Combinatorial treatment with carboxyamidotriazole- orotate and temozolomide in sc-implanted human LOX IMVI melanoma xenografts
Bibliographic record
Abstract
Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1(4-(4-chlorobenzoyl)-3, 5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide (CAI). CTO possesses increased solubility as compared to CAI as the free base. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor-operated, calcium-channel-mediated calcium influx. CTO can inhibit calcium-sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cy, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl. Methods: Different combinations of CTO and temozolomide were first tested in female athymic NCr- nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously implanted human LOX IMVI melanoma xenografts. Results: Oral CTO at doses of 513 or 342 mg/kg/dose Q1D × 14 resulted in inhibition of tumor growth ( p <0.001 and p =0.004). Oral TEM at doses of 90 and 60 mg/kg/dose Q4D × 3 resulted in dose-dependent inhibition of tumor growth ( p <0.001 and p <0.001). Oral CTO at 513 or 342 mg/kg/dose in combination with temozolomide 90 mg/kg/dose resulted in comparable tumor inhibition to temozolomide alone. However, oral CTO at 513 mg/kg/dose in combination with temozolomide 60mg/kg/dose resulted in additive antitumor activity compared to each drug alone. Also, CTO at 342 mg/kg/dose in combination with temozolomide 60mg/kg/dose had more than additive antitumor activity and was statistically different from the group treated with temozolomide 60 mg/kg/dose alone ( p =0.001). Conclusions: These results suggest that this combination of previously configured therapeutic doses of temozolomide with CTO enhances the sensitivity of temozolomide and may permit use of lower temozolomide doses to obtain an optimum antitumor effect in combination therapy. This dose-dilution combinatorial strategy fulfills the need for increased tumor sensitivity and efficacy. Additionally, this strategy reduces drug resistance and toxicity associated with dose dense strategy of temozolomide treatment in this melanoma model.
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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".