Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts

Tsukihara,Hiroshi; Nakagawa,Fumio; Sakamoto,Kazuki; Ishida,Keiji; Tanaka,Nozomu; Okabe,Hiroyuki; Uchida,Junji; Matsuo,Kenichi; Takechi,Teiji

doi:10.3892/or.2015.3876

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts

Authors:
- Hiroshi Tsukihara
- Fumio Nakagawa
- Kazuki Sakamoto
- Keiji Ishida
- Nozomu Tanaka
- Hiroyuki Okabe
- Junji Uchida
- Kenichi Matsuo
- Teiji Takechi
View Affiliations

Affiliations: Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan, Applied Pharmacology Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo, Tsukuba, Ibaraki 300-2611, Japan
Published online on: March 23, 2015 https://doi.org/10.3892/or.2015.3876
Pages: 2135-2142
Copyright: © Tsukihara et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

TAS-102 is a novel oral nucleoside antitumor agent that consists of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5, and was approved in Japan in March 2014 for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. In the present study, we used colorectal cancer xenografts to assess whether the efficacy of TAS-102 could be improved by combining it with bevacizumab, cetuximab or panitumumab. TAS-102 was orally administered twice a day from day 1 to 14, and bevacizumab, cetuximab and panitumumab were administered intraperitoneally twice a week for 2 weeks. Growth inhibitory activity was evaluated based on the relative tumor volume (RTV) after 2 weeks of drug administration and time taken for the relative tumor volume to increase five-fold (RTV5). Tumor growth inhibition and RTV5 with TAS-102 and bevacizumab combination treatment were significantly better than those with TAS-102 or bevacizumab alone in the SW48 and HCT116 tumor models, and the concentration of phosphorylated FTD in tumors determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was higher in the TAS-102 and bevacizumab combination group than in the TAS-102 monotherapy group. The combination of TAS-102 and cetuximab or panitumumab was also significantly more effective than either monotherapy in the SW48 tumor model. There was no significant difference in the body weight between the mice treated with TAS-102 monotherapy and any of the combination therapies on day 29. Our preclinical findings indicate that the combination therapy of TAS-102, bevacizumab and cetuximab or panitumumab is a promising treatment option for colorectal cancer.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
2	Armand JP, Ducreux M, Mahjoubi M, Abigerges D, Bugat R, Chabot G, Herait P, de Forni M and Rougier P: CPT-11 (irinotecan) in the treatment of colorectal cancer. Eur J Cancer. 31A:1283–1287. 1995. View Article : Google Scholar : PubMed/NCBI
3	Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol. 26:2013–2019. 2008. View Article : Google Scholar : PubMed/NCBI
4	Sobrero AF, Maurel J, Fehrenbacher L, et al: EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 26:2311–2319. 2008. View Article : Google Scholar : PubMed/NCBI
5	Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 25:1658–1664. 2007. View Article : Google Scholar : PubMed/NCBI
6	Grothey A, Van Cutsem E, Sobrero A, et al: CORRECT Study Group: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 381:303–312. 2013. View Article : Google Scholar
7	Emura T, Nakagawa F, Fujioka A, Ohshimo H, Yokogawa T, Okabe H and Kitazato K: 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. 13:249–255. 2004.PubMed/NCBI
8	Dexter DL, Wolberg WH, Ansfield FJ, Helson L and Heidelberger C: The clinical pharmacology of 5-trifluoromethyl-2′-deoxyuridine. Cancer Res. 32:247–253. 1972.PubMed/NCBI
9	Tanaka N, Sakamoto K, Okabe H, et al: Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep. 32:2319–2326. 2014.PubMed/NCBI
10	Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, Yamada Y and Asao T: Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides. Biochem Pharmacol. 59:1227–1236. 2000. View Article : Google Scholar : PubMed/NCBI
11	Emura T, Suzuki N, Fujioka A, Ohshimo H and Fukushima M: Potentiation of the antitumor activity of α, α, α-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo. Int J Oncol. 27:449–455. 2005.PubMed/NCBI
12	Emura T, Suzuki N, Yamaguchi M, Ohshimo H and 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. 25:571–578. 2004.PubMed/NCBI
13	Emura T, Murakami Y, Nakagawa F, Fukushima M and Kitazato K: A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med. 13:545–549. 2004.PubMed/NCBI
14	Murakami Y, Kazuno H, Emura T, Tsujimoto H, Suzuki N and Fukushima M: Different mechanisms of acquired resistance to fluorinated pyrimidines in human colorectal cancer cells. Int J Oncol. 17:277–283. 2000.PubMed/NCBI
15	Utsugi T: New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol. 43:945–953. 2013. View Article : Google Scholar : PubMed/NCBI
16	Yoshino T, Mizunuma N, Yamazaki K, et al: TAS-102 monotherapy for pretreated metastatic colorectal cancer: A double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 13:993–1001. 2012. View Article : Google Scholar : PubMed/NCBI
17	Yoshino T, Mayer R, Falcon A, et al: RECOURSE study group: Results of a multicenter, randomized, double-blind, phase III study of TAS-102 vs. placebo, with best supportive care (BSC), in patients (pts) with metastatic colorectal cancer (MCRC) refractory to standard therapies (RECOURSE). Ann Oncol. 25(Suppl 2): 1–117. 2014. View Article : Google Scholar
18	Welch S, Spithoff K, Rumble RB and Maroun J; Gastrointestinal Cancer Disease Site Group: Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: A systematic review. Ann Oncol. 21:1152–1162. 2010. View Article : Google Scholar
19	Van Cutsem E, Köhne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 360:1408–1417. 2009. View Article : Google Scholar : PubMed/NCBI
20	Bokemeyer C, Bondarenko I, Makhson A, et al: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 27:663–671. 2009. View Article : Google Scholar
21	Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 28:4697–4705. 2010. View Article : Google Scholar : PubMed/NCBI
22	Dunn EF, Iida M, Myers RA, Campbell DA, Hintz KA, Armstrong EA, Li C and Wheeler DL: Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. Oncogene. 30:561–574. 2011. View Article : Google Scholar :
23	Nukatsuka M, Saito H, Nakagawa F, Tsujimoto H, Sakamoto K, Tsukioka S, Uchida J, Kiniwa M, Kobunai T and Takechi T: Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice. Exp Ther Med. 3:755–762. 2012.PubMed/NCBI
24	Balin-Gauthier D, Delord JP, Rochaix P, Mallard V, Thomas F, Hennebelle I, Bugat R, Canal P and Allal C: In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. Cancer Chemother Pharmacol. 57:709–718. 2006. View Article : Google Scholar
25	Bauer P, Röhmel J, Maurer W and Hothorn L: Testing strategies in multi-dose experiments including active control. Stat Med. 17:2133–2146. 1998. View Article : Google Scholar : PubMed/NCBI
26	Shelton JW, Waxweiler TV, Landry J, Gao H, Xu Y, Wang L, El-Rayes B and Shu HK: In vitro and in vivo enhancement of chemoradiation using the oral PARP inhibitor ABT-888 in colorectal cancer cells. Int J Radiat Oncol Biol Phys. 86:469–476. 2013. View Article : Google Scholar : PubMed/NCBI
27	Price TJ, Hardingham JE, Lee Ck, et al: 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. 29:2675–2682. 2011. View Article : Google Scholar : PubMed/NCBI
28	Kim ST, Park KH, Shin SW and Kim YH: Dose KRAS mutation status affect on the effect of VEGF therapy in metastatic colon cancer patients? Cancer Res Treat. 46:48–54. 2014. View Article : Google Scholar : PubMed/NCBI
29	Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 7:987–989. 2001. View Article : Google Scholar : PubMed/NCBI