<i>In vitro</i> and <i>in vivo</i> irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells
Bibliographic record
Abstract
OBJECTIVE: To study irinotecan (CPT-11)-induced changes in expression profiles of genes associated with cell cycle control and apoptosis in myeloid leukemia cells in vitro and in vivo. METHODS: HL60 cells were exposed to clinically achievable concentrations of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11, and blood sampled from patients with acute myeloid leukemia and chronic myeloid leukemia in myeloid blast transformation treated with CPT-11. Gene expression changes were studied by cDNA microarray and correlated with biological responses by studying DNA distributions by flow cytometry. RESULTS: cDNA microarray analysis showed down-regulation and up-regulation of specific cell cycle-associated genes, consistent with loss of S-phase cells and temporary delay of G(1)-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G(2)-M and G(1) were delayed in G(1) and entered S phase only 6 to 8 hours after drug removal, consistent with the observed changes in gene expression. Proapoptotic changes in gene transcription included down-regulation of antiapoptotic genes and up-regulation of proapoptotic genes. Many gene expression changes observed following in vitro SN-38 exposure were also seen following in vivo administration of 10 or 15 mg/m(2) CPT-11; notably, proapoptotic changes included reduced transcription of survivin pathway-associated genes and increased transcription of death receptor 5. CONCLUSION: CPT-11-induced changes in gene expression profiles in vitro and in vivo are consistent with temporary delay in G(1)-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.
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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".