Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer
Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of pacli...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:2da8bb17075a4bb7a21f579be94bb87f2021-11-11T09:35:00ZTissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer1663-981210.3389/fphar.2021.759146https://doaj.org/article/2da8bb17075a4bb7a21f579be94bb87f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.759146/fullhttps://doaj.org/toc/1663-9812Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance.Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa.Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: −3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0–48 h: r = 0.72; p < 0.01).Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.Ruben A. G. van EerdenLeni van DoornFemke M. de ManNiels HeerscheMichail DoukasThierry P. P. van den BoschEsther Oomen-de HoopPeter de BruijnSander BinsEman IbrahimSuzan NikkessenLena E. FribergStijn L. W. KoolenStijn L. W. KoolenManon C. W. SpaanderRon H. J. MathijssenFrontiers Media S.A.articletissue pharmacokineticsintratumoralpaclitaxelpharmacokineticsesophageal cancerABCB1Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
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EN |
| topic |
tissue pharmacokinetics intratumoral paclitaxel pharmacokinetics esophageal cancer ABCB1 Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
tissue pharmacokinetics intratumoral paclitaxel pharmacokinetics esophageal cancer ABCB1 Therapeutics. Pharmacology RM1-950 Ruben A. G. van Eerden Leni van Doorn Femke M. de Man Niels Heersche Michail Doukas Thierry P. P. van den Bosch Esther Oomen-de Hoop Peter de Bruijn Sander Bins Eman Ibrahim Suzan Nikkessen Lena E. Friberg Stijn L. W. Koolen Stijn L. W. Koolen Manon C. W. Spaander Ron H. J. Mathijssen Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer |
| description |
Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance.Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa.Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: −3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0–48 h: r = 0.72; p < 0.01).Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor. |
| format |
article |
| author |
Ruben A. G. van Eerden Leni van Doorn Femke M. de Man Niels Heersche Michail Doukas Thierry P. P. van den Bosch Esther Oomen-de Hoop Peter de Bruijn Sander Bins Eman Ibrahim Suzan Nikkessen Lena E. Friberg Stijn L. W. Koolen Stijn L. W. Koolen Manon C. W. Spaander Ron H. J. Mathijssen |
| author_facet |
Ruben A. G. van Eerden Leni van Doorn Femke M. de Man Niels Heersche Michail Doukas Thierry P. P. van den Bosch Esther Oomen-de Hoop Peter de Bruijn Sander Bins Eman Ibrahim Suzan Nikkessen Lena E. Friberg Stijn L. W. Koolen Stijn L. W. Koolen Manon C. W. Spaander Ron H. J. Mathijssen |
| author_sort |
Ruben A. G. van Eerden |
| title |
Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer |
| title_short |
Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer |
| title_full |
Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer |
| title_fullStr |
Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer |
| title_full_unstemmed |
Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer |
| title_sort |
tissue type differences in abcb1 expression and paclitaxel tissue pharmacokinetics in patients with esophageal cancer |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/2da8bb17075a4bb7a21f579be94bb87f |
| work_keys_str_mv |
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