PMID- 15539941
OWN - NLM
STAT- MEDLINE
DCOM- 20050721
LR  - 20200930
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 3
IP  - 11
DP  - 2004 Nov
TI  - Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor 
      synergy with 5-fluorouracil in ApcMin/+ mice.
PG  - 1169-76
AB  - 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.
FAU - Murphy, John T
AU  - Murphy JT
AD  - Department of Biological Sciences and the Center for Colon Cancer Research, 
      University of South Carolina, Columbia, South Carolina 29208, USA.
FAU - Tucker, Jody M
AU  - Tucker JM
FAU - Davis, Celestia
AU  - Davis C
FAU - Berger, Franklin G
AU  - Berger FG
LA  - eng
GR  - R01 CA080361/CA/NCI NIH HHS/United States
GR  - CA80361/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20041102
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (Adenomatous Polyposis Coli Protein)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - FCB9EGG971 (raltitrexed)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Adenoma/metabolism/pathology/prevention & control
MH  - Adenomatous Polyposis Coli Protein/genetics/*physiology
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Drug Synergism
MH  - Epithelial Cells/cytology
MH  - Female
MH  - Fluorouracil/administration & dosage
MH  - Intestinal Neoplasms/metabolism/*pathology/*prevention & control
MH  - Loss of Heterozygosity
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Quinazolines/administration & dosage
MH  - Thiophenes/administration & dosage
MH  - Tumor Burden
EDAT- 2004/11/13 09:00
MHDA- 2005/07/22 09:00
CRDT- 2004/11/13 09:00
PHST- 2004/11/13 09:00 [pubmed]
PHST- 2005/07/22 09:00 [medline]
PHST- 2004/11/13 09:00 [entrez]
AID - 1220 [pii]
AID - 10.4161/cbt.3.11.1220 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2004 Nov;3(11):1169-76. doi: 10.4161/cbt.3.11.1220. Epub 2004 
      Nov 2.