18. Comparison of Antitumor Activity of Cytosine Deaminase::Uracil Phosphoribosyl Transferase (CD::UPRT) and Purine Nucleoside Phosphorylase (PNP) Suicide Genes Using Replicative but Non-Disseminative Adenovirus Vectors
Bibliographic record
Abstract
Cancer gene therapy using suicide genes has shown great potential in tumor models. To improve efficacy, recent attention has focused on the use of oncolytic vectors. To date this strategy has not resulted in vectors with anti-tumor activities sufficiently potent to sustain complete tumor regression. In this study, we pursued a modified approach that makes use of viral DNA replication but not of oncolysis. This approach is based on the protease-deleted adenovirus vector (AdV) (Oualikene et al. 2000). Such vectors are designed to convert transduced cells into mega-factories for suicide genes. To evaluate this strategy, we compared the activity in vitro of two suicide genes: CD::UPRT and PNP in the Replicative but Non-Disseminative (RND) AdVs. In AdVs the CD::UPRT or PNP transgene and the E1A gene were introduced as a bicistronic cassette under the control of the CMV5 promoter. Adenoviruses were generated by introducing the expression cassette in the E1 region of an AdV backbone deleted for E1, E3, and the protease gene. Due to the protease deletion, these AdVs can no longer form viral particles, even following replication resulting from E1A expression. The resulting Ad(dPS)C::U-IRES-E1A, and Ad(dPS)PNP-IRES-E1A were grown in protease-complementing 293 cells. When tested for anti-tumor activities in two human and one murine glioblastoma cell lines and one ovarian cancer cell line, Ad(dPS)PNP-IRES-E1A outperformed its counterpart, the Ad(dPS)C::U-IRES-E1A, by up to 16-fold in human glioblastoma and 5 fold in human ovarian cancer cells. Both RND virus performed better than non replicative counterparts. In bystander assays, the number of transduced cells sufficient to convey the anti-tumor activity to the entire cell population could be reduced by more than 10-and 8-fold when comparing Ad(dPS)PNP-IRES-E1A to Ad(dPS)C::U-IRES-E1A on glioblastoma and ovarian cancer cells respectively. In a three-dimensional spheroid culture model, when both RND AdVs were compared, anti-tumor activity was significantly better (ANOVA p<0.001) for Ad(dPS)PNP-IRES-E1A in all cancer cell models, ranging from 3-fold in ovarian cancer up to 10-fold in glioblastoma spheroids. In conclusion, the RND AdV platform substantially improves anti-tumor activity of suicide gene therapy. Using this strategy, the suicide gene PNP performed better than CD::UPRT in both glioblastoma and ovarian cancer cells. This work demonstrates that the protease-deleted AdV platform can provide vectors that are potentially safer than conditional oncolytic AdVs and yet generate sufficient anti-tumor activity to eradicate large tumors. Results with Ad(dPS)PNP-IRES-E1A are promising and work with animal models is in progress.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".