Enhancement of docetaxel cytotoxicity in multidrug resistant variant cell lines of human head and neck squamous cell carcinoma HN-5a and promyelocytic leukemia HL-60 by N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (DPPE; Tesmilifene)
Bibliographic record
Abstract
540 DPPE, a pyrilamine analog which binds to intracellular histamine receptors, has demonstrated a large survival benefit in a phase III advanced breast cancer clinical trial, when combined with doxorubicin, versus doxorubicin alone (J Clin Oncol, 22: 269, 2004). Currently, a pivotal (registration) phase III confirmatory trial in advanced breast cancer is nearing its accrual goal. We sought to characterize the interaction of DPPE with several cell lines and cytotoxic drugs to obtain information helpful in elucidating its mechanism of action. We utilized as a model system the paired cell lines HN-5a and HN-5a/V15e; HL-60 and HL-60/MX2; and HT-29 and HT-29/carbo-15d. In each case the parent cell line is chemotherapy drug-sensitive and the derivative is drug-resistant: HN-5a/V15e overexpresses P-glycoprotein (Pgp) and is multidrug resistant; HL-60/MX2 has altered topoisomerase II and overexpresses MRP (but not Pgp); and HT-29/carbo-15d is resistant to platinum drugs. Cytotoxicity was measured by a vital stain (AlamarBlue) after 4 days of continuous exposure to anticancer drug in the absence and presence of DPPE. Drug sensitivities were compared by determining concentrations that inhibited proliferation by 50% (IC50). HN-5a/V15e, HL-60 and HL-60/MX2 were sensitized to docetaxel, reducing the IC50 for docetaxel by about 50% at concentrations of DPPE that were non-inhibitory (HN-5a/V15e) or less than 30% inhibitory (HL-60 lines). HN-5a/V15e cells were sensitized by DPPE to doxorubicin and epirubicin up to 50% (concentration dependent), but HL-60 and HL-60/MX2 were not. HT-29/carbo-15d cells were sensitized by 15-25% to cisplatin and 5-fluorouracil by non-inhibitory concentrations of DPPE, but HT-29 cells were not. DPPE has a variety of intracellular activities (including: antihistaminic; lipoxygenase inhibition; cytochrome P450 inhibition; Pgp inhibition), some of which are concentration dependent. The ability of DPPE to enhance the cytotoxicity of a range of chemotherapeutics in a spectrum of cell types may be a reflection of its pleiotropic activities. The potentiation of drug cytotoxicity in these cell lines suggests that DPPE might be effective in the treatment of tumours that have developed resistance to standard chemotherapy. This study was funded by a grant from YM BioSciences, Inc., Mississauga, Canada.
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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) | 0.001 | 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".