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. 2017 Oct 16;17(1):684.
doi: 10.1186/s12885-017-3677-7.

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

Wayne J Aston  1   2 , Danika E Hope  1   2 , Anna K Nowak  1   2   3 , Bruce W Robinson  1   2 , Richard A Lake  1   2 , W Joost Lesterhuis  4   5
Affiliations

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

Wayne J Aston et al. BMC Cancer. .

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; MTD; Maximum tolerated dose; Mice; Supportive care.

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Conflict of interest statement

Ethics approval

All experiments were conducted according to the University of Western Australia Animal Ethics Committee approvals (Protocols RA/3/100/1139, RA/3/100/1217) and the Harry Perkins Institute for Medical Research Animal Ethics Committee (AEC029–2015) and the code of conduct of the National Health and Medical Research Council of Australia.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Maximum Tolerated Dosages for Chemotherapy in BALB/c mice. Body weight as a percentage of original of mice dosed with (a) 5-FU, (b) bleomycin, (c) cisplatin, (d) cyclophosphamide, (e) docetaxel, (f) doxorubicin, (g) etoposide, (h) gemcitabine, (i) irinotecan, (j) vinorelbine. *Clinical score ≥ 3. #Weight/clinical score did not return to baseline. Depicted are mean weights as percentage of starting weights with SEM (n = 3 mice/group)
Fig. 2
Fig. 2
Maximum tolerated doses in C57BL/6 J mice. Individual body weights as a percentage of original for C57BL/6 J mice (n = 3 per group) treated with (a) vinorelbine 10 mg/kg, (b) cisplatin 6 mg/kg or cisplatin 8 mg/kg (c)
Fig. 3
Fig. 3
Effect of repeated cycles of chemotherapy given at MTD. Individual body weights as a percentage of starting weight for BALB/c mice (n = 3 per group) treated with repeated cycles of (a) vinorelbine 10 mg/kg, (b) cisplatin 6 mg/kg and (c) cisplatin 4 mg/kg. Doses were repeated when mice recovered to 100% of their starting weight. Arrows indicate dosing of respective chemotherapeutics. For vinorelbine this was day 0, 7, 14; for cisplatin 6 mg/kg this was day 0, 9; for cisplatin 4 mg/kg this was day 0, 8, 16
Fig. 4
Fig. 4
Effect of supportive treatment on cisplatin-induced weight loss. Individual maximum body weight loss as compared to starting weight for mice treated with cisplatin at MTD with or without ondansetron (a). Maximum weight loss shown for cisplatin 6 mg/kg plus dexamethasone at varied dosages (b) and cisplatin 6 mg/kg plus ondansetron 1 mg/kg and dexamethasone 0.2 mg/kg (c). Depicted are mean weight loss with SEM, n = 3 for all groups. **p < 0.01
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