Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ mice.
The thymidylate synthase (TS) inhibitors raltitrexed (RTX) and 5-fluorouracil (FUra) have shown promising anti-tumor activity in preclinical and clinical settings for the treatment of colorectal cancer. Though the effects of these two agents have been reasonably well-characterized in cell lines, knowledge of their modes of action in vivo is limited. Here, we utilize the Apc(Min/+) mouse, an animal model of intestinal tumorigenesis, to study the effects of RTX treatment alone and in combination with FUra. Rather surprisingly, RTX monotherapy resulted in a dose dependent 4-10-fold increase in tumor number. The majority of these adenomas (74-95%) were rather small (i.e., less than 1 mm in diameter) and exhibited loss of heterozygosity at the Apc locus, suggesting an increase in mutational events leading to tumor development. RTX augmented BrdU-labeling of crypt epithelial cells, and retarded the movement of these cells along the crypt-villus axis. Co-administration of FUra and RTX resulted in a significant reduction in tumor number compared to mice treated with either RTX or FUra alone (P < 0.0001). In addition, FUra abrogated the RTX-mediated increase in BrdU labeling. In all, the results show that RTX increases tumor burden in the Apc(Min/+) mouse, yet enhances the anti-tumor effect of FUra. This is the first illustration of in vivo synergy of RTX and FUra in a genetically predisposed animal model. Possible mechanisms underlying the current observations are discussed.
Murphy
John T
JT
Department of Biological Sciences and the Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina 29208, USA.
Tucker
Jody M
JM
Davis
Celestia
C
Berger
Franklin G
FG
D000236:Adenoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D004357:Drug Synergism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011799:Quinazolines / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage; D047368:Tumor Burden
D025601:Adenomatous Polyposis Coli Protein; D011799:Quinazolines; D013876:Thiophenes; C068874:raltitrexed; D005472:Fluorouracil