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01-06-2020 | Metastasis | Original Article

Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil

Authors: Yoshiaki Fujimoto, Ryota Nakanishi, Mamoru Nukatsuka, Kazuaki Matsuoka, Koji Ando, Takeshi Wakasa, Hiroyuki Kitao, Eiji Oki, Yoshihiko Maehara, Masaki Mori

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2020

Abstract

Purpose

Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model.

Methods

Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed.

Results

FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days.

Conclusion

These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity.

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Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A (2012) TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 13(10):993–1001. https://doi.org/10.1016/s1470-2045(12)70345-5 CrossRefPubMed

Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A, Grp RS (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919. https://doi.org/10.1056/NEJMoa1414325 CrossRefPubMed

Bando H, Doi T, Muro K, Yasui H, Nishina T, Yamaguchi K, Takahashi S, Nomura S, Kuno H, Shitara K, Sato A, Ohtsu A (2016) A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201). Eur J Cancer (Oxford, England: 1990) 62:46–53. https://doi.org/10.1016/j.ejca.2016.04.009 CrossRef

Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalcin S, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J (2018) Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19(11):1437–1448. https://doi.org/10.1016/s1470-2045(18)30739-3 CrossRefPubMed

Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, Yamada Y, Asao T (2000) Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. Biochem Pharmacol 59(10):1227–1236. https://doi.org/10.1016/s0006-2952(00)00253-7 CrossRefPubMed

Sakamoto K, Yokogawa T, Ueno H, Oguchi K, Kazuno H, Ishida K, Tanaka N, Osada A, Yamada Y, Okabe H, Matsuo K (2015) Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2'-deoxy-5-fluorouridine into DNA. Int J Oncol 46(6):2327–2334. https://doi.org/10.3892/ijo.2015.2974 CrossRefPubMedPubMedCentral

Kitao H, Morodomi Y, Niimi S, Kiniwa M, Shigeno K, Matsuoka K, Kataoka Y, Iimori M, Tokunaga E, Saeki H, Oki E, Maehara Y (2016) The antibodies against 5-bromo-2'-deoxyuridine specifically recognize trifluridine incorporated into DNA. Sci Rep 6:25286. https://doi.org/10.1038/srep25286 CrossRefPubMedPubMedCentral

Takahashi K, Yoshisue K, Chiba M, Nakanishi T, Tamai I (2018) Contribution of equilibrative nucleoside transporter(s) to intestinal basolateral and apical transports of anticancer trifluridine. Biopharm Drug Dispos 39(1):38–46. https://doi.org/10.1002/bdd.2110 CrossRefPubMed

Edahiro K, Iimori M, Kobunai T, Morikawa-Ichinose T, Miura D, Kataoka Y, Niimi S, Wakasa T, Saeki H, Oki E, Kitao H, Maehara Y (2018) Thymidine kinase 1 Loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity. Mol Cancer Res 16(10):1483–1490. https://doi.org/10.1158/1541-7786.MCR-17-0686 CrossRefPubMed

10.

Kataoka Y, Iimori M, Niimi S, Tsukihara H, Wakasa T, Saeki H, Oki E, Maehara Y, Kitao H (2019) Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level. Sci Rep 9(1):7964. https://doi.org/10.1038/s41598-019-44399-6 CrossRefPubMedPubMedCentral

11.

Emura T, Nakagawa F, Fujioka A, Ohshimo H, Yokogawa T, Okabe H, Kitazato K (2004) An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA. Int J Mol Med 13(2):249–255. https://doi.org/10.3892/ijmm.13.4.545 PubMed

12.

Tanaka N, Sakamoto K, Okabe H, Fujioka A, Yamamura K, Nakagawa F, Nagase H, Yokogawa T, Oguchi K, Ishida K, Osada A, Kazuno H, Yamada Y, Matsuo K (2014) Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep 32(6):2319–2326. https://doi.org/10.3892/or.2014.3487 CrossRefPubMedPubMedCentral

13.

Matsuoka K, Iimori M, Niimi S, Tsukihara H, Watanabe S, Kiyonari S, Kiniwa M, Ando K, Tokunaga E, Saeki H, Oki E, Maehara Y, Kitao H (2015) Trifluridine induces p53-dependent sustained G2 phase Arrest with Its Massive Misincorporation into DNA and Few DNA strand Breaks. Mol Cancer Ther 14(4):1004–1013. https://doi.org/10.1158/1535-7163.mct-14-0236 CrossRefPubMed

14.

Nakanishi R, Kitao H, Kiniwa M, Morodomi Y, Iimori M, Kurashige J, Sugiyama M, Nakashima Y, Saeki H, Oki E, Maehara Y (2017) Monitoring trifluridine incorporation in the peripheral blood mononuclear cells of colorectal cancer patients under trifluridine/tipiracil medication. Sci Rep 7(1):16969. https://doi.org/10.1038/s41598-017-17282-5 CrossRefPubMedPubMedCentral

15.

Suzuki N, Nakagawa F, Takechi T (2017) Trifluridine/tipiracil increases survival rates in peritoneal dissemination mouse models of human colorectal and gastric cancer. Oncol Lett 14(1):639–646. https://doi.org/10.3892/ol.2017.6258 CrossRefPubMedPubMedCentral

16.

Backus HH, Dukers DF, van Groeningen CJ, Vos W, Bloemena E, Wouters D, van Riel JM, Smid K, Giaccone G, Pinedo HM, Peters GJ (2001) 5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients. Ann Oncol 12(2):209–216. https://doi.org/10.1023/a:1008331525368 CrossRefPubMed

17.

Swales JG, Hamm G, Clench MR, Goodwin RJA (2019) Mass spectrometry imaging and its application in pharmaceutical research and development: a concise review. Int J Mass Spectrom 437:99–112. https://doi.org/10.1016/j.ijms.2018.02.007 CrossRef

18.

Yamashita F, Komoto I, Oka H, Kuwata K, Takeuchi M, Nakagawa F, Yoshisue K, Chiba M (2015) Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse. Cancer Chemother Pharmacol 76(2):325–333. https://doi.org/10.1007/s00280-015-2805-9 CrossRefPubMed

19.

Utsugi T (2013) New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol 43(10):945–953. https://doi.org/10.1093/jjco/hyt131 CrossRefPubMedPubMedCentral

20.

Kuboki Y, Nishina T, Shinozaki E, Yamazaki K, Shitara K, Okamoto W, Kajiwara T, Matsumoto T, Tsushima T, Mochizuki N, Nomura S, Doi T, Sato A, Ohtsu A, Yoshino T (2017) TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol 18(9):1172–1181. https://doi.org/10.1016/S1470-2045(17)30425-4 CrossRefPubMed

21.

Pfeiffer P, Yilmaz M, Moller S, Zitnjak D, Maltha L, Krogh M, Winther S, Petersen L, Hejlersen F, Thomsen K, Qvortrup C (2019) Bevacizumab improves efficacy of trifluridine/tipiracil (TAS-102) in patients with chemorefractory metastatic colorectal cancer: a Danish randomized trial. Ann Cncol Official J Eur Soc Med Oncol 30(Suppl 4):iv130–iv131. https://doi.org/10.1093/annonc/mdz154.013 CrossRef

Title: Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil
Authors: Yoshiaki Fujimoto
Ryota Nakanishi
Mamoru Nukatsuka
Kazuaki Matsuoka
Koji Ando
Takeshi Wakasa
Hiroyuki Kitao
Eiji Oki
Yoshihiko Maehara
Masaki Mori
Publication date: 01-06-2020
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
Colorectal Cancer
Colorectal Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04072-6

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