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Mining the adenovirus virome for oncolytics against multiple solid tumor types.

ABSTRACT: Although there are 55 serotypes of adenovirus (Ad) that infect humans, Ad serotype 5 (Ad5) is the most widely studied because of the availability of commercial kits for its genetic manipulation. In fact, engineered Ad 5 is currently being used in all of the 87 global clinical trials utilizing Ad for the treatment of cancer. Unfortunately, Ad5 is one of the most seroprevalent serotypes, meaning that this virus has to confront additional immunological barriers to be effective in Ad5-immune patients. In this work, we compare Ad5 to 13 other adenoviral serotypes from species B, C, D and E for oncolytic potential in both immunodeficient mouse and immunocompetent hamster models. Our results indicate that species D Ads are not effective oncolytics against most solid tumors. Conversely, lower seroprevalent Ad6 and Ad11 had anti-cancer activity comparable to Ad5. This work strongly supports the consideration of Ad6-based oncolytic therapies for the treatment of breast, ovarian, kidney and liver tumors.

SUBMITTER: Chen CY

PROVIDER: S-EPMC3176962 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Mining the adenovirus virome for oncolytics against multiple solid tumor types.

Chen C Y CY Weaver E A EA Khare R R May S M SM Barry M A MA

Cancer gene therapy 20110902 10

Although there are 55 serotypes of adenovirus (Ad) that infect humans, Ad serotype 5 (Ad5) is the most widely studied because of the availability of commercial kits for its genetic manipulation. In fact, engineered Ad 5 is currently being used in all of the 87 global clinical trials utilizing Ad for the treatment of cancer. Unfortunately, Ad5 is one of the most seroprevalent serotypes, meaning that this virus has to confront additional immunological barriers to be effective in Ad5-immune patient ...[more]

PMID: 21886190

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Project description:Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2α (Topo2α), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy.

Dataset Information

Mining the adenovirus virome for oncolytics against multiple solid tumor types.

Publications

Mining the adenovirus virome for oncolytics against multiple solid tumor types.

Similar Datasets

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