Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ mice.
Cancer Biol Ther
; 3(11): 1169-76, 2004 Nov.
Article
em En
| MEDLINE
| ID: mdl-15539941
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína da Polipose Adenomatosa do Colo
/
Neoplasias Intestinais
Limite:
Animals
Idioma:
En
Revista:
Cancer Biol Ther
Assunto da revista:
NEOPLASIAS
/
TERAPEUTICA
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos