Abstract C210: Microregional distribution and activity of camptothecins in tumor xenografts.
Bibliographic record
Abstract
Abstract Background: The tumor microenvironment plays an important role in determining the activity of many anticancer drugs and one critically important factor that has recently garnered considerable interest is the micro-regional distribution of anticancer drugs within tumors. One of the key issues being whether chemotherapy drugs reach all the cells within a tumor at concentrations high and long enough to exert a therapeutic effect. Irinotecan and topotecan are two camptothecin analogues with differing pharmacological and physicochemical properties, both exhibit clinical activity though are not curative. In this study the micro-regional distribution of the two analogues was compared to their pattern of activity with tumor cryosections. Methods: Using whole tissue section mapping and multiplexed immunostaining techniques irinotecan and topotecan fluorescence was detected in relation to tumor vasculature in cryosections from HCT116 xenografts 1, 2, 4, 8 & 24 hours following their administration. The tissue sections were subsequently stained to map drug activity via apoptosis and proliferation status at early (1–24 hours) and late (1–14 days) times after treatment. Results: Topotecan exhibited a faster and more uniform tissue distribution than irinotecan but experienced significant wash-out within the first 2 hours following treatment. Irinotecan exhibited a larger concentration gradient in relation to tumor blood vessels but appeared to benefit from a longer retention within the tissue, with significant exposure occurring out to 8–24 hours following treatment. Interestingly, irinotecan did not appear to permeate equally from all vessels within the tumors. Some areas of the tumors received much higher exposure than others. At 50 mg/kg irinotecan and 10 mg/kg topotecan, both agents were able to exert a uniform block of cycling tumor cells within 4 hours of treatment but by 24 hours tumor proliferation status had returned to near normal levels indicating neither drug was retained long enough to exert activity on cells that were out of cycle at time of treatment. Conclusions: Development of new camptothecin analogues might benefit from design strategies to increase tumor retention and uniformity in tissue distribution. While both irinotecan and topotecan were able to exert a significant and uniform cell cycle block within 4 hours of treatment in the HCT116 xenografts, due to their short retention proliferation was seen to recover by 24 hours. Irinotecan appeared to distribute less uniformly within the tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C210.
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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) | 0.000 | 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".