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© 2003 American Society for Clinical Oncology
Can Colorectal Cancer Patients With Thymidylate Synthase–Overexpressing Liver Metastases Have an Overall Survival Advantage With Hepatic Arterial Infusion Alone?Department of Medical Oncology, University "La Sapienza", Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy To the Editor: We read with great interest the article by Gonen et al,1 published in the February 2003 issue of the Journal of Clinical Oncology. We think their results deserve some comments. In this study, the authors reported that patients with resectable thymidylate synthase overexpressing (TS+) liver metastases from colorectal cancer have better overall survival (OS) when treated by hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) rather than by SYS alone. Conversely, patients with TS negative (TS-) metastatic colorectal cancer treated with SYS plus HAI had similar OS compared with SYS alone. The authors concluded it is not clear whether their findings are related to the higher doses given by HAI or "the regional application that may produce higher intracellular levels." We believe this hypothetic mechanism of action needs further exploration. Several studies support the findings that the overexpression of TS is linked to resistance to TS-targeting chemotherapeutic drugs (ie, fluorouracil [FU] and floxuridine [FUDR]).2,3 Moreover, it is well known that the TS inhibition rate is correlated with the tumor response rate and that the TS gene amplification and overexpression of TS protein can lead to FU resistance.3,4 Recently, polymorphic tandem repeats located in the TS enhancer region have been shown to influence TS overexpression in colon-cancer patients.3–5 Moreover, some authors discovered that by HAI it was possible to reach lower TS mRNA and higher ribonucleotide reductase activity than with SYS, suggesting that HAI was a more effective method of administration than SYS.6 It would also be interesting to clarify, in the same series of patients, the role of the thymidine phosporylase (TP), an enzyme involved in the metabolism of FU. TP is the first enzyme in the metabolic activation pathway of FU to fluorodeoxyribonucleotides, and it could be used to increase the sensitivity of cancer cells to this antipyrimidine agent.7 Increasing tumoral TP activity with 2'-deoxyinosine (d-Ino) showed a near 4,000-fold increase of LS174T human colorectal cells’ sensitivity to FU in vitro.8 This potentiation of tumor response was accompanied by a total change in the FU anabolic pathway with a 5,000% increase of cytosolic fluorodeoxyuridine monophosphate, a stronger and longer inhibition of TS, and a 300% augmentation of DNA damage.9 Furthermore, it has recently been shown that low gene expression levels of TS, dihydropyrimidine dehydrogenase (DPD), and TP are associated with response and survival in patients with colorectal cancer.10 Moreover, the levels of TP and DPD and the ratio of TP to DPD in patients with liver metastases are lower in those who do not respond to doxifluridine administred through hepatic arterial infusion.11 In contrast, Metzger et al observed that high TP mRNA levels were predictive for a poor response to FU-leucovorin (LV) therapy for colorectal cancer. In their patient group, six of the seven patients receiving FU-LV had high TP levels and poor survival, suggesting that high TP levels are a poor prognostic factor in patients with colorectal cancer treated with FU-LV.12 Most likely, patients with low levels of TP are unable to properly metabolize FU administered by systemic infusion. This may explain why the group of patients with TS+ liver metastases have a better OS when FUDR is administred by HAI. It is in fact known that FUDR is directly transformed to 5-fluoro-2'-deoxyuridine-monophosphate, the TS direct inhibitor, without being metabolized by TP. It still needs to be understood whether low levels of TP may be associated with TS overexpression or whether TP expression is an independent factor that adds to TS positivity in worsening the prognosis of patients with metastatic colorectal cancer. For this reason, we believe it may be interesting to evaluate the OS of patients with TS+ metastases treated with HAI alone compared to the other two previously described arms. These observations could strengthen the authors’ findings and better clarify the response of TS+ liver metastases to chemotherapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Gonen M, Hummer A, Zervoudakis A, et al: Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer. J Clin Oncol 21:406–412, 2003
2. Davies MM, Johnston PG, Kaur S, et al: Colorectal liver metastasis thymidylate synthase staining correlates with response to hepatic arterial floxuridine. Clin Cancer Res 5:325–328, 1999
3. Wu Q, Dolnick BJ: Detection of thymidylate synthase modulators by a novel screening assay. Mol Pharmacol 63:167–173, 2003 4. Copur S, Aiba K, Drake JC, et al: Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil. Biochem Pharmacol 49:1419–1426, 1995[CrossRef][Medline] 5. Berg RW, Ferguso PJ, DeMoor JM, et al: The means to an end of tumour cell resistance to chemotherapeutic drugs targeting thymidylate synthase: Shoot the messenger. Curr Drug Targets 3:297–309, 2002[CrossRef][Medline] 6. Kubota T, Watanabe M, Otani Y, et al: Different pathways of 5-fluorouracil metabolism after continuous venous or bolus injection in patients with colon carcinoma: Possible predictive value of thymidylate synthetase mRNA and ribonucleotide reductase for 5-fluorouracil sensitivity. Anticancer Res 22:3537–3540, 2002[Medline] 7. Evrard A, Cuq P, Robert B, et al: Enhancement of 5-fluorouracil cytotoxicity by human thymidine-phosphorylase expression in cancer cells: In vitro and in vivo study. Int J Cancer 80:465–470, 1999[CrossRef][Medline]
8. Ciccolini J, Peillard L, Evrard A, et al: Enhanced antitumor activity of 5-fluorouracil in combination with 2'-deoxyinosine in human colorectal cell lines and human colon tumor xenografts. Clin Cancer Res 6:1529–1535, 2000
9. Ciccolini J, Cuq P, Evrard A, et al: Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment greatly enhances 5-fluorouracil antitumor activity in vitro and in vivo. Mol Cancer Ther 1:133–139, 2001
10. Salonga D, Danenberg KO, Johnson M, et al: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6:1322–1327, 2000 11. Ishida H, Fujioka M, Oshawa T, et al: Effect of peroral doxifluridine plus hepatic arterial infusion for synchronous liver metastasis of colorectal cancer: Correlation with the expression of thymidine phosphorylase and dihydropyrimidine dehydrogenase in primary colorectal cancer lesions. Gan To Kagaku Ryoho 28:1624–1627, 2001[Medline]
12. Metzger R, Danenberg K, Leichman GC, et al: High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with non-response to 5-fluorouracil. Clin Cancer Res 4:2371–2376, 1998
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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