This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarke, S. J. Articles by Jackman, A. L. Search for Related Content PubMed PubMed Citation Articles by Clarke, S. J. Articles by Jackman, A. L.

Balb/c Mice as a Preclinical Model for Raltitrexed-induced Gastrointestinal Toxicity¹

The CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Surrey SM2 5NG, United Kingdom

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor used for the treatment of advanced colorectal cancer. RTX induces proliferating tissue toxicities that are largely confined to the intestine, with diarrhea being a severe side effect in a small but significant minority of patients. Similarly, weight loss and diarrhea were observed in BALB/c mice, and a maximum tolerated dose (MTD) was determined as approximately 5–10 mg/kg/day x 5 days. At an equivalent dose of 10 mg/kg/day x 5 days (d1–5), DBA2 mice lost considerably less weight, leading to a higher MTD (>500 mg/kg/day x 5 days), and there was no evidence of diarrhea. Histopathological consequences of damage, such as changes in small intestinal crypt architecture and villus atrophy induced by the 10-mg/kg/day dose, were greater and of longer duration in BALB/c mice. A higher dose of RTX (100 mg/kg/day x 5) induced weight loss and histopathological damage similar to that seen in BALB/c mice (10 mg/kg/day x 5) but was of later onset, nadir, and recovery. Small changes to the colon were only observed in BALB/c mice. Pretreatment levels of plasma thymidine, deoxyuridine (1 µM), and folate (40 ng/ml) were similar in both mouse strains. A single injection of radiolabeled RTX (5 mg/kg/day) did not lead to any marked difference 24 h later in the total drug concentration and distribution of polyglutamates (comprising 70–80% of drug extracted) in the liver, kidney, and intestinal epithelium (large and small intestine) between the two mouse strains. Further studies used a RIA to measure RTX polyglutamate formation in tissues at various times and drug doses. This led to the conclusion that, although there was a higher accumulation of RTX in BALB/c small intestinal epithelium (days 4–6), it may be an effect secondary to another undetermined cause of increased drug sensitivity. This model represents a vehicle by which the etiology and treatment of severe clinical toxicity induced by RTX may be evaluated.

This article has been cited by other articles:

				D. D. Gibbs, D. S. Theti, N. Wood, M. Green, F. Raynaud, M. Valenti, M. D. Forster, F. Mitchell, V. Bavetsias, E. Henderson, et al. BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to {alpha}-Folate Receptor-Overexpressing Tumors Cancer Res., December 15, 2005; 65(24): 11721 - 11728. [Abstract] [Full Text] [PDF]

				G. W. Aherne, A. Hardcastle, E. Ward, D. Dobinson, T. Crompton, M. Valenti, L. Brunton, and A. L. Jackman Pharmacokinetic/Pharmacodynamic Study of ZD9331, a Nonpolyglutamatable Inhibitor of Thymidylate Synthase, in a Murine Model Following Two Curative Administration Schedules Clin. Cancer Res., September 1, 2001; 7(9): 2923 - 2930. [Abstract] [Full Text] [PDF]

				C. L. van der Wilt, H. H. J. Backus, K. Smid, L. Comijn, G. Veerman, D. Wouters, D. A. Voorn, D. G. Priest, M. A. Bunni, F. Mitchell, et al. Modulation of Both Endogenous Folates and Thymidine Enhance the Therapeutic Efficacy of Thymidylate Synthase Inhibitors Cancer Res., May 1, 2001; 61(9): 3675 - 3681. [Abstract] [Full Text]

				D. M. Pritchard, L. Bower, C. S. Potten, A. L. Jackman, and J. A. Hickman The Importance of p53-Independent Apoptosis in the Intestinal Toxicity Induced by Raltitrexed (ZD1694, Tomudex): Genetic Differences between BALB/c and DBA/2 Mice Clin. Cancer Res., November 1, 2000; 6(11): 4389 - 4395. [Abstract] [Full Text] [PDF]

				D. C. Farrugia, G. W. Aherne, L. Brunton, S. J. Clarke, and A. L. Jackman Leucovorin Rescue from Raltitrexed (Tomudex)-induced Antiproliferative Effects: In Vitro Cell Line and in Vivo Mouse Studies Clin. Cancer Res., September 1, 2000; 6(9): 3646 - 3656. [Abstract] [Full Text]