title: Fasting protects against the side effects of irinotecan but preserves its anti-tumor effect in Apc15lox mutant mice.
abstract: Irinotecan is a widely used topoisomerase-I-inhibitor with a very narrow therapeutic window because of its severe toxicity. In the current study we have examined the effects of fasting prior to irinotecan treatment on toxicity and anti-tumor activity. FabplCre;Apc(15lox/+) mice, which spontaneously develop intestinal tumors, of 27 weeks of age were randomized into 3-day fasted and ad libitum fed groups, followed by treatment with a flat-fixed high dose of irinotecan or vehicle. Side-effects were recorded until 11 days after the start of the experiment. Tumor size, and markers for cell-cycle activity, proliferation, angiogenesis, and senescence were measured. Fasted mice were protected against the side-effects of irinotecan treatment. Ad libitum fed mice developed visible signs of discomfort including weight loss, lower activity, ruffled coat, hunched-back posture, diarrhea, and leukopenia. Irinotecan reduced tumor size in fasted and ad libitum fed groups similarly compared to untreated controls (2.4 ± 0.67 mm and 2.4 ± 0.82 mm versus 3.0 ± 1.05 mm and 2.8 ± 1.08 mm respectively, P < 0.001). Immunohistochemical analysis showed reduced proliferation, a reduced number of vascular endothelial cells, and increased levels of senescence in tumors of both irinotecan treated groups. In conclusion, 3 days of fasting protects against the toxic side-effects of irinotecan in a clinically relevant mouse model of spontaneously developing colorectal cancer without affecting its anti-tumor activity. These results support fasting as a powerful way to improve treatment of colorectal carcinoma patients.
authors.affiliation: a Department of Surgery ; Erasmus University Medical Center ; Rotterdam , the Netherlands.
authors.forename: Sander A
authors.initials: SA
authors.lastname: Huisman
authors.forename: Wendy
authors.initials: W
authors.lastname: Bijman-Lagcher
authors.forename: Jan N M
authors.initials: JN
authors.lastname: IJzermans
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D005215:Fasting; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D000077146:Irinotecan; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin
keywords: APC; colorectal cancer; fasting; irinotecan; mouse models