5′- <i>S</i> -(3-Aminophenyl)-5′-thioadenosine, a Novel Chemoprotective Agent for Reducing Toxic Side Effects of Fluorouracil in Treatment of MTAP-Deficient Cancers
Bibliographic record
Abstract
Nucleobase analogue (NBA) drugs, such as 5-fluorouracil (5-FU), are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests that the use of S-methyl-5'-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We hypothesized that an MTA analogue can retain the protective function of MTA without undesired side effects. We screened a library of MTA analogues and identified 5'-S-(3-aminophenyl)-5'-thioadenosine (m-APTA) as a substrate of MTAP that could be converted to adenine, a necessary step for protection of normal cells from NBA toxicity. It selectively protected MTAP-expressing cells from 5-FU toxicity while it did not interfere with the cytotoxicity of 5-FU on isogenic MTAP-deficient cell lines. At effective dose, m-APTA protected the mouse hosts from 5-FU-induced toxicity (i.e., anemia) without the induction of hypothermia. Importantly, m-APTA provided host protection without compromising the efficacy of 5-FU on MTAP-deficient bladder cancer xenografts. In silico docking studies revealed that, unlike MTA, m-APTA interacts inefficiently with adenosine A1 receptor, providing a plausible explanation of the superior safety profile of m-APTA. Therefore, m-APTA can significantly improve the translational potential of the combination treatment strategy that selectively reduces NBA toxicity in normal cells while targeting MTAP-deficient cancers.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".