Comparison of Molecular Strategies for Breast Cancer Virotherapy using Oncolytic Adenovirus

Bazan‐Peregrino, Miriam; Carlisle, Robert; Hernández-Alcoceba, Rubén; Iggo, Richard; Homicsko, Krisztian; Halldén, Gunnel; Mautner, Vivien; Shen, Jerry; Fisher, Kerry D.; Seymour, Leonard W.

doi:10.1089/hgt.2008.047

Cited by 10 publications

(17 citation statements)

References 7 publications

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“…Of note, these differences that became evident after only 7 days of culture are expected to amplify upon extended virus propagation. Consistent with findings by others, 8,26,34,35 ONYX-015 was attenuated compared with Ad5, whereas AdD24 was similarly effective as Ad5. In our experiments, the latter was not influenced by the presence or absence of the E3 region, whereas insertion of an RGD motif or a p53 expression cassette yielded a small potency enhancement.…”

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confidence: 90%

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions

et al. 2010

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Oncolytic adenoviruses are being investigated as potential anti-cancer agents. Selective lytic replication in cancer cells is essential for an effective and safe treatment. In this study, we compared 11 oncolytic adenoviruses in relevant cell cultures to assess their use for treating oral cancer and pre-cancerous lesions. We determined the cytotoxicity of oncolytic adenovirus infection and calculated selectivity indices for cytotoxicity to cancer cells compared with normal oral keratinocytes and fibroblasts. Keratinocytes were very sensitive to wild-type adenovirus serotype 5 (Ad5); 1-to 3-log more than head and neck squamous cell carcinoma (HNSCC) cells. The potencies of oncolytic adenoviruses to kill HNSCC cells within 7 days after infection ranged from approximately 10 times less potent to approximately 10 times more potent than Ad5. The selectivity indices determined on fibroblasts and keratinocytes differed markedly. Two oncolytic adenoviruses were more selective than Ad5 for HNSCC cells compared with fibroblasts; and five viruses showed selective replication on HNSCC cells compared with keratinocytes. Overall, CRAd-S.RGD with E1A driven by the survivin promoter and an infectivity-enhancing capsid modification showed the most favourable cytotoxicity pattern; being very potent in killing HNSCC cells, only slightly less effective than Ad5 in killing pre-neoplastic keratinocytes and the least toxic to normal keratinocytes.

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confidence: 90%

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions

et al. 2010

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“…31 This deletion restricts replication mainly to cancer cells as demonstrated for E1ACR2-deleted viruses. 21,[37][38][39][40] The additional E1B19K deletion also attenuates viral replication in normal cells through abortive replication in response to extrinsically induced apoptosis. 28,29,35,36 Therefore, the double-deleted AdDD mutant has two viral functions deactivated to prevent amplification in normal tissue while potent replication and spread can proceed in pancreatic tumors that frequently have both deregulated cell cycle and apoptosis pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Higher toxicity in proliferating normal cells was also reported with other replication-selective mutants such as dl922-947 despite the attenuated replication. 21,37 However, for the dl922-947 virus the toxicity was likely caused by the additional E3B deletion that also has a role in anti-apoptotic functions. 19,21,37 Importantly, inclusion of the E1ACR2 deletion in AdDD resulted in lower toxicity to normal cells compared with the single-deleted AdD19K, and was similar to that of wild-type virus, while replication was significantly lower.…”

Section: Discussionmentioning

confidence: 99%

“…21,37 However, for the dl922-947 virus the toxicity was likely caused by the additional E3B deletion that also has a role in anti-apoptotic functions. 19,21,37 Importantly, inclusion of the E1ACR2 deletion in AdDD resulted in lower toxicity to normal cells compared with the single-deleted AdD19K, and was similar to that of wild-type virus, while replication was significantly lower. Even though both AdD19K and AdDD were more potent than ONYX-015, our previous in vivo data using immunocompetent models 31 indicate that these mutants administered alone would not be sufficiently efficacious in eliminating tumors in the clinic despite the presence of intact E3 genes.…”

Section: Discussionmentioning

confidence: 99%

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The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

et al. 2011

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Pancreatic adenocarcinomas are aggressive and frequently develop resistance to all current therapies. Replication-selective adenoviruses can overcome resistance to chemotherapeutics through their sensitizing effects on drug-induced cell killing. We previously found that adenovirus deleted in the anti-apoptotic E1B19K gene enhanced gemcitabine-induced apoptotis. Here we demonstrate that our engineered double-deleted AdDD mutant (deleted in the pRb-binding E1ACR2 region and E1B19K) selectively replicates and enhances cell killing in combination with DNA-damaging cytotoxic drugs in pancreatic cancer cells. Combinations of AdDD with gemcitabine, irinotecan or cisplatin resulted in two-to fourfold decreases in EC 50 (half maximal effective concentration) values and was more efficent than similar combinations with wild-type virus, the dl1520 (ONYX-015) and dl922-947 mutants. AdDD replication was impaired in normal bronchial human epithelial cells and did not sensitize the cells to drugs. Gemcitabine-insensitive AsPC-1, BxPC-3 and PANC-1 cells were efficiently killed by irinotecan in combination with AdDD. Suboptimal doses of AdDD and gemcitabine significantly prolonged time to tumor progression in two human pancreatic tumor xenograft in vivo models, PT45 and SUIT-2. We conclude that AdDD has low toxicity to normal cells while potently sensitizing pancreatic cancer cells to DNA-damaging drugs, and holds promise as an improved therapeutic strategy for pancreatic cancer.

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“…Greater efficacy of dl922-947 compared to dl1520 has been reported in numerous solid malignancies in preclinical models. 22,[28][29][30][31] Synergistic interactions were reported for an AdD24 mutant with irinotecan in glioblastoma cells and for dl922-947 with mitoxantrone or docetaxel in prostate cancer cells. 31,32 A tropism-modified version, adenovirus type 5 (Ad5)/3-D24, induced synergistic effects with gemcitabine in ovarian cancer cell lines and increased efficacy in murine in vivo models, albeit with higher toxicity to normal tissue than that reported for dl1520.…”

Section: Introductionmentioning

confidence: 99%

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

et al. 2011

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Pancreatic adenocarcinoma has a poor prognosis and frequently develops resistance to standard chemotherapeutics. Oncolytic adenoviruses represent a promising approach to overcome treatment resistance. The replication-selective dl922-947 adenovirus, defective in pRb binding, targets cancers with deregulated cell cycle control, such as the majority of pancreatic tumors. Cell killing efficacy was higher for dl922-947 than for adenovirus type 5 (Ad5) and the clinically approved dl1520 in pancreatic cancer cells with K-ras, p16 and p53 mutations. Combinations of dl922-947 and 5-fluorouracil or gemcitabine (2resulted in strong synergistic cell killing in Suit-2 and the highly drug-and virus-resistant Hs766T cells. Viral uptake increased in response to drugs, but was independent of the expression levels of the viral attachment receptor coxsackie and adenovirus receptor (CAR), whereas expression levels of the internalization receptors a v b 3 -and a v b 5 -integrins were increased. Early viral E1A expression was potently induced with drugs contributing to the synergistic effects. The dl922-947 mutant was more efficacious than Ad5 in vivo in Hs766T and Suit-2 xenograft models. In combination with gemcitabine, median survival was further prolonged. We demonstrate that dl922-947 is highly efficacious in pancreatic cancers and conclude that oncolytic adenoviruses harboring the E1ACR2 deletion have great potential for development into future clinical candidates for pancreatic cancer.

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Comparison of Molecular Strategies for Breast Cancer Virotherapy using Oncolytic Adenovirus

Cited by 10 publications

References 7 publications

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions

The oncolytic adenovirus AdΔΔ enhances selective cancer cell killing in combination with DNA-damaging drugs in pancreatic cancer models

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

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