ODE-Adefovir As Potential Therapeutic Agent In AML
Bibliographic record
Abstract
Abstract Adefovir is an antiviral adenosine monophosphate analogue from the class of acyclic nucleoside phosphonate (ANP). During 0n-patent drug library screen, we discovered adefovir-dipivoxil (adefovir-DP) as potentially active against AML. Second-generation formulations Of adefovir, including ODE-adefovir and HDP-adefovir, have been designed to overcome adefovir-DP pharmacodynamic disadvantages. To characterize the activity of the above-mentioned agents in AML, we undertook this study. In AML cell lines (OCI/AML-1, -2, -3, -4 and -5) adefovir-DP appeared to be highly potent with IC50 ranging from 45.8 to 252.5 nM. ODE-adefovir was equally potent as adefovir-DP (IC50 from 51.7 nM to 205.3 nM), whereas HDP-adefovir was significantly less potent (224.8±19.6 to 956.3±14.4 nM). Similar results were obtained when we tested the activity of these agents in primary AML patient samples. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP in normal hematopoietic cells, with IC50 at 40 and 1µM, respectively. In addition, ODE-adefovir at dose 15mg/kg/day showed potent activity against AML in NOD/SCID-mouse human-leukemia model with reduction in human leukemia in mouse bone marrow > 50%in all mice tesed within 14 days. Based on its chemical structure, we hypothesized that the plausible mechanisms of ODE-adefovir cytotoxicity in AML are cell-cycle arrest and DNA damage. Indeed, treatment of OCI/AML-2 cells with ODE-adefovir induced increase of the cells in the S phase from 9% to 30%. Moreover, ODE-adefovir increased the expression of pH2Ax, a hallmark of DNA damage, within 2h of treatment. Plus, there was increase in phosphorylation of P53; transactivation of proapoptotic genes, Puma, Noxa and BAX; and induction of the intrinsic apoptotic pathway, as shown by the cleavage of caspases 7 and 9. Further investigation unveiled strong synergism between ODE-adefovir and cytarabine, a mainstay drug in the treatment of AML, without any cross-resistance between both agents, thus making their co-administration potentially beneficial. MRP4 expression appeared to influence AML cells response to ODE-adefovir and its inhibition potentiates this response. Taken together, our findings emphasize the potential cytotoxic activity of adefovir in AML and the importance of choice of appropriate formulation for such purpose. Further, they indicate that the development of ODE-adefovir for clinical testing in AML is warranted. Disclosures: Off Label Use: Adefovir dipivoxil is a drug used for the treament of hepatitis B. WE found it is cytotoxic for AML.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".