Immunohistochemical analysis of organic anion transporter 2 and reduced folate carrier 1 in colorectal cancer: Significance as a predictor of response to oral uracil/ftorafur plus leucovorin chemotherapy

Nishino,Satoshi; Itoh,Ayumi; Matsuoka,Hiroshi; Maeda,Kotaro; Kamoshida,Shingo

doi:10.3892/mco.2013.104

Immunohistochemical analysis of organic anion transporter 2 and reduced folate carrier 1 in colorectal cancer: Significance as a predictor of response to oral uracil/ftorafur plus leucovorin chemotherapy

Authors:
- Satoshi Nishino
- Ayumi Itoh
- Hiroshi Matsuoka
- Kotaro Maeda
- Shingo Kamoshida
View Affiliations

Affiliations: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Hyogo 654-0142, Japan, Department of Surgery, School of Medicine, Fujita Health University Toyoake, Aichi 470-1192, Japan
Published online on: April 15, 2013 https://doi.org/10.3892/mco.2013.104
Pages: 661-667

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Colorectal cancer is one of the most common malignancies in developed countries and chemotherapy is the standard treatment option for advanced colorectal cancer. Identification of biomarkers for predicting response to uracil̸ftorafur plus leucovorin (UFT/LV) chemotherapy is an important issue in colorectal cancer treatment. Organic anion transporter 2 (OAT2) and reduced folate carrier 1 (RFC1) are the major uptake transporters of 5-fluorouracil (5-FU) and LV, respectively. In the present study, the correlation between OAT2 and RFC1 expression and histological response to preoperative UFT-based (UFT or UFT/LV) chemotherapy was investigated. Pre‑treatment biopsy specimens obtained from 45 patients were evaluated for OAT2 and RFC1 expression levels by using an immunohistochemical approach. A high expression of OAT2 and RFC1 was significantly correlated with good response to UFT-based chemotherapy (P<0.0001 and P=0.002, respectively). In multivariate logistic regression analysis, a high OAT2 expression was an independent predictor of good response to UFT-based chemotherapy (P=0.02), unlike RFC1 expression. High expression levels of OAT2 were significantly correlated with a good response in the UFT-treated (P=0.04) as well as the UFT̸LV‑treated (P<0.0005) groups; however, RFC1 expression levels were significantly correlated with a good response only in the UFT̸LV‑treated group (P=0.02). Therefore, immunohistochemical analysis of OAT2 and RFC1 may serve as a useful tool for predicting the efficacy of UFT/LV treatment regimens in colorectal cancer patients.

View Figures

View References

1.	Fujii S, Ikenaka K, Fukushima M and Shirasaka T: Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann. 69:763–772. 1978.PubMed/NCBI
2.	Milano G, Ferrero JM and François E: Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer. 91:613–617. 2004.PubMed/NCBI
3.	Anttila MI, Sotaniemi EA, Kairaluoma MI, Mokka RE and Sundquist HT: Pharmacokinetics of ftorafur after intravenous and oral administration. Cancer Chemother Pharmacol. 10:150–153. 1983. View Article : Google Scholar : PubMed/NCBI
4.	Longley DB, Harkin DP and Johnston PG: 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 3:330–338. 2003. View Article : Google Scholar : PubMed/NCBI
5.	Borner MM, Schöffski P, de Wit R, et al: Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer. 38:349–358. 2002. View Article : Google Scholar
6.	Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 20:3617–3627. 2002. View Article : Google Scholar
7.	Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 20:3605–3616. 2002. View Article : Google Scholar : PubMed/NCBI
8.	Lembersky BC, Wieand HS, Petrelli NJ, et al: Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 24:2059–2064. 2006. View Article : Google Scholar
9.	Dobson PD and Kell DB: Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov. 7:205–220. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER and Figg WD: Pharmacogenetics of membrane transporters: an update on current approaches. Mol Biotechnol. 44:152–167. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Marzolini C, Tirona RG and Kim RB: Pharmacogenomics of the OATP and OAT families. Pharmacogenomics. 5:273–282. 2004. View Article : Google Scholar : PubMed/NCBI
12.	You G: The role of organic ion transporters in drug disposition: an update. Curr Drug Metab. 5:55–62. 2004. View Article : Google Scholar : PubMed/NCBI
13.	Kobayashi Y, Ohshiro N, Sakai R, Ohbatashi M, Kohyama N and Yamamoto T: Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol. 57:573–578. 2005.
14.	Sirotnak FM and Tolner B: Carrier-mediated membrane transport of folates in mammalian cells. Annu Rev Nutr. 19:91–122. 1999. View Article : Google Scholar : PubMed/NCBI
15.	Blehaut H, Mircher C, Ravel A, et al: Effect of leucovorin (folinic acid) on the developmental quotient of children with Down’s syndrome (trisomy 21) and influence of thyroid status. PLoS One. 5:e83942010.PubMed/NCBI
16.	Japanese Society for Cancer of the Colon and Rectum: Japanese Classification of Colorectal Carcinoma. 2nd English edition. Kanehara Shuppan Co. Ltd.; Tokyo: 2009
17.	Kamoshida S, Matsuoka H, Shiogama K, et al: Immunohistochemical analysis of thymidylate synthase, p16^INK4a, cyclin-dependent kinase 4 and cyclin D1 in colorectal cancers receiving preoperative chemotherapy: significance of p16^INK4a-mediated cellular arrest as an indicator of chemosensitivity to 5-fluorouracil. Pathol Int. 54:564–575. 2004.PubMed/NCBI
18.	Ichikawa W, Uetake H, Shirota Y, et al: Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Br J Cancer. 89:1486–1492. 2003. View Article : Google Scholar
19.	Sadahiro S, Suzuki T, Tanaka A, Okada K, Nagase H and Uchida J: Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer. Cancer Chemother Pharmacol. 70:285–291. 2012. View Article : Google Scholar
20.	Seithel A, Karlsson J, Hilgendorf C, Björquist A and Ungell AL: Variability in mRNA expression of ABC- and SLC-transporters in human intestinal cells: comparison between human segments and Caco-2 cells. Eur J Pharm Sci. 28:291–299. 2006. View Article : Google Scholar : PubMed/NCBI
21.	Odin E, Wettergren Y, Nilsson S, et al: Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients. Clin Cancer Res. 9:6012–6019. 2003.PubMed/NCBI
22.	Hlavata I, Mohelnikova-Duchonova B, Vaclavikova R, et al: The role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis. 27:187–196. 2012. View Article : Google Scholar : PubMed/NCBI