Abstract 5261: Irinophore C, a liposomal formulation of irinotecan, has anti-vascular effects in primary tumors of colorectal cancer grown orthotopically in mice
Bibliographic record
Abstract
Abstract Introduction: Colorectal cancer accounts for ∼10% of cancer deaths in North America. Our group has developed a series of primary tumors from human colorectal cancer tissue obtained during surgery. These tumors are passaged orthotopically in mice and maintain the complexity and heterogeneity of the original patient sample. We have used these tumors to examine the cytotoxic and anti-vascular effects of Irinophore CTM, a liposomal form of irinotecan, which is more efficacious and less toxic than the parent drug. Materials and Methods: Primary tumor tissues from colorectal cancer patients, were validated by a reference pathologist and implanted subcutaneously in SCID mice. Tumors that grew successfully were then passaged orthotopically on the ascending colon of new mice. When these tumors reached ∼200mm3, groups of mice were treated with saline, irinotecan (50mg/kg), or IrinophoreCTM (25mg/kg) once a week for 6 weeks. Separate groups of tumors, A, B and C were harvested on days 3, 21 and 42 after treatment started, respectively. Magnetic resonance imaging (MRI) was used to assess tumor perfusion in mice from group B. Treatment effects on tumor metabolism were assessed with 18F -fluorodeoxyglucose and positron emission tomography (FDG-PET) for groups A and C mice. Immunofluorescence staining was carried out on tumors from all treatment groups to determine levels of cell proliferation, apoptosis, hypoxia, and vessel density. Results: 4 of 14 samples were successfully propagated and maintain their original morphology. Irinophore CTM treatment reduced tumor volume by 54% to 92% compared to the untreated controls depending on the tumor line. No toxic effects were seen with Irinophore CTM. The aggregate data for cell proliferation (Ki67), necrosis (H&E) and cell death (TUNEL) indicate that Irinophore CTM has sustained cytotoxic activity compared to the free drug. Immunostaining data show irinotecan treatment did not change blood vessel density in the tumors; however, Irinophore CTM treatment did reduce vascular density in the tumors. The volume transfer coefficient, Ktrans, derived from MRI, decreased when tumors were treated with irinotecan, but increased with Irinophore CTM treatment. Differences in the metabolic activity of the tumors were also seen. Conclusion: Orthotopic models of colorectal cancer propagated from patient tumors were successfully developed. These models retain the characteristics of the original patient sample and are a good alternative to xenograft models grown from immortalized cell-lines. The anti-tumor activity of Irinophore CTM at lower doses is greater than irinotecan's, and with fewer side effects. Treatment with Irinophore CTM also reduces tumor metabolism and appears to improve vascular function. The data imply that Irinophore CTM has sustained anti-tumor activity and multiple mechanisms of action compared to irinotecan. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5261. doi:1538-7445.AM2012-5261
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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 | 0.000 | 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".