Anti‐metastatic effect of capecitabine on human colon cancer xenografts in nude mouse rectum

Abstract

Key words: capecitabine; lymph node metastasis; lung metastasis; thymidine phosphorylase; rectal xenograft modelGastrointestinal cancer is one of the most common internal malignancies and is one of the leading causes of cancer-related morbidity and mortality in the world. The primary definitive treatment modality is surgical excision. Adjuvant therapies subsequent to surgery have been studied extensively in recent years because of the high incidence of postoperative recurrences. More than 40 years after its development, 5-FU remains the chemotherapeutic mainstay for the management of patients with many types of cancer. In recent years, several new approaches to the treatment of cancer have undergone examination. These include the introduction of 2 novel cytotoxic compounds. Another strategy that has received attention has been the development of several oral forms of fluoropyrimidine, offering an alternative route of administration to intravenous 5-FU 1 . Capecitabine (N 4 -pentyloxycarbonyl-5Ј-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is designed to be activated to 5-FU by 3 sequential steps of enzyme reactions. 1 In humans, it is sequentially converted first to 5Ј-deoxy-5-fluorocytidine by carboxylesterase located in the liver, then to 5Ј-deoxy-5-fluorouridine by cytidine deaminase also with high activity in the liver and in various solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) with high activity in many types of tumors. [1][2][3] This oral fluoropyrimidine has an advantage over parental therapy with 5-FU in its potential for affording patients greater convenience and comfort. 4 -6 Randomized clinical trials that compared capecitabine with parenteral 5-FU/leucovorin against metastatic colorectal cancer demonstrated that capecitabine provides at least equivalence, a favorable benefit-risk ratio and greater patient preference making it an acceptable replacement for 5-FU/leucovorin. 4,5,7 Our interest focused on the possibility of capecitabine usage in the prevention of metastasis. Neoadjuvant or adjuvant chemotherapy to inhibit spontaneous metastasis or suppress occult micrometastasis may reduce the incidence of postoperative distant metastasis and improve survival. To confirm this possibility, large randomized clinical trials should be needed. These clinical trials are expensive and time consuming. Animal experiments may take their place to examine the efficacy of new therapeutic modalities. Here, we develop an animal model of gastrointestinal cancer by the intrarectal injection of tumor cells, which resulted in the formation of local tumors with lymph node and lung metastasis consistent with the progression of gastrointestinal cancer in humans.In our study, we examined the efficacy of capecitabine for the inhibition of metastasis and its mechanism for doing so by using a mouse metastasis model. MATERIAL AND METHODS AnimalsMale BALB/c-nu/nu mice aged 5 weeks were obtained from Charles River Japan, Inc. (Kanagawa, Japan). After at least 1 week of observation, th...

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

“…The HT29 and HCT116 cells are highly metastatic, whereas DLD-1 are not in mouse xenograft models. 6,17,21 We found that both CXCR3 and CXCR4 were highly expressed in HT29 and HCT116 cells, whereas both receptors were hardly expressed in DLD-1 (Fig. 2a).…”

“…18 We mainly used this pair of cell lines in this study, because they had the same genetic background with different metastatic potential. 19 To evaluate their metastatic activities in vivo, we performed the orthotopic transplantation model of CRC metastasis in mice 6,17,20 with the use of GFP marker. After injecting the cells into the rectal smooth muscle layer of nude mice, we macroscopically examined metastatic foci using GFP fluorescence.…”

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

“…At day 14 or 28, the para-aortic LNs were dissected and pooled for each mouse to quantify the metastasized cells by quantitative PCR (Ninomiya et al, 2004). All animal experiments were approved by the Animal Care and Use Committee of Kyoto University.…”

“…The rectal xenograft method offers a convenient animal model for colorectal cancer that can metastasize to the draining para-aortic LNs (Kashtan et al, 1992;Tsutsumi et al, 2001;Ninomiya et al, 2004). For example, it was reported that HT29 metastasized to LNs in all tumor-bearing mice (10/10) (Tsutsumi et al, 2001), whereas LS174T did not (0/5) (Kashtan et al, 1992).…”

“…To quantify the metastasized DLD-1 cells to the paraaortic LNs, we determined the level of human b-globinrelated sequence (HBB) by quantitative PCR (Ninomiya et al, 2004). One day after inoculation, we detected no amplified signals from LNs.…”