Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect

Abstract

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa-and E1B 55 kDa-deleted oncolytic adenovirus (AdÀDE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for AdÀDE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (AdÀDE1B55). Consistent with this observation, higher levels of p53, phosphop53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with AdÀDE1B19/55 compared with those treated with AdÀDE1B55, indicating that the E1B 19 kDa present in AdÀDE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with AdÀDE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of AdÀDE1B19/55 and radiation was more efficacious than the combination of AdÀDE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDadeleted oncolytic Ad.

Adenoviral E4orf3 and E4orf6 Proteins, But Not E1B55K, Increase Killing of Cancer Cells by Radiotherapy in vivo

“…Replicative control virus Ad300wt presented significant reduction of tumor growth combined with RT (p < 0.001), but not alone (data not shown). Interestingly, and in accord with in vitro results by us and others (20,24,25), recombinant viruses had antitumor efficacy even in the absence of radiation (Fig. 5).…”

“…4). E4orf3-or E4orf6-expressing viruses without radiation had an effect on clonogenicity, as reported (20,24,25), and the effect of rAdE4orf6 was particularly pronounced, but combined with radiation the effect of both viruses was further enhanced.…”

“…However, rAdE4orf6, rAdE4orf3, and Ad300wt showed persistent gH2AX levels at 24 h after combination treatment, suggesting inhibition of DSB repair. The radiosensitizing effect of wt adenovirus has been previously reported (9,24,25).…”

Molecular characterization of apoptosis induced by CARF silencing in human cancer cells

“…31 Previously, adenovirus with E1 deletions exhibited enhanced efficacy and tumorilytic activities when administered in conjunction with radiotherapy or chemotherapeutic drugs. 32,33 Alternatively, using the mutant adenovirus as anticancer gene carriers had also demonstrated increased oncolytic efficacy. 34 Thus, in our study, we utilized Ad-DB7 as a gene carrier for shCARF.…”

The combination of chemotherapy with HVJ-E containing Rad51 siRNA elicited diverse anti-tumor effects and synergistically suppressed melanoma

“…32 If the EF is two-fold greater than the control, the combination effect is defined as synergistic. The EF of the combination of DTIC with Rad51 siRNA was 3 against the combination of DTIC with PBS, whereas the EF of the combination of DTIC with sc-siRNA was 1 against the combination of DTIC with PBS.…”