Characterization of a transport and detoxification pathway for the antitumour drug bleomycin in <i>Saccharomyces cerevisiae</i>
Bibliographic record
Abstract
BLM (bleomycin) is effective in combination therapy against various cancers including testicular cancer. However, several other cancers such as colon cancer are refractory to BLM treatment. The exact mechanism for this differential response of cancer cells to the drug is not known. In the present study, we created fluorescently labelled BLM-A5, which retained nearly full genotoxic potential, and used this molecule to conduct the first study to understand the transport pathway of the drug in Saccharomyces cerevisiae. Uptake studies revealed that fluoro-BLM-A5 is transported into the cell in a concentration-dependent manner. Transport of a non-saturating concentration of fluoro-BLM-A5 was modest for the first 90 min, but thereafter it was sharply induced until 300 min. The inducible transport was completely abolished by the addition of cycloheximide, suggesting that BLM-A5 uptake into the cell is dependent on new protein synthesis. Interestingly, transport of fluoro-BLM-A5 was blocked if the cells were preincubated with increasing concentrations of spermine. Moreover, a mutant lacking the Ptk2 kinase, necessary for positively regulating polyamine transport, was defective in fluoro-BLM-A5 uptake and exhibited extreme resistance to the drug. A simple interpretation of these results is that BLM-A5 may enter the cell through the polyamine transport system. We showed further that after the uptake, fluoro-BLM-A5 accumulated into the vacuole of the parent, but localized to the cytoplasm of mutants disrupted for the END3 gene required for an early step of the endocytotic pathway. In general, mutants with a defect in the endocytic pathway to the vacuole were hypersensitive to BLM-A5. We suggest that BLM-A5 is transported across the yeast plasma membrane and sequestered into the vacuole for detoxification.
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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".