Table 1.
OVs Encoding p53 or p53 Family Members
| OV Name | Virus Genome Modifications | Transgene Location in Viral Genome | Transgene Modifications | Cancer Targeted | Toxicological Study | In Vitro Effects | In Vivo Tumor and Mice Models | Virus Dose (Total) and Injection Mode | In Vivo Effects | Therapeutic Combination | References |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Adenovirus SG600-p53 | E1a CR2-deleted 24 nt (nt 923–946); E1a under hTERT promoter; E1b under HRE cis-elements | TP53 between E1a and E1b | WT gene under CMV promoter | – | yes | – | – | 1–4 × 1011 VP/kg (i.v.) for safety pharmacology, 2.5 × 1013 VP/kg (i.m.) for acute toxicity test via one injection | ↑ safety ↑ toleration no adverse effects | – | 57 |
| Adenovirus SG600-p53 | E1a CR2-deleted 24 nt (nt 923–946); E1a under hTERT promoter; E1b under HRE cis-elements | TP53 between E1a and E1b | WT gene under CMV promoter | lung, liver, cervical, pancreas | no | ↑ oncoselectivity ↑ p53 expression ↑ cytotoxicity | lung subcutaneous xenograft (NCI-H1299) BALB/c nude mice | 5 × 108 to 2 × 109 PFU (i.t.) via five injections | ↓ tumor growth ↑ necrosis areas ↑ p53 level in cancer cells injected ↑ apoptosis | – | 168 |
| Adenovirus SG635-p53 | E1a CR2-deleted 24 nt (nt 923–946); E1a under hTERT promoter; E1b under HRE cis-elements Ad35 (shaft + knob) | TP53 between E1a and E1b | WT gene under CMV promoter | breast | no | ↑ infectivity ↑ viral replication ↑ p53 expression ↑ viral progeny production ↑ cytotoxicity | breast subcutaneous xenograft (Bcap-37) BALB/c nude mice | 1 × 109 PFU (i.t.) via five injections | ↑ cell growth inhibition ↑ necrosis area ↑ viral progeny production ↑ p53 level in cancer cells injected | – | 169 |
| Adenovirus AdSurp-p53 | E1a under Survivin promoter | TP53 upstream E1a | WT gene under CMV promoter | gallbladder, hepatic | no | ↑ cytotoxicity ↑ oncoselectivity ↑ p53 level ↑ viral proliferation | gallbladder subcutaneous xenograft (EH-GB1) BALB/c nude mice | 1 × 109 PFU (i.t.) via five injections | ↑ tumor growth inhibition ↑ p53 expression in cancer cells ↑ apoptosis ↑ necrosis area | – | 170 |
| Adenovirus AdCB016-mp53(268N) | E1a CR1-deleted (aa 27–80); E1a CR2-deleted 24 nt (aa 122–129) | TP53 in E3 | mutation (D268N) | cervical | no | ↑ oncoselectivity ↑ cytotoxicity ↑ resistance to HPV E6 ↑ p53 transactivation function in E6-positive cells | ND | ND | ND | – | 94 |
| Adenovirus OV.shHDAC1.p73 | E1a CR2-deleted 24 nt (nt 923–946); shHDAC1 between E4 and right terminal repeat | TP73 in fiber | WT gene | melanoma | no | ↑ cytotoxicity lifting of epigenetic blockage ↑ apoptosis ↑ autophagy no inhibition of viral replication ↑ viral progeny production | subcutaneous xenograft (SK-Mel-147) NMRI nude mice | 3 × 108 PFU (i.t.) via three injections | ↓ tumor growth no recurrence ↑ survival | shRNA against HDAC1 | 127 |
| Adenovirus Adp53rc | ADP deletion | TP53 in fiber; E3 deletion | WT gene | lung | no | no inhibition of viral replication ↑ viral spread ↑ p53 level exogenous p53 in the nucleus ↑ oncolytic activity ↑ apoptosis | – | – | – | – | 171 |
| Adenovirus Adp53W23S | ADP deletion; E3 deletion | TP53 in fiber | mutation (W23S) | lung, colorectal | no | no inhibition of viral replication ↑ viral spread ↑ resistance to E1b-55kD and MDM2 nuclear localization of p53 no export to cytosol ↑ p53 level ↑ p53 half-life (stability) ↑ cytotoxicity mildly decreased p53 transactivation | subcutaneous xenograft (A549) NCrNU-M nude mice | 1 × 109 PFU (i.t.) via one injection | Tumor size unaffected by p53 expression ↑ p53 expression in cancer cells from virus-infected areas p53 nuclear expression | – | 83 |
| Adenovirus AdΔ24-p53 | E1a CR2-deleted 24 nt (aa 122–129) | TP53 in E3 | WT gene | diverse human cancer cells | no | ↑ cytotoxicity ↑ early virus release oncolysis independent of E1a binding to pRb and independent of E3 functions | – | – | – | – | 74 |
| Adenovirus AdΔ24-p53 | E1a CR2-deleted 24 nt (aa 122–129) | TP53 in E3 | WT gene | neuroblastoma | no | ↑ cytotoxicity effect independent of endogenous p53 cellular status | subcutaneous xenografts (IGR-N91, IGR-NB8) SPF-Swiss athymic nude mice | 5 × 108 PFU (i.t.) via five injections | ↓ tumor growth ↑ cell lysis ↑ apoptosis ↑ fibrous fascicles ↑ necrosis areas | – | 76 |
| Adenovirus AdΔ24-p53 | E1a CR2-deleted 24 nt (aa 122–129) | TP53 in E3 | WT gene | glioma, glioblastoma | no | ↑ cytotoxicity effect independent of endogenous p53 cellular status replication in normal brain tissue ex vivo, but low amount of progeny virus produced | subcutaneous xenografts (IGRG88, IGRG121) SPF-Swiss athymic nude mice | 5 × 107 to 5 × 109 PFU (i.t.) via five injections | ↓ tumor growth ↑ mice survival no inhibition of viral replication ↑ apoptosis ↑ inflammatory cell infiltration (lymphocyte, macrophage) ↑ necrosis areas | – | 75 |
| Adenovirus AdΔ24-p53 | E1a CR2-deleted 24 nt (aa 122–129) | TP53 in E3 | WT gene | glioma | no | ↑ cytotoxicity with radiotherapy no change of viral replication with radiotherapy ↑ apoptosis with radiotherapy, radiotherapy does not increase p53 phosphorylation no increase of p53 on co-treatment outcome | subcutaneous xenograft (U-87MG) SPF-athymic nude mice | 1 × 109 PFU (i.t.) via three injections | ↓ tumor growth viral replication allowed no detection of exogenous p53 ↑ survival no benefits brought by exogenous p53 | radiotherapy | 106 |
| Adenovirus AdΔ24-p53(14/19) | E1a CR2-deleted 24 nt (aa 122–129) | TP53 in E3 | mutation (2 nt substitutions) T > A leading to L14Q; T > G leading to F19S | gastric, osteosarcoma, lung, ovarian, astrocytoma | no | ↑ cytotoxicity ↑ resistance to MDM2 ↑ p53 stability ↑ p53 half-life mutation provokes moderate loss of p53 transactivation function | – | – | – | – | 172 |
| Adenovirus S7605-11R-p53 | E1a under hTERT promoter; absence of E1b and its promoter too | TP53 in E3 | fused with 11R (polyarginine peptide), CMV promoter | gallbladder | no | ↑ cytotoxicity ↑ oncoselectivity | BALB/c nude mice (EH-GB2) | 1 × 109 PFU (i.t.) via five injections | ↓ cell growth ↑ necrotic foci ↑ p53 level in cells ↑ apoptosis | – | 99 |
| VSV-mp53 | WT | murine TP53 between G and L | WT gene | breast, melanoma | yes | WT M protein blocks host mRNA export ↑ oncoselectivity ↑ p53 level | TS/A-luc tumor cells (injected i.v.) in BALB/c mice and BALB/c nude mice | 5 × 107 or 5 × 108 PFU (i.v.) via one injection for toxicity test, increasing doses from 1 × 108 to 1 × 109 PFU (i.v. and i.n.) | ↑ virus attenuation in immunocompetent mice ↓ cell growth ↑ mice survival fatal toxicity after i.n. injection in nude mice | – | 62 |
| VSV-M(mut)-mp53 | M (matrix protein) mutations (aa 52–54) | murine TP53 between G and L | WT gene | breast, melanoma | yes | M(mut) allows host mRNA export ↑ oncoselectivity ↑ p53 level | TS/A-luc tumor cells (injected i.v.) in BALB/c mice and BALB/c nude mice | 5 × 107 or 5 × 108 PFU (i.v.) via one injection for toxicity test, increasing doses from 1 × 108 to 1 × 109 PFU (i.v. and i.n.) | ↑ virus attenuation in immunocompetent mice ↓ toxicity ↓ cell growth ↑ mice survival ↑ anti-tumor immunity (IFN, CD49b+ NK, CD8+ T responses) ↓ inflammatory cytokines (IL-6, IP-10) fatal toxicity after i.n. injection in nude mice | – | 62 |
| VSV-p53wt | M (matrix protein) mutation ΔM51 | TP53 between G and L | WT gene | pancreas | no | no inhibition of viral replication ↑ oncoselectivity ↓ IFN response (NF-κB inhibition) nuclear localization of exogenous p53 | – | – | – | – | 67 |
| VSV-p53CC | M (matrix protein) mutation ΔM51 | TP53 between G and L | chimeric p53CC | pancreas | no | no inhibition of viral replication ↑ oncoselectivity ↓ IFN response (NF-κB inhibition) counteract dominant-negative effects from endogenous mutant p53 nuclear localization of exogenous p53 | – | – | – | – | 67 |
| Newcastle disease virus rNDV-p53 | WT | TP53 between F and HN | WT gene | hepatoma | yes | ↓ cell growth ↑ exogenous p53 level no inhibition of viral replication with exogenous p53 ↑ early apoptosis (reduction of mitochondrial membrane potential) | subcutaneous xenograft (H22) ICR mice | 1 × 107 PFU (i.t.) via one injection 10 systemic injections for toxicity study | ↓ tumor growth ↑ mice survival ↑ apoptosis no toxicity and no serum chemistries changes | – | 61 |
Mode of injections: i.m., intramuscular; i.n., intranasally; i.t., intratumoral; i.v., intravenous. CMV, cytomegalovirus; CPU, colony-forming unit; ND, not determined; PFU, plaque-forming unit; VP, viral particles.