Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model

Overview

Journal J Clin Med

Specialty General Medicine

Date 2020 Dec 18

PMID 33333866

Citations 1

Authors

Kenta Tsunekuni

Hisato Kawakami

Kazuaki Matsuoka

Hideki Nagase

Seiichiro Mitani

Kazuhiko Nakagawa

Affiliations

Soon will be listed here.

Abstract

Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower ( < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of mutations.

Citing Articles

Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G).

Takahashi N, Hara H, Nagashima K, Hirata K, Masuishi T, Matsumoto T BMC Cancer. 2023; 23(1):726.

PMID: 37543568 PMC: 10403909. DOI: 10.1186/s12885-023-11199-1.

References

Price T, Hardingham J, Lee C, Weickhardt A, Townsend A, Wrin J . Impact of KRAS and BRAF Gene Mutation Status on Outcomes From the Phase III AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer. J Clin Oncol. 2011; 29(19):2675-82. DOI: 10.1200/JCO.2010.34.5520. View

Kataoka Y, Iimori M, Fujisawa R, Morikawa-Ichinose T, Niimi S, Wakasa T . DNA Replication Stress Induced by Trifluridine Determines Tumor Cell Fate According to p53 Status. Mol Cancer Res. 2020; 18(9):1354-1366. DOI: 10.1158/1541-7786.MCR-19-1051. View

Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M . A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol. 2004; 25(3):571-8. View

Fujiwara Y, Oki T, HEIDELBERGER C . Fluorinated pyrimidines. XXXVII. Effects of 5-trifluoromethyl-2'-deoxyuridine on the synthesis of deoxyribonucleic acid of mammalian cells in culture. Mol Pharmacol. 1970; 6(3):273-80. View

Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H . Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep. 2015; 33(5):2135-42. PMC: 4391594. DOI: 10.3892/or.2015.3876. View

Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A . Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8 T cells in the tumor microenvironment. J Immunother Cancer. 2018; 6(1):106. PMC: 6186121. DOI: 10.1186/s40425-018-0403-1. View

Awasthi N, Schwarz M, Zhang C, Schwarz R . Augmentation of -Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models. Mol Cancer Ther. 2018; 17(11):2353-2364. PMC: 6215503. DOI: 10.1158/1535-7163.MCT-18-0489. View

Mayer R, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N . Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015; 372(20):1909-19. DOI: 10.1056/NEJMoa1414325. View

Pfeiffer P, Yilmaz M, Moller S, Zitnjak D, Krogh M, Petersen L . TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020; 21(3):412-420. DOI: 10.1016/S1470-2045(19)30827-7. View

10.

Castle J, Loewer M, Boegel S, de Graaf J, Bender C, Tadmor A . Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. BMC Genomics. 2014; 15:190. PMC: 4007559. DOI: 10.1186/1471-2164-15-190. View

11.

Komohara Y, Fujiwara Y, Ohnishi K, Takeya M . Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 2015; 99(Pt B):180-185. DOI: 10.1016/j.addr.2015.11.009. View

12.

Reyes P, HEIDELBERGER C . Fluorinated pyrimidines. XXVI. Mammalian thymidylate synthetase: its mechanism of action and inhibition by fluorinated nucleotides. Mol Pharmacol. 1965; 1(1):14-30. View

13.

Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau H, Prokharau A . Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018; 19(11):1437-1448. DOI: 10.1016/S1470-2045(18)30739-3. View

14.

Fujimoto Y, Nakanishi R, Nukatsuka M, Matsuoka K, Ando K, Wakasa T . Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil. Cancer Chemother Pharmacol. 2020; 85(6):1029-1038. DOI: 10.1007/s00280-020-04072-6. View

15.

Jain R . Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001; 7(9):987-9. DOI: 10.1038/nm0901-987. View

16.

Limagne E, Thibaudin M, Nuttin L, Spill A, Derangere V, Fumet J . Trifluridine/Tipiracil plus Oxaliplatin Improves PD-1 Blockade in Colorectal Cancer by Inducing Immunogenic Cell Death and Depleting Macrophages. Cancer Immunol Res. 2019; 7(12):1958-1969. DOI: 10.1158/2326-6066.CIR-19-0228. View

17.

Matsuoka K, Nakagawa F, Kobunai T, Takechi T . Trifluridine/tipiracil overcomes the resistance of human gastric 5-fluorouracil-refractory cells with high thymidylate synthase expression. Oncotarget. 2018; 9(17):13438-13450. PMC: 5862589. DOI: 10.18632/oncotarget.24412. View

18.

Hilberg F, Roth G, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U . BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008; 68(12):4774-82. DOI: 10.1158/0008-5472.CAN-07-6307. View

19.

Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y . Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. Biochem Pharmacol. 2000; 59(10):1227-36. DOI: 10.1016/s0006-2952(00)00253-7. View

20.

Zhao P, Wang Y, Kang X, Wu A, Yin W, Tang Y . Dual-targeting biomimetic delivery for anti-glioma activity remodeling the tumor microenvironment and directing macrophage-mediated immunotherapy. Chem Sci. 2018; 9(10):2674-2689. PMC: 5914428. DOI: 10.1039/c7sc04853j. View