Abstract 935: Lapatinib and other tyrosine kinase inhibitors greatly potentiate doxorubicin-induced damage to cardiac myocytes
Bibliographic record
Abstract
Abstract Lapatinib (Tykerb) is dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways. Lapatinib has been shown in a clinical trial to produce low levels of cardiotoxicity that is reversible. Using a neonatal rat cardiac myocyte model we have investigated the ability of lapatinib alone, and in combination with doxorubicin, to damage myocytes. Lapatinib alone at pharmacological concentrations only slightly induced myocyte damage. However, doxorubicin-induced myocyte damage was greatly potentiated by the addition of low nanomolar lapatinib concentrations. Because trastuzumab also targets ERBB2 receptors, the lapatinib/doxorubicin combination also provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Lapatinib treatment alone had little or no effect on myocyte mitochondrial membrane potential, on oxidation of intracellular DCF (dichlorofluorescein), on intracellular ATP levels, or on caspase 3/7 induction. While the doxorubicin cardioprotective agent dexrazoxane was able to greatly reduce doxorubicin-induced myocyte damage, it could only partially reduce the increase in myocyte damage produced by the lapatinib/doxorubicin treatment. Lapatinib alone had little effect on the phosphorylation status of ACC (acetyl-coenzyme A carboxylase) and AKT. Lapatinib alone decreased phosphorylated ERK (MAPK), which may have, in part, contributed to the increased doxorubicin-mediated myocyte damage. As measured by flow cytometry lapatinib-treated myocytes demonstrated an increased accumulation of doxorubicin. As lapatinib is a strong inhibitor of several ATP-dependent ABC-type efflux transporters, this likely occurred because lapatinib blocked doxorubicin efflux, thereby increasing intracellular doxorubicin concentrations. These results suggest that the clinical use of concurrent doxorubicin and lapatinib should be approached with care due to the possibility of lapatinib increasing doxorubicin cardiotoxicity. Several other kinase inhibitors (imatinib, dasatinib, sorafenib, sunitinib, gefitinib, pazopanib, nilotinib, erlotinib, vandetanib and canertinib) were also examined for their ability to potentiate doxorubicin-induced myocyte damage and induce an increase in intracellular doxorubicin levels. Support: CIHR and a Canada Research Chair in Drug Development to BBH. 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 935. doi:1538-7445.AM2012-935
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".