Abstract 1773: The addition of Reolysin, an oncolytic reovirus, to irinotecan shows synergistic anticancer activity in colorectal cancer cell lines
Bibliographic record
Abstract
Abstract Recent clinical data suggests that the anti EGFR antibodies, cetuximab and panitumumab, are ineffective in patients with colorectal cancer whose tumors harbor a mutation in the kras oncogene. Currently, for these patients, the only option after failure of front line therapy is irinotecan, and there is no drug that can be combined with it to improve clinical outcomes. We studied in vitro, the combination of Reolysin and irinotecan to develop a novel therapeutic approach for these patients. Reolysin (reovirus Serotype 3) has been shown to replicate specifically in tumors bearing an activated ras pathway. This specificity coupled with its relatively nonpathogenic nature in humans makes it an attractive anti-cancer therapy candidate. We have performed in vitro studies of Reo (multiplicity of infection 1 to 10), iri (0.5-10 µM), as single agents and in combination in human colorectal cancer cells to study the role of kras mutation. Reolysin was obtained from Oncolytics Biotech Inc. and irinotecan was obtained commercially. A panel of 8 colorectal cancer cell lines were infected with Reolysin (multiplicity of infection 1 to 10), irinotecan (0.5-10 µM), as a single agent or in combination. The cells were exposed to Reolysin for 6-8 hours and to irinotecan for 72 hours. Viable cells were determined 72 hours post treatment using MTT assay. The effect of Reolysin and irinotecan combination on cell viability was assessed using CalcuSyn software (Biosoft, UK) that generates combined cytotoxic effect by calculating combination indices (CIs). A CI of <1 indicates synergy, 1 denotes additive effect, and >1 denotes antagonism. We found that Reolysin and irinotecan as single agents were cytotoxic to all colon cell lines studied. Further, when Reolysin was combined with irinotecan, there was evidence of synergistic cytotoxicity in all (HT29, HCT116, DLD, KM12, SKCO-1, SW620, LIM2405) except one (SW948) cell line. There appears to be no association between kras mutation status and synergism. To further explore these findings and understand the mechanistic basis of drug synergism we are studying the effect of Reolysin and irinotecan in isogenic HCT116 (kras mutant) and Hke3 (kras WT) cell lines. In summary, the combination of Reolysin and irinotecan is synergistic in colorectal cancer cell lines including those with kras mutation and is worthy of exploration in human patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1773.
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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 | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".