Abstract 2985: Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment
Bibliographic record
Abstract
Abstract Dianhydrogalactitol (VAL-083) is a unique bi-functional alkylating agent causing methylation of N7-guanine and inter-strand DNA crosslinks. VAL-083 is a small water-soluble molecule that readily crosses the blood-brain-barrier. In China, VAL-083 is approved as a chemotherapeutic drug for the treatment of chronic myelogenous leukemia (CML) and lung cancer. In the United States, VAL-083 has been evaluated in more than 40 National Cancer Institute (NCI)-sponsored phase I and phase II clinical trials. Preclinical studies and clinical trial data suggested antineoplastic effects of VAL-083 in a variety of malignancies, including lung cancer, brain tumors, leukemia, cervical cancer, and ovarian cancer. Here we report new insight into VAL-083 mechanism of action by showing that VAL-083 leads to irreversible cell cycle arrest and cell death caused by replication-dependent DNA damage. In lung (H2122, H1792, H23 and A549) and prostate (PC3 and LNCaP) cancer cell lines, VAL-083 treatment caused irreversible cell cycle arrest in late S and G2 phase as measured by propidium iodide (PI) and immunofluorescent (IF) staining in synchronized cultures. Importantly, VAL-083 was cytotoxic to all cell lines tested (IC50 range 3.06 - 25.7 μM). Western blot and IF analyses of DNA repair markers were employed to investigate the DNA damage response induced by VAL-083 in cancer cells. VAL-083 treatment led to phosphorylation of the proximal DNA double-strand break (DSB) sensor Ataxia Telangiectasia Mutated kinase (ATM), the single-strand DNA-binding Replication Protein A (RPA32), and the histone variant H2A.X (γH2A.X). Importantly, the DNA damage was specific to cells in S phase indicating that VAL-083-induced DNA cross-links translates into more severe DNA lesions during replication. Furthermore, S/G2 phase cell cycle arrest and increased phosphorylation of γH2A.X in cancer cells persisted after pulse-treatment with VAL-083, indicating irreversible DNA lesions. Taken together, VAL-083 displayed broad anti-neoplastic activity in lung and prostate cancer cells through the induction of replication-dependent DNA damage. Elucidation of the molecular mechanisms underlying VAL-083 cytotoxicity in cancer cells will offer help in identifying and predicting efficacy of combination treatments. Citation Format: Beibei Zhai, Anne Steino, Jeffrey Bacha, Dennis Brown, Mads Daugaard. Molecular mechanisms of dianhydrogalactitol (VAL-083) in cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2985.
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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) | 0.003 | 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".