Bioanalytical investigation of type I and type II epidermal growth factor (EGFR)-DNA targeting combi-molecules in «in vitro» and «in vivo» tumour models
Bibliographic record
Abstract
Solid tumours are characterized by the overexpression of several receptors that promote growth and antiapoptotic signalling. Their overexpression is associated with tumour progression and reduced sensitivity to anticancer drugs. Thus, in order to block the progression of such tumours, strategies to block receptor and induce additional damage in the cells are required. Here, we studied molecules termed, "combi-molecules", designed to block one such receptor, the epidermal growth factor receptor, (EGFR) and damage DNA. Combi-molecules are classified into two types: type I and type II. Type I combi-molecules require hydrolytic cleavage for releasing the EGFR and DNA targeting species, whereas the type II can generate the two species without requirement for degradation. Despite significant evidence of the high potency of the two types of combi-molecules, the parameters governing their potency in vivo remained elusive. This thesis describes bioanalytical approaches to elucidate the inverse potency of type II combi-molecules ZR2003 in vitro vs. in vivo and to analyse the degradation pathways of type I combi-molecule ZRS1 in vitro and in vivo. ZR2003 was 6-fold more potent than the clinical drug Iressa in vitro but slightly less potent than the latter in vivo. Tumour analysis showed that the difference of potency in vivo may be due to lower levels of absorption of ZR2003 in vivo when compared to Iressa. These results were in agreement with the levels of absorption observed in human ovarian cancer cell OV90 aggregates, indicating that the latter 3D organ-like model could be used to predict ZR2003 absorption in vivo. Studies on type I combi-molecule ZRS1 showed that while the drug was stable ex vivo, its decomposition was rapid in vivo and this was in agreement with data obtained from the 3D organ-like model. However, a new metabolite of ZRS1, FD105Ac, was detected in vivo but not in vitro, suggesting that the 3D organ-like model could not predict ZRS1 in vivo metabolism. Overall, the study showed that the reverse magnitude of potency of Iressa and type II combi-molecule ZR2003 from in vitro to in vivo may not be due to differences in their mode of action but rather to their differential plasma and tumour absorption. The results from the analysis of type I combi-molecule ZRS1 suggests that while it is unstable in vivo, its degradation and metabolism lead to high concentrations of EGFR inhibitory metabolites.
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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".