Adenovirus-Mediated Human Endostatin Gene Delivery Demonstrates Strain-Specific Antitumor Activity and Acute Dose-Dependent Toxicity in Mice
Bibliographic record
Abstract
Purified recombinant mouse endostatin protein has been reported to regress established murine solid tumors by inhibiting the proliferation of endothelial cells. To develop a clinical gene therapy strategy with endostatin, we cloned the cDNA of human endostatin by RT-PCR from human placenta. A 150-bp sequence encoding the IgG leader peptide was fused in frame to the 5' end of the endostatin cDNA and recombinant adenoviruses, AdENDO-YFP and AdENDO, carrying endostatin gene expression cassettes were rescued. AdENDO-YFP infects cultured mammalian cells at high efficiency and expresses a biologically active human endostatin in secreted form at high levels both in vitro and in vivo. When delivered in vivo, a strain-specific expression pattern was observed, with the highest and longest endostatin expression in 129/J mice. After systemic delivery of 2 x 10(9) PFU of AdENDO-YFP into 129/J mice, human endostatin expression was achieved at a mean value of 1.34 +/- 0.42 microg/ml of serum (n = 6) and inhibition of lung metastasis was observed in an EOMA tumor model. However, high dose intravenous delivery of AdENDO-YFP and AdENDO was associated with severe acute toxicity in recipient mice that included loss of weight, bleeding, and death of animals. These events were not observed with the injection of identical doses of a control adenovirus that did not contain the endostatin gene. Because the endostatin adenovirus-associated acute toxicity was also observed in immunodeficient NCRNU-M nude mice, the toxicity does not appear to be the result of the immunogenicity against human endostatin or the EYFP protein.
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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) | 0.001 | 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 | 0.001 |
| 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".