Increase of therapeutic effects by treating melanoma with targeted combinations of c-myc antisense and doxorubicin.
Bibliographic record
Abstract
C106 Patients with advanced or metastatic melanoma have a very poor prognosis, due to the resistance of melanoma cells to conventional chemotherapy. We previously reported that coated cationic liposomes (CCL) targeted with a monoclonal antibody against the disialoganglioside GD2 and containing c-myc antisense oligodeoxynucleotides (αGD2-CCL[c-myc-as]) resulted in selective inhibition of the proliferation of GD2-positive melanoma cells in vitro, while inducing apoptosis and partial tumor growth arrest in melanoma xenografts. Our aim in this work was to define the role of c-myc-asODN treatment in the susceptibility to doxorubicin (DXR) in human melanoma cells, both in vitro and in vivo. To determine chemosensitization of melanoma cells to DXR by c-myc antisense oligodeoxynucleotides (asODNs), human melanoma cells were incubated for 2 h with αGD2-CCL[c-myc-as] (10 μM asODN concentration). After washing, cells were then incubated with DXR (concentrations ranging from 0.061 μg/ml DXR to 250 μg/ml) and the inhibition of cell proliferation determined after 48 hours by the MTT assay. Annexin V-FITC and propidium iodide (PI) double staining were used to detect apoptotic and necrotic cells after treatments. For in vivo experiments, athymic mice were injected subcutaneously with the human melanoma cell, MZ2-MELand intravenously treated, every day for 3 days, with 3.5mg ODN/kg of αGD2-CCL[c-myc-as], untargeted liposomal DXR (SL[DXR]) or αGD2-targeted liposomal DXR (αGD2-SIL[DXR]) at 2 mg DXR/kg, or with a combination of the ODN and DXR formulations. Histological evaluation of cryopreserved tumor tissues was performed at 7 and 14 d from the end of treatment, using mAbs against the Ki-67 proliferation antigen, the endothelial marker CD31 and TUNEL for detecting apoptosis. In vitro cytotoxicity studies revealed that growth of melanoma cells was inhibited to a greater extent by αGD2-CCL[c-myc-as] than by the corresponding untargeted formulations or by free c-myc-as. Targeted c-myc-as sensitized cells to DXR, reducing the IC50 by approximately 10-fold. Scrambled ODNs had no effect on the IC50 of DXR. Compared to either treatment alone, combination of targeted c-myc-as and DXR resulted in earlier apoptosis and necrosis after 2 days of treatment. In vivo experiments revealed that liposomal formulations of c-myc-as and DXR, both targeted via GD2, led to the most pronounced delay in tumor growth when administered in a sequential manner. As a result, their combination translates into a statistically significant suppression of blood vessel density and an enhanced apoptosis, compared to all treatments given separately. Our data indicate the increasing cell sensitivity to DXR by targeted c-myc-asODNs as a promising basis for developing novel anti-tumor strategy against advanced melanoma. F.P. is a recipient of a Fondazione Italiana per la Lotta al Neuroblastoma fellowship.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".