Induction of an anti-angiogenesis factor, Thrombospondin 1 (TSP-1), by a novel histone deacetylase inhibitor, MGCD0103, in human cancer cells in vitro and in vivo
Bibliographic record
Abstract
739 MGCD0103 is a novel non-hydroxamate histone deacetylase inhibitor which specifically targets HDAC1, 2, 3 and 11. Previously, we have shown that MGCD0103 has broad-spectrum antitumor activities in preclinical animal models and its preliminary clinical activity has been shown in multiple Phase II trials in patients with relapsed or refractory Hodgkin’s lymphoma or Non-Hodgkin lymphoma , high-risk myelodysplastic syndrome (MDS) and acute myologenous leukemia (AML). To further understand the mechanism of action of MGCD0103, we investigated the anti-angiogenesis activity and specific components of the angiogenesis pathways that were modulated by MGCD0103. We found MGCD0103 significantly inhibits tubule growth of cultured human endothelial cells in a dose-dependent manner in vitro. In addition, MGCD0103 can induce transcription of an anti-angiogenesis factor, thrombospondin 1 (TSP-1), in human cancer cells in vitro independent of their tissue origins. Synergistic induction of TSP-1 was observed in human cancer cells treated with MGCD0103 in combination of a DNA demethylation agent in vitro. Microarray analysis of peripheral blood mononuclear cells or bone marrow mononuclear cells from five AML patients, who were treated with MGCD0103 either alone or in combination with Vidaza, revealed that the upregulation of expression of TSP-1 in patients with clinical response (n=2) but not in those without response (n=3). Using real time RT-PCR analysis on more clinical samples from patients treated with a combination of Vidaza and MGCD0103 , we further observed induction of TSP-1 transcription in the AML patients with clinical response but not in those without response. The utility of TSP-1 expression as a potential biomarker of MGCD0103 in clinical trials will be discussed.
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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".