The influence of the proton pump inhibitor pantoprazole on the distribution of doxorubicin in solid tumors with and without expression of P-glycoprotein
Bibliographic record
Abstract
3233 Background: Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. Limited drug distribution is an important cause of drug resistance in solid tumors1. Basic drugs (such as doxorubicin) may be sequestered in acidic organelles, and this may contribute to drug resistance by (i) diverting drugs from their target DNA and (ii) decreasing drug that is available for penetration to more distant cells. P-glycoprotein (PgP) is expressed on endosomal membranes of PgP expressing cells, and sequestration of drugs in acidic endosomes contributes to drug resistance in such cells2. Proton pump inhibitors, such as pantoprazole (PPZ), raise endosomal pH and decrease sequestration of basic drugs in acidic compartments3, 4, this may allow more drug to interact with DNA while decreased net cellular uptake of drug may allow greater penetration to cells distant from blood vessels. Here we investigate whether PPZ enhances the distribution of doxorubicin in solid tumors. Methods: Wild-type and PgP overexpressing multilayered cell cultures (MCCs) were used to evaluate the penetration of radiolabeled doxorubicin with and without pre-treatment with PPZ. Nude mice bearing MCF-7 human mammary tumors with high or low expression of PgP were treated with doxorubicin with or without prior PPZ or PgP inhibitors. Tumors were excised, frozen, sectioned and imaged for doxorubicin and for CD31 (a blood vessel marker) using immunofluorescence. The relationship between doxorubicin and distance to the nearest blood vessel was quantified in tumor sections1. Results: Doxorubicin had better tissue penetration in MCC and tumors that over-expressed PgP than in wild type MCC or tumors, presumably due to lower cellular uptake of drug by cells. Reversal of PgP with classical inhibitors (e.g. verapamil, PSC-833) decreased penetration of doxorubicin in MCC and tumors. Pretreatment with PPZ markedly increased penetration of doxorubicin in PgP-overexpressing (but not wild-type) MCCs and tumors. Studies of the effect of PPZ on doxorubicin-induced growth delay of wild-type and PgP-expressing tumors are in progress. Conclusions/Discussion: Pantoprazole (in contrast to classical PgP inhibitors) leads to better distribution of doxorubicin in PgP overexpressing MCCs and solid tumors. This is presumably because of decreased sequestration of drug in acidic organelles and decreased uptake of drug by proximal cells. Use of PPZ to enhance the distribution and cytotoxicity of doxorubicin in tumors that express PgP might be a novel and effective treatment strategy. 1 Tredan O et al, JNCI 2007;99: 4441-54. 2Rajagopal A, Simon SM, Mol Biol Cell 2003;14: 3389-99. 3Lee CM, Tannock IF, Br J Cancer 2006;94:863-9 4Luciani F et al, JNCI 2004;96:1702-13
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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".