Abstract C182: Use of an oncolytic adenovirus (ONYX-015) <i>in vitro</i> to enhance chemotherapy
Bibliographic record
Abstract
Abstract Oncolytic adenoviruses have been proposed as therapeutic anticancer agents. They exploit differences between normal and tumor tissues to selectively infect and/or preferentially replicate in tumor cells. ONYX-015 is a genetically modified adenovirus that replicates only in cells that are deficient in p53, a tumor suppressor gene mutated in over 50% of human cancers. ONYX-015 contains a mutation in the E1B gene resulting in production of an inactive E1B 55 kDa protein that no longer inactivates p53. Consequently, the virus replicates only in p53(−/−) cells. However, the effectiveness of ONYX-015 critically depends on its ability to enter cells. This is dependent on virus binding to the Coxsackievirus and Adenovirus Receptor (CAR) on the cell surface. ONYX-015 is a potential option for treatment of drug-resistant tumors because the mechanism underlying virus cytotoxicity should not, in theory, be blocked by tumor cell strategies that mediate resistance to chemotherapeutic drugs. In fact, acquisition of cisplatin-resistance in an ovarian carcinoma cell line conferred enhanced sensitivity to ONYX-015 in vitro (Ganly et al., Gene Therapy, 8: 369-375, 2001). Therefore, drug-resistant tumors may be a potential clinical target for ONYX-015. Our objective was to characterize relative ONYX-015 sensitivity in human tumor cell lines that are differentially resistant to platinum-based anticancer drugs (assessed by metabolism-based viability assay) with and without combined melphalan treatment, an antitumor alkylating agent. Further, we investigated CAR protein and mRNA expression by immunoblot and RT-PCR analysis, respectively. Acquired carboplatin-resistance in a head and neck squamous cell carcinoma cell line (HN-5a) resulted in ONYX-015 resistance (approximately 15-fold increase in IC-50 in carboplatin-resistant HN-5a cells) whereas cisplatin-resistance in a human colon adenocarcinoma cell line (HT-29) conferred enhanced sensitivity to ONYX-015 (approximately 90% decrease in IC-50 in cisplatin-resistant HT-29 cells). Although CAR mRNA and protein levels differ among cell lines, the acquisition of drug-resistance did not induce changes in CAR mRNA or protein expression. The cytotoxicity of the combination of ONYX-015 and melphalan was greater-than-additive when compared to the effects of two treatments alone. This phenomenon appeared to be schedule-dependent with melphalan pretreatment or combination treatment being more effective than ONYX-015 pretreatment. We hypothesized that melphalan treatment up-regulated CAR expression, resulting in enhanced virus internalization. In support of this hypothesis we observed that treatment with 50 M melphalan induced a 2.5-fold increase in CAR mRNA by 24-h in the parental HN-5a cell line. CAR protein expression was increased 2-fold after 48-h but not 24-h treatment with melphalan. Therefore, pretreatment of cells with melphalan may enhance viral entry into cells via up-regulation of CAR. Variations in CAR expression, whether or not induced by chemotherapeutic drugs, may influence and predict viral uptake and oncolytic activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C182.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".