (a) Mean tumor volumes ?SEM in BALB/c nude mice (n = 8/group) after three intratumoral injections of phosphate-buffered saline (PBS) or viruses (1 ?1010 particles/injection), measured until the first mouse in each group has a PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28346523 tumor dimension of >1.44 cm2. (b) Percentage of progression-free mice utilizing the Kaplan eier method. (c) Viral DNA replication in tumor tissues soon after one injection of 1 ?1010 particles. Final results are shown in imply arbitrary units normalized against total DNA ?SEM. (d) Production of infectious virus particles, shown in mean plaque-forming units (PFU)/ng of total DNA ?SEM.cancer cell lines tested (P < 0.05), four of them (PaTu 8988t, DU 145, DLD-1, and Calu-1) showed an equivalent cytotoxicity to Ad5 (P > 0.05), with five of them (2,4,6-trihydroxyacetophenoneXBiological Activity SUIT-2, PANC-1, SW620, OVCAR-3, and IGROV1) nonetheless much more sensitive to Ad5 (P < 0.05). Overall, Ad11-Ad5-EP is significantly more potent than Ad11 in all the 19 cancer cell lines tested, and effective in killing 68 (13/19) of the cancer cell lines tested in Figure 5b,c as well as Supplementary Figure S2, showing equivalent or even better efficacy than Ad5 and Ad11.not apply to PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/25017212 Ad11-Ad5-P. Its E1A mRNA levels were comparable to or reduced than that of Ad5, yet significantly extra Ad11-Ad5-P DNA and infectious particles have been made.Ad11-Ad5-eP has 7-MethylguanosineIn Vitro improved E1A transcription and virus replication when compared with Ad11 As expected, the enhanced potency of Ad11-Ad5-EP correlated with E1A gene expression.Mutants nonetheless showed improved cell killing than Ad5, even though surprisingly Ad
Mutants nonetheless showed better cell killing than Ad5, though surprisingly Ad11-Ad5-EP demonstrated an even stronger cytotoxicity than Ad11 (Figure 5b). In five Ad11-less sensitive cell lines, the potency of Ad11-Ad5-EP was significantly improvedMolecular Therapy vol. 20 no. two feb.in comparison with that of Ad11 (Figure 5c). It was comparable to Ad5 in 3 cancer cell lines (MIA PaCa-2, MDA-MB-231, and HCT 116), with only 1 cell line (LNCaP) nevertheless additional sensitive to Ad5 (P < 0.05). Strikingly, the lung cancer cell line A549 was most sensitive to Ad11-Ad5-EP, with its EC50 nearly 30 times less than that of Ad5 (P < 0.01). The potency of Ad11-Ad5-P was largely similar to that of Ad11, except that it was significantly less cytotoxic to Capan-2 and MCF7. To confirm further the potential of Ad11-Ad5-EP as a potential backbone for the development of new oncolytic adenoviruses, we compared the cytotoxicities of Ad5, Ad11, and Ad11-Ad5-EP in other nine cancer cell lines that were sensitive to Ad5 (less sensitive to Ad11) by MTS assay.
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