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Cancer Biol Ther. 2004 Nov 2;3(11).
Raltitrexed Increases Tumorigenesis as a Single
Agent Yet Exhibits Anti-Tumor Synergy with 5-Fluorouracil in Apc(Min/+)
Mice(1).
Murphy JT, Tucker JM, Davis C, Berger FG.
Department
of Biological Sciences and the Center for Colon Cancer Research,
University of South Carolina, Columbia, South Carolina 29208, USA.
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. Coadministration 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.
PubMed
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