A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice

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Abstract

Background: Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation. Methods: To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints. Results: We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice. Conclusion: These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.

Original languageEnglish
Article number684
JournalBMC Cancer
Volume17
Issue number1
DOIs
Publication statusPublished - 16 Oct 2017

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Maximum Tolerated Dose
Drug Therapy
Inbred C57BL Mouse
Dexamethasone
Weight Loss
Weights and Measures
Therapeutics
Research
Pharmaceutical Preparations
Neoplasms

Cite this

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title = "A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice",
abstract = "Background: Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation. Methods: To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints. Results: We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice. Conclusion: These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.",
keywords = "Cancer, Chemotherapy, Dose optimization, Maximum tolerated dose, Mice, MTD, Supportive care",
author = "Aston, {Wayne J.} and Hope, {Danika E.} and Nowak, {Anna K.} and Robinson, {Bruce W.} and Lake, {Richard A.} and Lesterhuis, {W. Joost}",
year = "2017",
month = "10",
day = "16",
doi = "10.1186/s12885-017-3677-7",
language = "English",
volume = "17",
journal = "BMC Cancer",
issn = "1471-2407",
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number = "1",

}

TY - JOUR

T1 - A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice

AU - Aston, Wayne J.

AU - Hope, Danika E.

AU - Nowak, Anna K.

AU - Robinson, Bruce W.

AU - Lake, Richard A.

AU - Lesterhuis, W. Joost

PY - 2017/10/16

Y1 - 2017/10/16

N2 - Background: Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation. Methods: To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints. Results: We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice. Conclusion: These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.

AB - Background: Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation. Methods: To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints. Results: We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice. Conclusion: These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.

KW - Cancer

KW - Chemotherapy

KW - Dose optimization

KW - Maximum tolerated dose

KW - Mice

KW - MTD

KW - Supportive care

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