Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer
Abstract Introduction Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. Methods...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Adis, Springer Healthcare
2023-01-01
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| Series: | Oncology and Therapy |
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| Online Access: | https://doi.org/10.1007/s40487-022-00215-2 |
| _version_ | 1797865298073747456 |
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| author | Sandrine Barbier Benjamin Beaufils Ricardo de Miguel Melissa Reyre Yannick Le Meitour Andreanne Lortie Marc Hillairet de Boisferon Sophie Chaumeron Anne Espirito Lina Fossati Pauline Lagarde Stephan Klinz Arunthathi Thiagalingam Stéphane Lezmi Florence Meyer-Losic |
| author_facet | Sandrine Barbier Benjamin Beaufils Ricardo de Miguel Melissa Reyre Yannick Le Meitour Andreanne Lortie Marc Hillairet de Boisferon Sophie Chaumeron Anne Espirito Lina Fossati Pauline Lagarde Stephan Klinz Arunthathi Thiagalingam Stéphane Lezmi Florence Meyer-Losic |
| author_sort | Sandrine Barbier |
| collection | DOAJ |
| description | Abstract Introduction Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. Methods We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week. Results Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. Conclusion This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer. |
| first_indexed | 2024-04-09T23:06:40Z |
| format | Article |
| id | doaj.art-be2e3c3c269d460ab70f6f7799bd0e5d |
| institution | Directory Open Access Journal |
| issn | 2366-1070 2366-1089 |
| language | English |
| last_indexed | 2024-04-09T23:06:40Z |
| publishDate | 2023-01-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Oncology and Therapy |
| spelling | doaj.art-be2e3c3c269d460ab70f6f7799bd0e5d2023-03-22T10:41:29ZengAdis, Springer HealthcareOncology and Therapy2366-10702366-10892023-01-0111111112810.1007/s40487-022-00215-2Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic CancerSandrine Barbier0Benjamin Beaufils1Ricardo de Miguel2Melissa Reyre3Yannick Le Meitour4Andreanne Lortie5Marc Hillairet de Boisferon6Sophie Chaumeron7Anne Espirito8Lina Fossati9Pauline Lagarde10Stephan Klinz11Arunthathi Thiagalingam12Stéphane Lezmi13Florence Meyer-Losic14Ipsen InnovationIpsen InnovationIpsen InnovationIpsen InnovationIpsen InnovationIpsen InnovationOncodesignOncodesignOncodesignIpsen InnovationIpsen InnovationIpsen BioscienceIpsen BioscienceIpsen InnovationIpsen InnovationAbstract Introduction Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. Methods We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week. Results Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. Conclusion This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer.https://doi.org/10.1007/s40487-022-00215-2Liposomal irinotecanPancreatic cancerPatient-derived xenograftTherapeutic indexTumor model |
| spellingShingle | Sandrine Barbier Benjamin Beaufils Ricardo de Miguel Melissa Reyre Yannick Le Meitour Andreanne Lortie Marc Hillairet de Boisferon Sophie Chaumeron Anne Espirito Lina Fossati Pauline Lagarde Stephan Klinz Arunthathi Thiagalingam Stéphane Lezmi Florence Meyer-Losic Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer Oncology and Therapy Liposomal irinotecan Pancreatic cancer Patient-derived xenograft Therapeutic index Tumor model |
| title | Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer |
| title_full | Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer |
| title_fullStr | Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer |
| title_full_unstemmed | Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer |
| title_short | Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer |
| title_sort | liposomal irinotecan shows a larger therapeutic index than non liposomal irinotecan in patient derived xenograft models of pancreatic cancer |
| topic | Liposomal irinotecan Pancreatic cancer Patient-derived xenograft Therapeutic index Tumor model |
| url | https://doi.org/10.1007/s40487-022-00215-2 |
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