Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in ApcMin/+ mice

Tucker, J.; Davis, Celestia; Kitchens, Maria E.; Bunni, Marlene A.; Priest, David G.; Spencer, H. Trent; Berger, Franklin G.

doi:10.1016/s0304-3835(02)00402-0

Cited by 36 publications

(37 citation statements)

References 30 publications

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“…25 FUra functions primarily as a TS inhibitor through generation of FdUMP; however, it is also toxic as a consequence of incorporation of its other metabolites (i.e., FdUTP and FUTP) into DNA and RNA. To determine the impact of a "pure" TS inhibitor, we examined the effects of RTX, a folate analog whose sole known target is TS.…”

Section: Resultsmentioning

confidence: 99%

“…Genotypes were determined by PCR analysis of tail DNA to detect the Min allele. 25 For drug treatments, mice were randomized to appropriate treatment groups at weaning, and were provided free access to a folic acid-deficient diet (LabDiet, #5831, PMI Nutrition International, Richmond, IN). This diet, which contained 1% succinylsulfanthiozole to inhibit folic acid synthesis by intestinal flora, was utilized to reduce the high level of plasma folates normally found in mice.…”

Section: Methodsmentioning

confidence: 99%

“…25 Generally, this involved three treatment weeks, with two intermittent rest weeks. The doses and schedules are summarized in Table 1, and are referred to where appropriate in the text.…”

Section: Methodsmentioning

confidence: 99%

“…24 For example, our laboratory has recently developed a FUra treatment protocol that results in a 60-80% suppression of tumor formation in the Apc Min/+ mouse. 25 In the current study, we have examined the impact of RTX treatment, both alone and in combination with FUra, on tumor development in the Apc Min/+ mouse. We observed that RTX on its own increases tumor number in a dose-dependent fashion, it exerts a powerful anti-tumor effect in combination with FUra.…”

Section: Introductionmentioning

confidence: 99%

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Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ Mice1

Murphy

Tucker²,

Davis³

et al. 2004

Cancer Biology & Therapy

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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 (CRC). 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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…25 Generally, this involved three treatment weeks, with two intermittent rest weeks. The doses and schedules are summarized in Table 1, and are referred to where appropriate in the text.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ Mice1

Murphy

Tucker²,

Davis³

et al. 2004

Cancer Biology & Therapy

Self Cite

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show abstract

“…They were genotyped by using allele-specific PCR analysis of tail DNA (62). Mice were randomly selected on sex and body weight bases, divided into groups, housed four per cage, and provided with standard rodent chow (Harland Teklad Rodent Diet 8604, Harland Teklad, Madison, WI) and water ad libitum.…”

Section: Animal Experimentsmentioning

confidence: 99%

Delivery of CD44 shRNA/Nanoparticles within Cancer Cells

Misra

Hascall

Giovanni

et al. 2009

Journal of Biological Chemistry

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Our studies have shown that constitutive interactions between hyaluronan and CD44 on tumor cells induces various anti-apoptotic cell survival pathways through the formation of a multimeric signaling complex that contains activated receptor tyrosine kinases. Inhibition of the hyaluronan-CD44 interactions on tumor cells by hyaluronan-CD44 interaction antagonists suppresses these activities by disassembling the complex. Although the anti-tumor activity of hyaluronan-oligosaccharides, a hyaluronan-CD44 interaction antagonist, is effective in sensitizing tumor cells to chemotherapeutic agents and reducing tumor growth in xenografts, hyaluronan-oligosaccharide alone was not effective in reducing tumor progression in Apc Min/؉ mice. We now show in vitro and in vivo that targeted inhibition of the expression of CD44v6 depletes the ability of the colon tumor cells to signal through hyaluronanCD44v6 interactions. First, we cloned oligonucleotides coding CD44v6 shRNA into a conditionally silenced pSico vector. Second, using pSico-CD44v6 shRNA and a colon-specific Fabpl promoter-driven Cre recombinase expression vector packaged into transferrin-coated nanoparticles, we successfully delivered the CD44v6 shRNA within pre-neoplastic and neoplastic colon malignant cells. Third, using the Apc Min/؉ mice model, we demonstrated that inhibition of the CD44v6 expression reduces the signaling through a hyaluronan/CD44v6-pErbB2-Cox-2 interaction pathway and reduced adenoma number and growth. Together, these data provide insight into the novel therapeutic strategies of short hairpin RNA/nanoparticle technology and its potential for silencing genes associated with colon tumor cells.

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Lentivirus‐mediated somatic recombination and development of a novel mouse model for sporadic colorectal cancer

Vaish

Kim

Shim

2016

Genes Chromosomes & Cancer

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In this study, we have developed a novel mouse model for sporadic colorectal cancer (CRC) by utilizing APC conditional knockout (Apc(CKO) ) mouse and lentivirus encoding Cre recombinase and a reporter gene (EGFP or LacZ). Lentiviral transduction of colonic crypt stem cells allowed for the long-term expression of reporter gene as well as excision of floxed Apc alleles, which resulted in tumor development. Tumors represented adenoma stages along with the nuclear accumulation of β-catenin. Loss of E-cadherin at the cellular junctions and strong expression of Vimentin suggested the sign of active epithelial-mesenchymal transition. Moreover, nuclear staining of Ki67 inside epithelial cells of aberrant crypts demonstrated their higher proliferative nature. Erratic downstream signaling of activated Wnt/β-catenin, AKT/mTOR, and Notch pathways provided strong evidence towards the higher proliferative index of epithelial cells inside the aberrant crypts. These results do recapitulate the findings of previous APC mutant mouse models. Our model represents sporadic CRC more precisely as (i) tumors result from somatic mutations but not from germline; (ii) tumors develop in colon not in small intestine; (iii) few tumors develop at the distal end of colons. Additionally, our model allows for the long-term expression of the gene(s), which get integrated into the host cell genome and provides an ability to track the tumor growth. © 2016 Wiley Periodicals, Inc.

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Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in ApcMin/+ mice

Cited by 36 publications

References 30 publications

Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ Mice1

Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ Mice1

Delivery of CD44 shRNA/Nanoparticles within Cancer Cells

Lentivirus‐mediated somatic recombination and development of a novel mouse model for sporadic colorectal cancer

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