Review ArticleReviewsR

TAS-102 an Emerging Oral Fluoropyrimidine

JIEZHONG CHEN, MEI HAN and MUHAMMAD WASIF SAIF
Anticancer Research January 2016, 36 (1) 21-26;

Abstract

Colon cancer is a common type of cancer with high mortality. The standard therapy for colon cancer is 5-FU-based regimen, although the current response rate to 5-FU is only 10-15%. Various approaches have been used to improve the efficacy of 5-FU including inhibition of its degradation enzyme dihydropyrimidine dehydrogenase (DPD) such as S1, UTF, use of 5-FU pro-drug capecitabine to exploit thymidine phosphorylase (TP) and supplementation of reduced folate acid to increase cytotoxicity. TAS-102 is a newly-developed anti-folate drug containing the 5-FU analogue trifluridine (TFD) and tipiracil hydrochloride (TPI). TPI is an inhibitor of TFD degradation enzyme thymidine phosphorylase and thus increases the bioavailability of TFD. In the present review, we summarize recent progress with regard to TAS-102, including pre-clinical tests and clinical trials. We further propose several approaches to further improve the efficacy of TAS-102 including combination with targeted therapy and immune therapy.

Colorectal cancer is the third most common cancer type in men and the second most common in women worldwide, and is responsible for a large proportion of cancer-related deaths (1). The current therapeutic approach is not satisfactory. The main therapeutic anticancer drug used for colon cancer is 5-fluorouracil (5-FU) (2). 5-FU is an analogue of pyrimidine, which can interfere with DNA and RNA synthesis and inhibit thymidylate synthase (TS) (3). However, the response rate to 5-FU is only 10-15%. Several strategies have been adopted to improve the efficacy of 5-FU including inhibition of its degradation enzyme dihydropyrimidine dehydrogenase (DPD), use of 5-FU prodrug capecitabine (Xeloda) (Roche; Genetech, San Francisco, CA, USA) to exploit thymidine phosphorylase (TP) and supplement reduced folate acid to increase cytotoxicity. In addition, 5-FU has been combined with other chemotherapeutic drugs including leucovorin and oxaliplatin or irinotecan (4). Although the regimen has an extended median survival to 30 months, drug resistance has been a major problem. Drug resistance is usually caused by blocking apoptosis, increased drug metabolism, drug target alterations and decreased ability to repair DNA damage (3, 5). Activation of survival signaling pathways such as the PI3K/Akt pathway reduces the apoptosis caused by chemotherapeurtic drugs (6, 7). In vitro experiments showed that activation of the PI3K/Akt pathway by insulin reduced efficacy of 5-FU while inhibition of the pathway increased cytotoxic effects of these drugs on colon cancer cells (8). Akt activation increased the levels of the protein called X-linked inhibitor of apoptosis protein (XIAP) to decrease apoptosis (9, 10). EGFR signaling pathway inhibitor bevacizumab or cetuximab has also been included in the regimen and shown to increase treatment efficacy (11-13).

The initial agent used for inhibition of DPD is uracil that is a natural substrate of DPD and can thus prevent 5-FU breakdown by competition (14). UFT consists of Ft (tegafur) (Merck Serono, Korea United and Taiho, mostly in Asia, Europe, South America, Central America and South Africa) combined with uracil in a 1:4 molar ratio. It was shown to show greater efficacy than Ft alone. Later, a more potent DPD inhibitor CDHP (5-chloro-2,4-dihydroxypyridine) was developed, whose efficacy is 200-fold that of uracil. This led to development of S1 that includes Ft, CDHP and OXO (potassium oxonate) at molar ratio of 1.0:0.4:1.0). OXO can reduce gastrointestinal side-effects (15, 16).

TAS-102 is a new formula developed by Taiho Oncology (Taiho Pharmaceutical Co., Ltd. Japan) that contains triflridine (TFD), an analogue of 5-FU and tipiracil hydrochloride (TPI), an inhibitor of TFD degradation enzyme thymidine phosphorylase (17). TAS-102 has been shown to significantly increase treatment efficacy. TAS-102 has been approved in Japan for refractory colorectal cancer and Taiho Oncology has launched application in USA. In the present review, we summarise most recent progress with regard to use of TAS-102 with emphasis in clinical trials and propose several approaches to further improve the efficacy of TAS-102.

Rationale

Chemically, TFD is a nucleotide analogue (5-trifluromethyl-2’-deoxyuridine) that can be incorporated into DNA, inhibiting DNA synthesis (Figure 1) (18). It also inhibits TS, which is necessary for the synthesis of deoxynucleotides. Decreased deoxynucleartides prevent DNA synthesis.

TFD is administered orally due to prolonged toxicity caused by i.v. injection (19). TFD is phosphorylated by thymidine kinase (TK) to TF-TMP, TF-TDP and TF-TTP. TF-TTP incorporated into DNA and cause DNA damage and cell deaths. TFD is catalyzed by thymidine phosphorylase (TP) into its inactive form.

TFD is rapidly degraded to its inactive form by TP, thus its efficacy is limited by its low bioavailability (20). TPI was invented to increase TFD bioavailability (21, 22). TPI can inhibit TP and thus increase the bioavailability of TFD. Different ratios of TFD to TPI have been tested and experiments showed that the ratio for the mixture at 1:0.5 reached the optimal efficacy (21, 22).

Pre-clinical Data

Single-agent studies. Both in vitro cell culture systems and in vivo animal experiments have been used to test the efficacy and toxicity of TAS-102 as well as the mechanisms of anti-tumor effects of TAS-102. The effectiveness of TAS-102 has been demonstrated in several xenograft mouse models (23-25). Tanaka et al. showed that TAS-102 increased median survival time of KM20C xenograft mice from 38 days to 70 days. The mechanism is due to FTD incorporation into DNA rather than inhibition of TS. Although both FTD and fluorodeoxyuridine (FdUrd) inhibited TS, washout experiments showed that the effect of FTD on TS was rapid while that of FdUrd persisted. The anti-tumor effect of TAS-102 is explained by decreased proliferation indicated by decreased Ki-67 and increased apoptosis indicated by observed swollen nuclei.

A recent study showed that TAS-102 caused hematological toxicity in a dose-dependent manner and this was in correlation with increased cytotoxicity to cancer cells (26). TFD can be also incorporated into blood cells and be the cause of side-effects. These side-effects limit the dosage of TAS-102 used clinically. Overcoming such side-effects will markedly increase treatment efficacy.

Combination Studies

In an animal model, TAS-102 has been tested in combination with irinotecan hydrochloride and showed promising results (27). In colorectal and gastric cancer xenograft-bearing nude mouse models (by KM12C, KM12C/5-FU, DLD-1/5-FU, and SC-2 cells respectively), combination of TAS-102 (orally administered twice a day from day 1 to 14), and irinotecan hydrochloride (administered intravenously on days 1 and 8) showed superior effect of tumor growth-inhibitory activity and RTV5 (period required to reach a tumor volume that was five-times greater than the initial volume) to TAS-102 or irinotecan hydrochloride as monotherapy.

Anti-EGFR antibodies bevacizumab, cetuximab and panitumumab have been shown to increase the efficacy of TAS-102 in a xenograft colon cancer mouse model (28). In a xenograft colorectal cancer model, the efficacy of TAS-102 was improved by combining it with bevacizumab, cetuximab or panitumumab. Combination use of TAS-102 (orally administered twice a day from day 1 to 14), and bevacizumab (administered intraperitoneally twice a week for 2 weeks) had a greater effect on tumor growth inhibition and longer RTV5 than those with TAS-102 or bevacizumab alone in the SW48 and HCT116 tumor models (28). It has also been revealed that the addition of anti-EGFR antibody increased the concentration of phosphorylated FTD in tumors compared to TAS-102 alone. There exist no clinical trials for combination therapy with TAS-102 and anti-EGFR antibodies.

Clinical Studies

Phase I. Phase I studies have been undertaken in both Japan and USA. In a phase I study, 21 Japanese patients were recruited for a dose escalation study from 30 to 70 mg/m2 per day (29). TAS-102 was administered orally twice daily on days 1-5 and 8-12 in a 28-day cycle. The treatment reached 50% disease control and median progression-free survival of 2.4 months. The side-effect is neutropenia grade 4 in a dose-dependent fashion. Two out of 21 patients had side-effects. In a USA study, Hong et al. tested TAS-102 in 14 patients and found that 50 mg/m2/day were tolerated (30). Several other phase I studies have been also performed, showing promising outcomes (31-33).

Hong et al. studied the pharmacokinectics of TAS-102 using repeating treatment course of oral administration once daily for 14 days followed by 7 days of rest (30). The initial dosage used was 100 mg/m2/day, that caused severe side-effects of grade 3 or 4 in course 1 in two out of 14 patients. Therefore, the dosage was adjusted to 50 mg/m2/day, in which no side-effect occurred and this dosage was identified as dose-limiting toxicity, as elevation of dosage to 60 mg/m2/day resulted in severe side-effects. FTD's Tmax was identified to be 0.506-1.33 h. T1/2 was 1.37-1.55 h. Approximately 1.0% to 16.7% of FTD in urine was not metabolized.

Figure 1.
Figure 1.

TFD can be converted into TF-TTP which incorporates into DNA to cause DNA damage. It can also inhibit TS to block deoxynucleotide synthesis. TFD is degraded into TF-thy by TP, which can be inhibited by TPI. TFD, Trifluridine; TF-TTP, Phosphorylated form of trifluridine; TS, thymidylate synthase; TF-thy, trifluorothymine; TP, thymidine phosphorylase; TPI, thymidine phosphorylase inhibitor.

In a phase I combination study for TAS-102 and irinotecan, 7 patients were treated with 50 mg/m2/day of TAS-102 plus 150 mg/m2 irinotecan and 3 patients treated with 60 mg/m2/day of TAS-102 plus 150 mg/m2 irinotecan (34). The later regimen showed severe side-effects including neutropenia, leukopenia, lymphopenia and anaemia. In terms of efficacy, 2 patients had partial responses. The pharmacokinectics of TAS-102 are not affected by irinotecan. Although the recommendation dose was identified as 50 mg/m2/day of TAS-102 plus 150 mg/m2 irinotecan, further studies with much higher number of patients are required. Doi et al. tried another dose for TAS-102 in a phase I study (29). It used 35 mg/m2 twice daily for 5 days and had 2 days for rest. This was then followed by another cycle then 14 days of rest. This approach increased the dosage to be used but not inducing severe adverse effects.

Phase II. Based on phase I studies, a phase II clinical trial was undertaken, performed in Japan with 169 colorectal cancer patients being recruited. The selected patients had a history with treatment of 2 or 3 regimens of chemotherapy and became resistant to fluoropyrimidine, irinotecan and oxaliplatin (35). The median survival was reported to be 9.0 months compared to 6.6 months in the placebo group. It has been reported that approximately 50% of patients (57 out of 113) had a side-effect of neutropenia at grade 3 or 4 while leucopenia and anaemia accounting for 20% and 17%.

Phase III. Recently, a phase III clinical trial was conducted and its results were reported (36). The double-blind trial was carried-out in multi-centres worldwide. As many as 800 patients were recruited. These patients were randomly selected for the TAS-102 treatment or for placebo. The patients were treated with TAS-102 at a dosage of 35 mg/m2 or placebo twice daily for 5 days followed by 2 days of rest. This was repeated once followed by 2 weeks of rest. The results showed that median overall survival increased from 5.3 months to 7.1 months (36). The side-effects included neutropenia (38%), leukopenia (21%), febrile neutropenia (4%). Although survival time was only extended by 2 months, the result is very promising (37, 38).

Ongoing Studies

At present, 12 clinical trials for TAS-102 are ongoing (https://clinicaltrials.gov/ct2/results?term=TAS-102). TAS-102 will be tested for solid tumors including metastatic colorectal cancer. It will also be tested in various conditions including hepatic and renal impairment as well as resistance to standard chemotherapy. Future studies should include combination of TAS-102 with inhibitors or antibodies used for targeted therapy.

Toxicities and Differences from S-1, Xeloda and UFT

The toxicity of TAS-102 is mild that can be solved by reducing dosage or short disruption. The main adverse effect of TAS-102 is bone marrow suppression. A study showed that neutropenia caused 22% patients to have one dose reduction while 31% patients to have a treatment interruption (35). Grade 3 or 4 neutropenia occurred in 50% of patients treated with TAS-102. Other haematological adverse effects included leucopenia (28%), anaemia (17%), lymphopenia (10%) and thrombocytopenia (4%). Non-haematological adverse effects were also found in low frequencies including fatigue (6%), diarrhea (6%), nausea (4%), anorexia (4%), febrile neutropenia (4%) and vomiting (4%). No grade 3 or 4 hand-foot syndrome and peripheral neuropathy were found. Hand-foot syndrome is a common adverse effect of xeloda. It was reported that xeloda caused 18.1% of this syndrome. Another adverse effect of xeloda was diarrhea, that occurred in 15.4 of patients (39).

TAS-102 A study showed that FTD's Tmax was identified to be 0.506 to 1.33 h (30). Mean T1/2 was 1.37-1.55 h. Approximately 1.0% to 16.7% of FTD in urine was not metabolized.

Discussion

Although TAS-102 has been shown to increase median survival rate by 2 months in the phase III clinical trial, further improvement of treatment efficacy is necessary for cancer patients. Several approaches are likely to increase TAS-102 efficacy dramatically including combination use with targeted therapy agents, combination with immunotherapy and nano-delivery of TAS-102 or TAS-102-based combination therapeutic agents.

Although the activation of signaling pathway has not been studied for drug resistance to TAS-102, activation of many signaling pathways has been shown to decrease the effects of 5-FU (3, 41). PI3K/Akt pathway is well-known to play key roles in carcinogenesis, metastasis and drug resistance in many cancers including colorectal cancer (42-47). Therefore, inhibition of the pathway has been extensively tested for treatment of cancer (48, 49). Activation of the PI3K/Akt has been shown to increase drug resistance in colon cancer cell lines and inhibition of that pathway increased the sensitivity of colon cancer cells to 5-FU and other chemotherapeutic agents (6, 8, 50). Activation of NF-kB pathway is also well-known to cause drug resistance to chemotherapeutic agents in cancer treatment (51, 52). In view of the important role of EGFR in colorectal cancer, antibodies against EGFR have been used clinically, a fact taken place in combination with 5-FU (53-55). The roles of these pathways in treatment efficacy of TAS-102 could be studied and thus combination therapy of TAS-102 with targeted therapy can be developed.

TAS-102 may be used together with immunotherapy in colorectal cancer. It is now realized that immune responses play key roles in anticancer treatment. Activated T-cells can kill cancer cells directly. However, cancer cells including colorectal cancer cells have developed an immune escape ability through increased expression of inhibitory molecules such as programmed death-ligand 1 (PD-L1) (56, 57). PD-L1 binds to programmed death-1 (PD-1) on T-cells, leading to T-cell dysfunction and apoptosis (58, 59). Anti-PD-L1/PD-1 antibodies have been developed to inhibit PD-L1/PD-1 to activate T-cells, showing effectiveness in a proportion of patients in clinical trials (60-62). Therefore, it is possible to combine TAS-102 with anti-PD-L1 or PD-1 antibody to further improve the efficacy of TAS-102.

Conclusion

TAS, although only by two months, has significantly increased median survival time. The mechanism lies in DNA synthesis damage rather than TS inhibition. Further improvement may include combination use with signaling molecule inhibitors and anti-PD-L1/PD-1 antibodies.

  • Received September 15, 2015.
  • Revision received November 5, 2015.
  • Accepted December 7, 2015.

References

  1. ↵
    1. Torre LA,
    2. Bray F,
    3. Siegel RL,
    4. Ferlay J,
    5. Lortet-Tieulent J,
    6. Jemal A
    : Global cancer statistics, 2012. CA: a cancer journal for clinicians 65(2): 87-108. 2015.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Hurwitz H,
    2. Fehrenbacher L,
    3. Novotny W,
    4. Cartwright T,
    5. Hainsworth J,
    6. Heim W,
    7. Berlin J,
    8. Baron A,
    9. Griffing S,
    10. Holmgren E,
    11. Ferrara N,
    12. Fyfe G,
    13. Rogers B,
    14. Ross R,
    15. Kabbinavar F
    : Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23): 2335-2342, 2004.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Longley DB,
    2. Harkin DP,
    3. Johnston PG
    : 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 3(5): 330-338, 2003.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Goldberg RM,
    2. Sargent DJ,
    3. Morton RF,
    4. Fuchs CS,
    5. Ramanathan RK,
    6. Williamson SK,
    7. Findlay BP,
    8. Pitot HC,
    9. Alberts S
    : A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1): 23-30, 2004.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Chen C,
    2. Chen J,
    3. Zhao K-N
    . Editorial (Thematic Issue: Signalling Pathways in Anti-cancer Drug Resistance). Curr Med Chem 21(26): 3007-3008, 2004.
    OpenUrl
  6. ↵
    1. West KA,
    2. Castillo SS,
    3. Dennis PA
    : Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat 5(6): 234-48, 2002.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Lee S,
    2. Choi E-J,
    3. Jin C,
    4. Kim DH
    : Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 97(1): 26-34, 2005.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Chen J,
    2. Katsifis A,
    3. Hu C,
    4. Huang XF
    : Insulin decreases therapeutic efficacy in colon cancer cell line HT29 via the activation of the PI3K/Akt pathway. Curr Drug Discov Technol 8(2): 119-25, 2011.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Dan HC,
    2. Sun M,
    3. Kaneko S,
    4. Feldman RI,
    5. Nicosia SV,
    6. Wang HG,
    7. Tsang BK,
    8. Cheng JQ
    : Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem 279(7): 5405-5412, 2004.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Shrader M,
    2. Pino MS,
    3. Lashinger L,
    4. Bar-Eli M,
    5. Adam L,
    6. Dinney CP,
    7. McConkey DJ
    : Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKT-mediated X-linked inhibitor of apoptosis protein expression. Cancer Res 67(4): 1430-1435, 2007.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Giantonio BJ,
    2. Catalano PJ,
    3. Meropol NJ,
    4. O'Dwyer PJ,
    5. Mitchell EP,
    6. Alberts SR,
    7. Schwartz MA,
    8. Benson AB 3rd.,
    9. Eastern Cooperative Oncology Group Study E3200
    : Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12): 1539-1544, 2007.
    OpenUrlAbstract/FREE Full Text
    1. Saltz LB,
    2. Clarke S,
    3. Díaz-Rubio E,
    4. Scheithauer W,
    5. Figer A,
    6. Wong R,
    7. Koski S,
    8. Lichinitser M,
    9. Yang TS,
    10. Rivera F,
    11. Couture F,
    12. Sirzén F,
    13. Cassidy J
    : Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12): 2013-2019, 2008.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Sobrero AF,
    2. Maurel J,
    3. Fehrenbacher L,
    4. Scheithauer W,
    5. Abubakr YA,
    6. Lutz MP,
    7. Vega-Villegas ME,
    8. Eng C,
    9. Steinhauer EU,
    10. Prausova J,
    11. Lenz HJ,
    12. Borg C,
    13. Middleton G,
    14. Kröning H,
    15. Luppi G,
    16. Kisker O,
    17. Zubel A,
    18. Langer C,
    19. Kopit J,
    20. Burris HA 3rd.
    . EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. JClin Oncol 26(14): 2311-2319, 2008.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. De Bruin M,
    2. Temmink OH,
    3. Hoekman K,
    4. Pinedo HM,
    5. Peters GJ
    : Role of platelet derived endothelial cell growth factor/thymidine phosphorylase in health and disease. Cancer Ther 4: 99-124, 2006.
    OpenUrl
  15. ↵
    1. Sanford M
    : S-1 (Teysuno®): a review of its use in advanced gastric cancer in non-asian populations. Drugs 73(8): 845-855, 2013.
    OpenUrlPubMed
  16. ↵
    1. Miyamoto Y,
    2. Sakamoto Y,
    3. Yoshida N,
    4. Baba H
    : Efficacy of S-1 in colorectal cancer. Expert Opin Pharmacother 15(12): 1761-1770, 2014.
    OpenUrlPubMed
  17. ↵
    1. Utsugi T
    : New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol 43(10): 945-953, 2013.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Temmink OH,
    2. Emura T,
    3. De Bruin M,
    4. Fukushima M,
    5. Peters GJ
    : Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci 98(6): 779-789, 2007.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Ansfield FJ,
    2. Ramirez G
    : Phase I and II studies of 2’-deoxy-5-(trifluoromethyl)-uridine (NSC-75520). Cancer Chemother Rep Part 1 55(2): 205, 1971.
    OpenUrlPubMed
  20. ↵
    1. Dexter DL,
    2. Wolberg WH,
    3. Ansfield FJ,
    4. Helson L,
    5. Heidelberger C
    : The clinical pharmacology of 5-trifluoromethyl-2’-deoxyuridine. Cancer Res 32(2): 247-253, 1972.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Fukushima M,
    2. Suzuki N,
    3. Emura T,
    4. Yano S,
    5. Kazuno H,
    6. Tada Y,
    7. Yamada Y,
    8. Asao T
    . Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2’-deoxyribonucleosides. Biochem Pharmacol 59(10): 1227-1236, 2000.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Emura T,
    2. Suzuki N,
    3. Fujioka A,
    4. Ohshimo H,
    5. 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(2): 449-455, 2005.
    OpenUrlPubMed
  23. ↵
    1. Tanaka N,
    2. Sakamoto K,
    3. Okabe H,
    4. Fujioka A,
    5. Yamamura K,
    6. Nakagawa F,
    7. Nagase H,
    8. Yokogawa T,
    9. Oguchi K,
    10. Ishida K,
    11. Osada A,
    12. Kazuno H,
    13. Yamada Y,
    14. Matsuo K
    : 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, 2014.
    OpenUrlCrossRefPubMed
    1. Emura T,
    2. Murakami Y,
    3. Nakagawa F,
    4. Fukushima M,
    5. Kitazato K
    : A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. IntJMol Med 13(4): 545-549, 2004.
    OpenUrl
  25. ↵
    1. Emura T,
    2. Suzuki N,
    3. Yamaguchi M,
    4. Ohshimo H,
    5. 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. IntJ Oncol 25(3): 571-578, 2004.
    OpenUrl
  26. ↵
    1. Yamashita F,
    2. Komoto I,
    3. Oka H,
    4. Kuwata K,
    5. Takeuchi M,
    6. Nakagawa F,
    7. Yoshisue K,
    8. Chiba M
    : Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse. Cancer Chemother Pharmacol 76(2): 325-333, 2015.
    OpenUrlPubMed
  27. ↵
    1. Nukatsuka M,
    2. Nakagawa F,
    3. Saito H,
    4. Sakata M,
    5. Uchida J,
    6. Takechi T
    : Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Irinotecan Hydrochloride on Human Colorectal and Gastric Cancer Xenografts. Anticancer Res 35(3): 1437-1445, 2015.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Tsukihara H,
    2. Nakagawa F,
    3. Sakamoto K,
    4. Ishida K,
    5. Tanaka N,
    6. Okabe H,
    7. Uchida J,
    8. Matsuo K,
    9. Takechi T
    : 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 33(5): 2135-2142, 2015.
    OpenUrlPubMed
  29. ↵
    1. Doi T,
    2. Ohtsu A,
    3. Yoshino T,
    4. Boku N,
    5. Onozawa Y,
    6. Fukutomi A,
    7. Hironaka S,
    8. Koizumi W,
    9. Sasaki T
    : Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours. Br J Cancer 107(3): 429-434, 2012.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Hong DS,
    2. Abbruzzese JL,
    3. Bogaard K,
    4. Lassere Y,
    5. Fukushima M,
    6. Mita A,
    7. Kuwata K,
    8. Hoff PM
    : Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer 107(6): 1383-1390, 2006.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Overman MJ,
    2. Kopetz S,
    3. Varadhachary G,
    4. Fukushima M,
    5. Kuwata K,
    6. Mita A,
    7. et al
    . Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest 26(8): 794-799, 2008.
    OpenUrlCrossRefPubMed
    1. Overman MJ,
    2. Varadhachary G,
    3. Kopetz S,
    4. Thomas MB,
    5. Fukushima M,
    6. Kuwata K,
    7. Wolff RA,
    8. Hoff P,
    9. Xiong H,
    10. Abbruzzese JL
    : Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Investigational new drugs 26(5): 445-454, 2008.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Green M,
    2. Pusztai L,
    3. Theriault R,
    4. Adinin R,
    5. Hofweber M,
    6. Fukushima M,
    7. Mita A,
    8. Bindra N,
    9. Hortobagyi GN
    : Phase I study to determine the safety of oral administration of TAS-102 on a twice daily (BID) schedule for five days a week (wk) followed by two days rest for two wks, every (Q) four wks in patients (pts) with metastatic breast cancer (MBC). ASCO Annual Meeting Proceedings; 2006.
  34. ↵
    1. Doi T,
    2. Yoshino T,
    3. Fuse N,
    4. Boku N,
    5. Yamazaki K,
    6. Koizumi W,
    7. Shimada K,
    8. Takinishi Y,
    9. Ohtsu A
    : Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer. Invest New Drugs 1-10, 2015.
  35. ↵
    1. Yoshino T,
    2. Mizunuma N,
    3. Yamazaki K,
    4. Nishina T,
    5. Komatsu Y,
    6. Baba H,
    7. Tsuji A,
    8. Yamaguchi K,
    9. Muro K,
    10. Sugimoto N,
    11. Tsuji Y,
    12. Moriwaki T,
    13. Esaki T,
    14. Hamada C,
    15. Tanase T,
    16. Ohtsu A
    : TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 13(10): 993-1001, 2012.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Mayer RJ,
    2. Van Cutsem E,
    3. Falcone A,
    4. Yoshino T,
    5. Garcia-Carbonero R,
    6. Mizunuma N,
    7. Yamazaki K,
    8. Shimada Y,
    9. Tabernero J,
    10. Komatsu Y,
    11. Sobrero A,
    12. Boucher E,
    13. Peeters M,
    14. Tran B,
    15. Lenz HJ,
    16. Zaniboni A,
    17. Hochster H,
    18. Cleary JM,
    19. Prenen H,
    20. Benedetti F,
    21. Mizuguchi H,
    22. Makris L,
    23. Ito M,
    24. Ohtsu A,
    25. RECOURSE Study Group
    : Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. New Engl J Med 372(20): 1909-1919, 2015.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Cleghorn S
    : TAS-102 for metastatic refractory colorectal cancer. Lancet Oncol 16(7): e314, 2015.
    OpenUrl
  38. ↵
    1. Mayor S
    : TAS-102 prolongs overall survival in refractory colorectal cancer, study shows. BMJ 350: h2620, 2015.
    OpenUrlFREE Full Text
  39. ↵
    1. Hoff PM,
    2. Ansari R,
    3. Batist G,
    4. Cox J,
    5. Kocha W,
    6. Kuperminc M,
    7. Maroun J,
    8. Walde D,
    9. Weaver C,
    10. Harrison E,
    11. Burger HU,
    12. Osterwalder B,
    13. Wong AO,
    14. Wong R
    . Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19(8): 2282-2292, 2001.
    OpenUrlAbstract/FREE Full Text
    1. Roxburgh P,
    2. Lumsden GR,
    3. Paul J,
    4. Harden S,
    5. Sweeting L,
    6. James A,
    7. Crellin A,
    8. Morrison R,
    9. Evans TR,
    10. McDonald AC
    : A phase I and pharmacokinetic study of capecitabine in combination with radiotherapy in patients with localised inoperable pancreatic cancer. Cancer Chemother Pharmacol 74(1): 131-139, 2014.
    OpenUrlPubMed
  41. ↵
    1. Akao Y,
    2. Noguchi S,
    3. Iio A,
    4. Kojima K,
    5. Takagi T,
    6. Naoe T
    : Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells. Cancer Lett 300(2): 197-204, 2011.
    OpenUrlCrossRefPubMed
  42. ↵
    1. Hirai H,
    2. Sootome H,
    3. Nakatsuru Y,
    4. Miyama K,
    5. Taguchi S,
    6. Tsujioka K,
    7. Ueno Y,
    8. Hatch H,
    9. Majumder PK,
    10. Pan BS,
    11. Kotani H
    : MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 9(7): 1956-1967, 2010.
    OpenUrlAbstract/FREE Full Text
    1. Vara JÁF,
    2. Casado E,
    3. de Castro J,
    4. Cejas P,
    5. Belda-Iniesta C,
    6. González-Barón M
    : PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2): 193-204, 2004.
    OpenUrlCrossRefPubMed
    1. Chang F,
    2. Lee J,
    3. Navolanic P,
    4. Steelman L,
    5. Shelton J,
    6. Blalock W,
    7. Franklin RA,
    8. McCubrey JA
    : Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 17(3): 590-603, 2003.
    OpenUrlCrossRefPubMed
    1. Garcia-Echeverria C,
    2. Sellers W
    : Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27(41): 5511-5526, 2008.
    OpenUrlCrossRefPubMed
    1. Chen J
    . Signaling pathways in HPV-associated cancers and therapeutic implications. Rev Med Virol 25(S1): 24-53, 2015.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Doorbar J,
    2. Egawa N,
    3. Griffin H,
    4. Kranjec C,
    5. Murakami I
    . Human papillomavirus molecular biology and disease association. Rev Med Virol 25(S1): 2-23, 2015.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Hennessy BT,
    2. Smith DL,
    3. Ram PT,
    4. Lu Y,
    5. Mills GB
    . Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Rev Drug Discov 4(12): 988-1004, 2005.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Luo J,
    2. Manning BD,
    3. Cantley LC
    : Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4): 257-262, 2003.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Chen J,
    2. Huang XF,
    3. Qiao L,
    4. Katsifis A
    : Insulin caused drug resistance to oxaliplatin in colon cancer cell line HT29. J Gastrointest Oncol 2(1): 27, 2011.
    OpenUrlPubMed
  51. ↵
    1. Nakanishi C,
    2. Toi M
    : Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nature Rev Cancer 5(4): 297-309, 2005.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Yang HY,
    2. Zhao L,
    3. Yang Z,
    4. Zhao Q,
    5. Qiang L,
    6. Ha J,
    7. Li ZY,
    8. You QD,
    9. Guo QL
    : Oroxylin a reverses multi-drug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-κB signaling pathway. Mol Carcinog 51(2): 185-195, 2012.
    OpenUrlPubMed
  53. ↵
    1. Hecht JR,
    2. Mitchell E,
    3. Chidiac T,
    4. Scroggin C,
    5. Hagenstad C,
    6. Spigel D,
    7. Marshall J,
    8. Cohn A,
    9. McCollum D,
    10. Stella P,
    11. Deeter R,
    12. Shahin S,
    13. Amado RG
    : A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27(5): 672-680, 2009.
    OpenUrlAbstract/FREE Full Text
    1. Zhang W,
    2. Gordon M,
    3. Lenz HJ
    : Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. Ann Med 38(8): 545-551, 2006.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Los M,
    2. Roodhart JM,
    3. Voest EE
    : Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 12(4): 443-450, 2007.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. Keir ME,
    2. Butte MJ,
    3. Freeman GJ,
    4. Sharpe AH
    : PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26: 677-704, 2008.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Topalian SL,
    2. Drake CG,
    3. Pardoll DM
    : Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24(2): 207-212, 2012.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Ribas A
    : Tumor immunotherapy directed at PD-1. N Engl J Med 366(26): 2517-2519, 2012.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Blank C,
    2. Mackensen A
    . Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol, Immunother 56(5): 739-45, 2007.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Lipson EJ,
    2. Sharfman WH,
    3. Drake CG,
    4. Wollner I,
    5. Taube JM,
    6. Anders RA,
    7. Xu H,
    8. Yao S,
    9. Pons A,
    10. Chen L,
    11. Pardoll DM,
    12. Brahmer JR,
    13. Topalian SL
    : Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19(2): 462-468, 2013.
    OpenUrlAbstract/FREE Full Text
    1. Topalian SL,
    2. Hodi FS,
    3. Brahmer JR,
    4. Gettinger SN,
    5. Smith DC,
    6. McDermott DF,
    7. Powderly JD,
    8. Carvajal RD,
    9. Sosman JA,
    10. Atkins MB,
    11. Leming PD,
    12. Spigel DR,
    13. Antonia SJ,
    14. Horn L,
    15. Drake CG,
    16. Pardoll DM,
    17. Chen L,
    18. Sharfman WH,
    19. Anders RA,
    20. Taube JM,
    21. McMiller TL,
    22. Xu H,
    23. Korman AJ,
    24. Jure-Kunkel M,
    25. Agrawal S,
    26. McDonald D,
    27. Kollia GD,
    28. Gupta A,
    29. Wigginton JM,
    30. Sznol M
    : Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. New Engl J Med 366(26): 2443-2454, 2012.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Hirano F,
    2. Kaneko K,
    3. Tamura H,
    4. Dong H,
    5. Wang S,
    6. Ichikawa M,
    7. Rietz C,
    8. Flies DB,
    9. Lau JS,
    10. Zhu G,
    11. Tamada K,
    12. Chen L
    : Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65(3): 1089-1096, 2005.
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
TAS-102 an Emerging Oral Fluoropyrimidine
JIEZHONG CHEN, MEI HAN, MUHAMMAD WASIF SAIF
Anticancer Research Jan 2016, 36 (1) 21-26;
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords