Publications by authors named "Fumio Nakagawa"

44 Publications

Aggressive Intraoperative Cisternal Clot Removal After Clipping Aneurismal Subarachnoid Hemorrhage in Elderly Patients.

World Neurosurg 2021 Mar 29;147:e482-e490. Epub 2020 Dec 29.

Department of Neurosurgery, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) in the elderly often has a poor prognosis even after surgical treatment in the acute phase. Additionally, subarachnoid clots are the strongest predictors of cerebral vasospasm and tend to be thicker and heavier due to cerebral atrophy. We aimed to compare the conventional surgical treatment in such patients and identify the independent predictors of a favorable outcome after aggressive surgical clot removal.

Methods: We included 40 patients with aSAH aged 70 or older. Each patient underwent aneurysmal clipping. We used the modified Rankin Scale to assess the primary outcome of neurologic status at discharge. We performed univariate analysis using the following factors: sex, age, neurologic, and general medical condition, radiographic data, aneurysm location, treatment approach, and timing of the aneurysm surgery. We divided the patients into irrigation and nonirrigation groups. We focused mainly on subarachnoid clots and analyzed them semiquantitatively using computed tomography.

Results: Clot removal was significantly greater in the irrigation group (n = 21) than in the nonirrigation group (n = 19). The period of intrathecal drainage was significantly shorter in the irrigation group (P = 0.002). The rate of occurrence of new low-density areas on CT scans was higher in the nonirrigation group. Outcomes were better in the irrigation group (P = 0.010).

Conclusions: In elderly patients with aSAH in the acute phase, aggressive surgical clot removal after clipping showed favorable outcomes by facilitating early out-of-bed mobilization.
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http://dx.doi.org/10.1016/j.wneu.2020.12.102DOI Listing
March 2021

Acquired resistance to trastuzumab/pertuzumab or to T-DM1 in vivo can be overcome by HER2 kinase inhibition with TAS0728.

Cancer Sci 2020 Jun 30;111(6):2123-2131. Epub 2020 Apr 30.

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

HER2-targeting antibodies (trastuzumab, pertuzumab) and a HER2-directed antibody-drug conjugate (trastuzumab emtansine: T-DM1) are used for the treatment of HER2-overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small-molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T-DM1 for evaluating the effect of TAS0728 on HER2 antibody-resistant populations. Treatment with trastuzumab and pertuzumab or with T-DM1 initially induced tumor regression in NCI-N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T-DM1, HER2-HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti-tumor effect associated with HER2-HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient-derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T-DM1, TAS0728 exerted a potent anti-tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T-DM1 are still dependent on oncogenic HER2-HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti-HER2 therapies.
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http://dx.doi.org/10.1111/cas.14407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293079PMC
June 2020

Modification of TRPV4 activity by acetaminophen.

Heliyon 2020 Jan 31;6(1):e03301. Epub 2020 Jan 31.

Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, 803-8580, Japan.

-Acetyl-p-aminophenol (APAP/acetaminophen) is a widely used analgesic/antipyretic with weaker inhibitory effects on cyclooxygenase compared to those of non-steroidal anti-inflammatory drugs. The effect of APAP is mediated by its metabolites, -arachidonoyl-phenolamine and -acetyl--benzoquinone imine, which activate transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or cannabinoid receptor type 1. However, the exact molecular mechanism underlying the cellular actions of APAP remains unclear. Recently, we observed that APAP promotes cell migration through TRPV4; in this study, we examined the effect of APAP on Ca-channel activity of TRPV4. In the rat cell line PC12 expressing TRPV4, GSK1016790A (GSK), a TRPV4 agonist, stimulated an increase in [Ca]; these effects were abrogated by HC-067047 treatment. This GSK-induced Ca entry through TRPV4 was inhibited by APAP in a dose-dependent manner, whereas APAP alone did not affect [Ca]. The specificity of the effect of APAP on TRPV4 was further confirmed using HeLa cells, which lack endogenous TRPV4 but stably express exogenous TRPV4 (HeLa-mTRPV4). GSK-induced [Ca] elevation was only observed in HeLa-mTRPV4 cells compared to that in the control HeLa cells, indicating the specific action of GSK on TRPV4. APAP dose-dependently suppressed this GSK-induced Ca entry in HeLa-mTRPV4. However, it is unlikely that the metabolites of APAP were involved in these effects as the reaction in this study was rapid. The results suggest that APAP suppresses the newly identified target TRPV4 without being metabolized and exerts antipyretic/analgesic and/or other effects on TRPV4-related phenomena in the body. The effect of APAP on TRPV4 was opposite to that on TRPV1 or TRPA1, as the latter is activated by APAP.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002858PMC
January 2020

TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours.

Br J Cancer 2020 03 20;122(5):658-667. Epub 2019 Dec 20.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT.

Methods: We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines.

Results: TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines.

Conclusion: TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.
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http://dx.doi.org/10.1038/s41416-019-0688-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054534PMC
March 2020

Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of nuclear factor κB pathways.

Cancer Sci 2019 Dec 23;110(12):3802-3810. Epub 2019 Oct 23.

Discovery and Preclinical Research Division, Taiho Pharmaceutical, Tsukuba, Japan.

The ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin-RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho-inhibitor of κBα and phospho-p100, impaired the activities of nuclear factor κB (NF-κB) transcription factors p65 and RelB, and decreased the expression of NF-κB target genes, suggesting that TAS4464 inhibits both the canonical and non-canonical NF-κB pathways. TAS4464 had similar effects in an in vivo human-MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies.
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http://dx.doi.org/10.1111/cas.14209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890451PMC
December 2019

Schlafen11 Expression Is Associated With the Antitumor Activity of Trabectedin in Human Sarcoma Cell Lines.

Anticancer Res 2019 Jul;39(7):3553-3563

Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan

Background/aim: Trabectedin is a DNA-damaging agent and has been approved for the treatment of patients with advanced soft tissue sarcoma. Schlafen 11 (SLFN11) was identified as a dominant determinant of the response to DNA-damaging agents. The aim of the study was to clarify the association between SLFN11 expression and the antitumor activity of trabectedin.

Materials And Methods: The antitumor activity of trabectedin was evaluated under different expression levels of SLFN11 regulated by RNA interference and CRISPR-Cas9 systems, and the combined antitumor activity of ataxia telangiectasia and Rad3-related protein kinase (ATR) inhibitor and trabectedin in sarcoma cell lines using in vitro a cell viability assay and in vivo xenograft models.

Results: SLFN11-knockdown cell lines had a lower sensitivity to trabectedin, compared to parental cells. ATR inhibitor enhanced the antitumor activity of trabectedin in SLFN11-knockdown cells and in a SLFN11-knockout xenograft model.

Conclusion: SLFN11 expression might be a key factor in the antitumor activity of trabectedin.
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http://dx.doi.org/10.21873/anticanres.13501DOI Listing
July 2019

[A Case of Metastatic Peripheral T-cell Lymphoma of the Central Nervous System During the Perinatal Period].

No Shinkei Geka 2019 May;47(5):559-563

Department of Neurosurgery, Shimane University Faculty of Medicine.

The diagnosis of malignant tumors during pregnancy is not uncommon; the incidence is one per six thousand pregnancies. However, the diagnosis of malignant lymphoma-especially T-cell lymphoma-during pregnancy is extremely rare. Thus, the early detection and management of T-cell lymphoma necessitates difficult decision-making. A 30-year-old woman developed consciousness disturbance on postpartum day three. Because brain MRI showed multiple edematous lesions in both hemispheres, vasculitis or encephalitis was initially suspected, and diagnostic therapy was initiated with the administration of steroids. One month later, the patient suddenly developed a subarachnoid hemorrhage followed by acute hydrocephalus. Emergent ventricular drainage and lesion biopsy were simultaneously performed. Based on the findings, the patient was diagnosed with peripheral T-cell lymphoma not otherwise specified(PTCL-NOS). Laboratory findings indicated Epstein-Barr virus(EBV)infection. Moreover, the same diagnosis was supported by breast and bone marrow biopsies. Thus, the brain lesions were presumed to be metastatic in nature. The prognosis of PTCL-NOS is severely poor in pregnant women as diagnosis is delayed owing to limitations of radiological examinations and because symptoms can be confused with those of other diseases or hyperemesis gravidarum. Additionally, the alteration of immunotolerance in association with pregnancy and EBV infection might have influenced the aggressive features of this case. When a pregnant woman presents with neurological symptoms, malignant lymphoma should be considered when making a differential diagnosis.
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http://dx.doi.org/10.11477/mf.1436203981DOI Listing
May 2019

TAS4464, A Highly Potent and Selective Inhibitor of NEDD8-Activating Enzyme, Suppresses Neddylation and Shows Antitumor Activity in Diverse Cancer Models.

Mol Cancer Ther 2019 07 15;18(7):1205-1216. Epub 2019 May 15.

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan.

NEDD8-activating enzyme (NAE) is an essential E1 enzyme of the NEDD8 conjugation (neddylation) pathway, which controls cancer cell growth and survival through activation of cullin-RING ubiquitin ligase complexes (CRL). In this study, we describe the preclinical profile of a novel, highly potent, and selective NAE inhibitor, TAS4464. TAS4464 selectively inhibited NAE relative to the other E1s UAE and SAE. TAS4464 treatment inhibited cullin neddylation and subsequently induced the accumulation of CRL substrates such as CDT1, p27, and phosphorylated IκBα in human cancer cell lines. TAS4464 showed greater inhibitory effects than those of the known NAE inhibitor MLN4924 both in enzyme assay and in cells. Cytotoxicity profiling revealed that TAS4464 is highly potent with widespread antiproliferative activity not only for cancer cell lines, but also patient-derived tumor cells. TAS4464 showed prolonged target inhibition in human tumor xenograft mouse models; weekly or twice a week TAS4464 administration led to prominent antitumor activity in multiple human tumor xenograft mouse models including both hematologic and solid tumors without marked weight loss. As a conclusion, TAS4464 is the most potent and highly selective NAE inhibitor reported to date, showing superior antitumor activity with prolonged target inhibition. It is, therefore, a promising agent for the treatment of a variety of tumors including both hematologic and solid tumors. These results support the clinical evaluation of TAS4464 in hematologic and solid tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0644DOI Listing
July 2019

Pyothorax-associated Angiosarcoma Metastasized to the Brain with Multiple and Progressively Expanding Hematomas: Case Report and Literature Review.

Asian J Neurosurg 2018 Jul-Sep;13(3):803-809

Department of Neurosurgery, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan.

The brain metastasis of angiosarcoma is very rare, and little is known about its clinical features or therapeutic strategy. A 74-year-old male was hospitalized for disturbance of consciousness. Radiological examination revealed multiple cerebral hematomas. Gadolinium contrast-enhanced magnetic resonance imaging showed no significant enhancement at any of the lesions. To detect a suspected metastatic brain tumor or abscess, a full-body scan was performed but revealed only a poorly enhanced mass in the removal cavity caused by thoracoplasty in the left upper chest. After admission, a cascade of expansion of those hematomas occurred in the right frontal, left parietal, and right temporal lobes, and each lesion thus had to be sequentially removed by craniotomies. The pathological diagnosis of the right frontal lesion was an abscess with hematoma. However, a malignant vascular tumor was highly suspected because of many CD31(+)/Ki-67(+) cells in the left parietal lesion. A mass in the scar caused by thoracoplasty was suspected to be the primary lesion, and brain metastasis of angiosarcoma was finally diagnosed. Whole-brain irradiation and systemic paclitaxel administration were performed, and a complete response for the brain lesions was obtained for 22 months; the patient then died of an intratracheal hemorrhage. This case represents the first report of multiple brain metastases from pyothorax-associated angiosarcoma accompanied by sequentially and gradually expanding hematomas, as well as the first case with the control of metastatic brain lesions for over 1 year after the onset of neurological symptoms. Control of the lesions could be achieved by their total removal with complete hemostasis, as well as additional radio- and chemotherapy.
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http://dx.doi.org/10.4103/ajns.AJNS_250_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159051PMC
October 2018

Effective Sequential Combined Chemotherapy with Trifluridine/Tipiracil and Regorafenib in Human Colorectal Cancer Cells.

Int J Mol Sci 2018 Sep 25;19(10). Epub 2018 Sep 25.

Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno Hiraishi, Kawauchi-Cho Tokushima, Tokushima 771-0194, Japan.

Salvage chemotherapy for refractory metastatic colorectal cancer using trifluridine/tipiracil (FTD/TPI) and regorafenib has shown survival benefits. We evaluated the antitumor effects of FTD or FTD/TPI combined with regorafenib in vitro and in vivo. SW620, HCT 116, and HT-29 human colorectal cancer cell lines were treated with FTD and regorafenib simultaneously and sequentially. Cell death, incorporation of FTD into DNA, and molecules related to FTD and regorafenib-associated cell death were investigated. The antitumor effects of FTD combined with regorafenib in SW620 and COLO205 xenografts were also evaluated. Cell death was greater after sequential treatment with FTD followed by regorafenib in SW620 cells, but not in HCT 116 and HT-29 cells, than after treatment with FTD alone, which was attributable to thymidylate synthase reduction with the induction of apoptosis. In contrast, simultaneous and sequential exposure to regorafenib followed by FTD, but not FTD alone, attenuated the cell death effect. Furthermore, combined FTD/TPI treatment followed by regorafenib had greater antitumor activity than either monotherapy in SW620 and COLO205 xenograft models. Treatment results following regorafenib administration subsequent to FTD or FTD/TPI suggest that sequential therapy with FTD/TPI prior to regorafenib may be effective in a clinical setting.
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http://dx.doi.org/10.3390/ijms19102915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213129PMC
September 2018

Trifluridine/tipiracil overcomes the resistance of human gastric 5-fluorouracil-refractory cells with high thymidylate synthase expression.

Oncotarget 2018 Mar 5;9(17):13438-13450. Epub 2018 Feb 5.

Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.

Trifluridine/tipiracil (FTD/TPI or TFTD, also known as TAS-102) is a combination of the antineoplastic thymidine analog, FTD, and thymidine phosphorylase inhibitor, TPI (molar ratio 1:0.5). FTD/TPI was approved in Japan, the United States, and the European Union for the treatment of unresectable advanced or recurrent colorectal cancer. We evaluated the and efficacy and mechanisms of action of FTD and FTD/TPI against 5-fluorouracil (5-FU)-resistant MKN45/5FU, MKN74/5FU, and KATOIII/5FU human gastric cancer cells overexpressing thymidylate synthase (TS) and their respective parent cell lines. MKN45/5FU and KATOIII/5FU cells were not cross-resistant to FTD, whereas MKN45/5FU cells were 3.7-fold more resistant than the parental cells . FTD was also incorporated into genomic DNA in a concentration-dependent manner in 5-FU-resistant and parental cells. Additionally, deoxyuridine monophosphate levels in MKN45/5FU cells after 24-h FTD treatment were 3.0-fold higher than those in parental cells, and FTD treatment for 72 h induced G2/M arrest in MKN45/5FU cells, unlike the S phase arrest in MKN45 cells. Thus, TS-overexpressing MKN45/5FU cells, but not MKN74/5FU and KATOIII/5FU cells, showed partial cross-resistance to FTD. However, FTD/TPI (administered orally twice a day) exhibited antitumor activity to the same extent in MKN45 and MKN45/5FU xenograft mouse models, overcoming cross-resistance to FTD. DNA incorporation rather than TS inhibition seems to be the main action of FTD under these conditions. Thus, FTD/TPI is a promising chemotherapeutic agent against gastric cancers recurring following 5-FU therapy.
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http://dx.doi.org/10.18632/oncotarget.24412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862589PMC
March 2018

Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts.

Chemotherapy 2018 24;63(1):46-52. Epub 2018 Jan 24.

Pharmacology Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.

Background/aim: A phase 3 trial of S-1, leucovorin (LV), and oxaliplatin for treating gastric cancer is now underway. However, the antitumor efficacy of the combination has not yet been examined in an in vivo preclinical study. This study examined the antitumor efficacy of combination therapy consisting of S-1, LV, and oxaliplatin against 4 human gastric cancer xenografts: NUGC-4, St-40, SC-2, and SC-4.

Methods: The antitumor efficacy was evaluated using human gastric cancer xenograft-bearing nude mice. S-1 and LV were administered orally once daily on days 1-7 at doses of 6.9 and 10 mg/kg, respectively. Oxaliplatin was administered intravenously at a dose of 8.3 mg/kg on day 1. The tumor volume was measured on day 15, and the relative tumor volume (RTV) was calculated.

Results: In all 4 xenograft models, S-1 alone and oxaliplatin alone, but not LV alone, had significant antitumor activities (p < 0.001). Combination therapy consisting of S-1 and LV resulted in a significantly smaller RTV than S-1 alone (p < 0.001). Combination therapy consisting of S-1 and oxaliplatin also resulted in a significantly smaller RTV than either S-1 alone (p < 0.001) or oxaliplatin alone (p < 0.001). Furthermore, combination therapy consisting of S-1, LV, and oxaliplatin resulted in the highest antitumor activity in these models (p < 0.001 vs. S-1 + LV; p < 0.001 or p = 0.003 vs. S-1 + oxaliplatin).

Conclusion: Combination therapy consisting of S-1, LV, and oxaliplatin administered according to a 1-week-on/1-week-off schedule may be useful for the treatment of patients with gastric cancer.
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http://dx.doi.org/10.1159/000486029DOI Listing
March 2018

Effect of acetaminophen on osteoblastic differentiation and migration of MC3T3-E1 cells.

Pharmacol Rep 2018 Feb 15;70(1):29-36. Epub 2017 Jul 15.

Division of Applied Pharmacology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan. Electronic address:

Background: N-acetyl-p-aminophenol (APAP, acetaminophen, paracetamol) is a widely used analgesic/antipyretic with weak inhibitory effects on cyclooxygenase (COX) compared to non-steroidal anti-inflammatory drugs (NSAIDs). The mechanism of action of APAP is mediated by its metabolite that activates transient receptor potential channels, including transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) or the cannabinoid receptor type 1 (CB1). However, the exact molecular mechanism and target underlying the cellular actions of APAP remain unclear. Therefore, we investigated the effect of APAP on osteoblastic differentiation and cell migration, with a particular focus on TRP channels and CB1.

Methods: Effects of APAP on osteoblastic differentiation and cell migration of MC3T3-E1, a mouse pre-osteoblast cell line, were assessed by the increase in alkaline phosphatase (ALP) activity, and both wound-healing and transwell-migration assays, respectively.

Results: APAP dose-dependently inhibited osteoblastic differentiation, which was well correlated with the effects on COX activity compared with other NSAIDs. In contrast, cell migration was promoted by APAP, and this effect was not correlated with COX inhibition. None of the agonists or antagonists of TRP channels and the CB receptor affected the APAP-induced cell migration, while the effect of APAP on cell migration was abolished by down-regulating TRPV4 gene expression.

Conclusion: APAP inhibited osteoblastic differentiation via COX inactivation while it promoted cell migration independently of previously known targets such as COX, TRPV1, TRPA1 channels, and CB receptors, but through the mechanism involving TRPV4. APAP may have still unidentified molecular targets that modify cellular functions.
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http://dx.doi.org/10.1016/j.pharep.2017.07.006DOI Listing
February 2018

Synergistic anticancer activity of a novel oral chemotherapeutic agent containing trifluridine and tipiracil in combination with anti-PD-1 blockade in microsatellite stable-type murine colorectal cancer cells.

Am J Cancer Res 2017 1;7(10):2032-2040. Epub 2017 Oct 1.

Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd.Tokushima 771-0194, Japan.

Trifluridine/tipiracil (FTD/TPI) is a combination of FTD, an antineoplastic thymidine-based nucleoside analog, and TPI, which acts to enhance the bioavailability of FTD . It is used to treat patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. We investigated the anticancer activity of FTD/TPI combined with anti-mouse programed cell death 1 (PD-1) monoclonal antibody (mAb) against CMT-93 cells, which are microsatellite stable (MSS)-type murine colorectal cancer cells. Tumor growth inhibition (TGI) after treatment with anti-mouse PD-1 mAb monotherapy (0.1 mg, i.p., days 1, 5, 9) and FTD/TPI monotherapy (150 mg/kg/day, p.o., days 1-14) were 86.7% and 52.7%, respectively, and that of the combination was 98.4%. The TGI of the combination therapy was significantly greater than that of each monotherapy (P<0.05). The combination therapy caused complete tumor regression in four out of five mice without body-weight reduction, but neither of the monotherapies resulted in complete tumor regression. Low dose FTD/TPI (75 and 100 mg/kg) combined with anti-mouse PD-1 mAb also showed significant antitumor activity against CMT-93 tumors. Flow cytometric analysis revealed that a higher CD8 T cell ratio among total lymphocytes and a lower regulatory T cells (Tregs) ratio in CD4 T cells in the combination group compared with that in the control group. These results suggested that the combination therapy induced a cytotoxic response from infiltrated cytotoxic CD8 T cells and reduced immunosuppressive activity as indicated by decreased Tregs. In this study, the combination therapy was found to have synergistically greater antitumor activity against CMT-93 cells. These preclinical findings indicated that FTD/TPI and anti-mouse PD-1 mAb combination therapy may be a promising treatment option, even for MSS-type colorectal cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665850PMC
October 2017

Trifluridine/tipiracil increases survival rates in peritoneal dissemination mouse models of human colorectal and gastric cancer.

Oncol Lett 2017 Jul 26;14(1):639-646. Epub 2017 May 26.

Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan.

A number of patients exhibit peritoneal dissemination of gastric or colorectal cancer, which is a predominant cause of cancer-associated mortality. Currently, there is no markedly effective treatment available. The present study was designed to determine the efficacy of trifluridine/tipiracil (TFTD), formerly known as TAS-102, which is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer refractory to standard therapies. Four colorectal cancer cell lines and one gastric cancer cell line were intraperitoneally inoculated into nude mice, as models of peritoneal dissemination. TFTD (200 mg/kg/day) was orally administered for 5 consecutive days followed by 2 drug-free days for 6 weeks. The increase in the lifespan (ILS) of the TFTD-treated mice compared with that of the drug-free control mice was 66.7, 43.3, 106.3, 98.3 and 133.3% for DLD-1, DLD-1/5-fluorouracil [5-fluorouracil (5FU)-resistant subline of DLD-1], HT-29 and HCT116 colorectal cancer cell lines, and MKN45 gastric cancer cell line, respectively. This ILS was similar to that of the irinotecan-treated mice (ILS, 70-84%), but was significantly (P<0.05) increased compared with that of the 5FU-, tegafur, gimeracil and potassium oxonate- and cisplatin-treated mice (ILS, 1-53%, 0.8-60% and 85%, respectively). No significant increase in body weight loss was observed during the dosing periods with any of the drugs used. The increase in CEA levels with progressive peritoneal dissemination was inhibited by TFTD treatment. TFTD also exhibited marked anticancer effects against Kirsten rat sarcoma viral oncogene homolog-mutated tumors and 5FU-resistant tumors. The results of the present study indicate that TFTD may be a potential drug against peritoneal dissemination of colorectal and/or gastric cancer in humans and may be utilized for chemo-naïve tumors and recurrent tumors following 5FU treatment.
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http://dx.doi.org/10.3892/ol.2017.6258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494646PMC
July 2017

Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts.

Oncol Rep 2016 Dec 27;36(6):3123-3130. Epub 2016 Oct 27.

Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima City, Tokushima 771-0194, Japan.

Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were higher than those associated with TFTD treatment alone. The preclinical findings indicate that the combination therapy with TFTD and nintedanib is a promising treatment option for colorectal cancer.
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http://dx.doi.org/10.3892/or.2016.5208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112602PMC
December 2016

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, TAS-102, with Oxaliplatin on Human Colorectal and Gastric Cancer Xenografts.

Anticancer Res 2015 Sep;35(9):4605-15

Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.

TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (at a molar ratio of 1:0.5) that was approved in Japan in 2014 for the treatment of unresectable advanced or recurrent colorectal cancer. In the present study, the enhancement of therapeutic efficacy using a combination of TAS-102 and oxaliplatin was evaluated in a xenograft-bearing nude mouse model of colorectal and gastric cancer. TAS-102 was orally administered twice-a-day from day 1 to 14, and oxaliplatin was administered intravenously on days 1 and 8. The in vivo growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, was estimated based on the period required to reach a tumor volume five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and RTV5 in mice administered TAS-102 with oxaliplatin were significantly superior to those associated with either monotherapy in mice with colorectal (HCT 116, SW-48; p<0.001) and gastric cancer (SC-2, MKN74; p<0.001). MKN74/5FU, a 5-fluorouracil-resistant MKN74 sub-line, was sensitive to both FTD and oxaliplatin in vitro. In vivo, TAS-102 alone was effective in MKN74/5FU, and its anti-tumor activity was significantly enhanced in combination with oxaliplatin (p<0.001). No significant decrease in body weight or toxicity was observed compared to either monotherapy. The present pre-clinical findings indicate that combination of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, and can be utilized in both chemo-naïve tumors and recurrent tumors after 5-fluorouracil treatment.
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September 2015

Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse.

Cancer Chemother Pharmacol 2015 Aug 18;76(2):325-33. Epub 2015 Jun 18.

Pharmacokinetics Research Laboratories, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan,

Purpose: Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated.

Methods: Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay.

Results: TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner.

Conclusions: A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.
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http://dx.doi.org/10.1007/s00280-015-2805-9DOI Listing
August 2015

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 May 23;33(5):2135-42. Epub 2015 Mar 23.

Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi-Cho, Tokushima-shi, Tokushima 771-0194, Japan.

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.
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http://dx.doi.org/10.3892/or.2015.3876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391594PMC
May 2015

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human colorectal and gastric cancer xenografts.

Anticancer Res 2015 Mar;35(3):1437-45

Translational Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.

TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5. TAS-102 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, enhancement of the therapeutic efficacy using a combination therapy of TAS-102 and irinotecan hydrochloride (CPT-11) was evaluated in a colorectal and gastric cancer xenograft-bearing nude mouse model. TAS-102 was orally administered twice a day from day 1 to 14, and CPT-11 was administered intravenously on days 1 and 8. The growth-inhibitory activity was evaluated based on the tumor volume and the growth-delay period, which was estimated based on the period required to reach a tumor volume that was five-times greater than the initial volume (RTV5). The tumor growth-inhibitory activity and the RTV5 of the group receiving TAS-102 with CPT-11 were significantly superior to those of both agents as monotherapy for mice with KM12C, KM12C/5-FU, DLD-1/5-FU, and SC-2 xenografts (p<0.01). No significant decrease in body weight was observed. The present pre-clinical findings indicated that the combination of TAS-102 and CPT-11 is a promising treatment option for colorectal or gastric cancer, not only for chemo-naïve tumors, but also for recurrent tumors after 5-fluorouracil (5-FU)-based chemotherapy.
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March 2015

Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.

Oncol Rep 2014 Dec 17;32(6):2319-26. Epub 2014 Sep 17.

Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan.

TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients.
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http://dx.doi.org/10.3892/or.2014.3487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240496PMC
December 2014

Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice.

Exp Ther Med 2012 May 13;3(5):755-762. Epub 2012 Feb 13.

Oncology Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194;

In this study, combination therapies using the oral fluoropyrimidine tegafur-gimeracil-oteracil (S-1) with several targeted agents or antibodies, were evaluated. First, the effects of tyrosine kinase inhibitors (erlotinib hydrochloride, sorafenib tosilate and sunitinib malate) against human non-small cell lung cancer (NSCLC), breast cancer and colorectal cancer were evaluated in vivo. The effects of the combination of S-1 and targeted antibodies (bevacizumab and cetuximab) against human colorectal cancers was also evaluated in vivo. S-1 and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, showed a significant inhibition of growth in human NSCLC (Lu-99 and PC-9 cell lines). The antitumor activity of the combination of S-1 and erlotinib against Lu-99 and PC-9 cancer cell lines was significantly superior to either monotherapy (P<0.05). Combination therapy using the multi-tyrosine kinase inhibitors, sorafenib or sunitinib, with S-1 against breast cancer (MX-1 cell line) and NSCLC (NCI-H460 cell line) was significantly superior to either monotherapy (P<0.01). The combination of the anti-vascular endothelial growth factor antibody bevacizumab or the anti-EGFR antibody, cetuximab, with S-1 against human colorectal cancer [Col-1, KM20C (bevacizumab) and DLD-1 (cetuximab) cell lines] and a 5-fluorouracil (5-FU)-resistant cell line (KM12C/5-FU) was significantly superior to either monotherapy (p<0.01). In particular, the growth of the Col-1 cells was completely inhibited by the combination of S-1 and bevacizumab. No toxic mortalities and no significant difference in the body weight changes of the animals treated with S-1 combined with the targeted agents or with the mono-therapies were observed; therefore, the treatments appeared to be well-tolerated. Our preclinical findings indicate that the combination therapies of S-1 and targeted agents are promising treatment options.
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http://dx.doi.org/10.3892/etm.2012.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438730PMC
May 2012

Efficacy of combination chemotherapy using oral fluoropyrimidine S-1 with oxaliplatin (SOX) against colorectal cancer in vivo.

Anticancer Res 2012 Jul;32(7):2807-12

Oncology Medical Affairs Department, Tokushima Research Center, Tokushima, Japan.

Oxaliplatin is effective when used with 5-fluorouracil (5-FU) and leucovorin, or with capecitabine (COX) for the treatment of colorectal cancer. In this experiment, we investigated the optimal combination schedule and antitumor activity of oral S-1 with oxaliplatin combination therapy (SOX) against human colorectal cancer xenografts in vivo. Using human colon cancer COL-1-bearing nude mice, oxaliplatin was administered at a total dose of 8.3 mg/kg on day 1 alone, on day 8 alone, or in divided doses administered on days 1 and 8 with S-1 (6.9 mg/kg, days 1-14). The antitumor activity of SOX, administered according to the divided schedule was significantly superior to both monotherapies (p<0.01), and the toxicity was tolerable. However, administration on day 8 alone failed to significantly increase the antitumor activity, when compared with that of monotherapy, while administration on day 1 alone was toxic in this model. Next, the efficacy of SOX was compared with that of COX (360 mg/kg, days 1-14). The antitumor effect of SOX was significantly superior to that of COX (p<0.01), with an equivalent toxicity; moreover SOX suppressed COL-1 tumor growth for a longer period of time (2.2 times) than did COX. The antitumor activity of SOX against the 5-FU-resistant colorectal cancer cell line KM12C/5-FU was equivalent to that of COX. The evaluation of intermittent SOX administration in a clinical trial might be of critical value.
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July 2012

Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks.

Exp Ther Med 2011 May 21;2(3):393-397. Epub 2011 Mar 21.

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan.

TAS-102 is an oral anticancer drug composed of trifluorothymidine (TFT) and TPI (an inhibitor of thymidine phosphorylase that strongly inhibits the biodegradation of TFT). Similar to 5-fluorouracil (5FU) and 5-fluoro-2'-deoxyuridine (FdUrd), TFT also inhibits thymidylate synthase (TS), a rate-limiting enzyme of DNA biosynthesis, and is incorporated into DNA. TFT exhibits an anticancer effect on colorectal cancer cells that have acquired 5FU and/or FdUrd resistance as a result of the overexpression of TS. Therefore, we examined the mode of action of TFT-induced DNA damage after its incorporation into DNA. When HeLa cells were treated with TFT, the number of ring-open aldehyde forms at apurinic/apyrimidinic sites increased in a dose-dependent manner, although we previously reported that no detectable excisions of TFT paired to adenine were observed using uracil DNA glycosylases, thymine DNA glycosylase or methyl-CpG binding domain 4 and HeLa whole cell extracts. To investigate the functional mechanism of TFT-induced DNA damage, we measured the phosphorylation of ATR, ATM, BRCA2, chk1 and chk2 in nuclear extracts of HeLa cells after 0, 24, 48 or 72 h of exposure to an IC(50) concentration of TFT, FdUrd or 5FU using Western blot analysis or an enzyme-linked immunosorbent assay (ELISA). Unlike FdUrd and 5FU, TFT resulted in an earlier phosphorylation of ATR and chk1 proteins after only 24 h of exposure, while phosphorylated ATM, BRCA2 and chk2 proteins were detected after more than 48 h of exposure to TFT. These results suggest that TFT causes single-strand breaks followed by double-strand breaks in the DNA of TFT-treated cells. TFT (as TAS-102) showed a more potent antitumor activity than oral 5FU on CO-3 colon cancer xenografts in mice, and such antitumor potency was supported by the increased number of double-strand breaks occurring after single-strand breaks in the DNA of the TFT-treated tumors. These results suggest that TFT causes single-strand breaks after its incorporation into DNA followed by double-strand breaks, resulting in DNA damage. This effect of TFT on DNA may explain its potent anticancer activity in cancer therapy.
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http://dx.doi.org/10.3892/etm.2011.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440718PMC
May 2011

In vivo evidence for a significant role of folylpolyglutamate synthase in combined chemotherapy with oral fluoropyrimidine, UFT or S-1, and leucovorin.

Oncol Rep 2011 May 4;25(5):1407-12. Epub 2011 Mar 4.

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd, 224-2 Hiraishi-ebisuno Kawauchi-cho, Tokushima 771-0194, Japan.

Combined chemotherapy with 5-fluorouracil and leucovorin (LV) has been widely used for the treatment of patients with colorectal cancer. Given that LV effects are attributable to increased levels of reduced folate in cancer cells, we attempted here to show the in vivo role of folylpolyglutamate synthetase (FPGS), which stabilizes intracellular reduced folate, in the anticancer activities of oral fluoropyrimidines, UFT or S-1, combined with LV. To this end, HCT-15 human colon cancer cells were knocked down for FPGS expression by RNA interference. The cell line stably expressing FPGS shRNA (FPGS shRNA HCT-15) was cloned and transferred subcutaneously into nude mice fed a low-folate diet. FPGS shRNA HCT-15 tumors expressed a significantly lower level of FPGS at protein and mRNA levels than parental HCT-15 cells, and the levels of reduced folate in FPGS shRNA HCT-15 tumors became 57% of those in parent after a single administration of 10 mg/kg of LV. Notably, FPGS downregulation did not affect the tumor growth or sensitivity to fluoropyrimidine. Importantly, we observed that LV given for 14 days failed to enhance the anticancer effects of UFT and S-1 in FPGS shRNA HCT-15. This was in keeping with the results that LV did not increase the ternary complex of TS, FdUMP and reduced folate. In conclusion, the present results provide in vivo evidence that intratumor FPGS plays an important role in the efficacy of oral fluoropyrimidine plus LV therapy for colorectal cancer.
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http://dx.doi.org/10.3892/or.2011.1206DOI Listing
May 2011

Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase.

Oncol Lett 2010 Nov 17;1(6):973-980. Epub 2010 Sep 17.

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan.

The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or 5-FU prodrugs in low folate diet-fed nude mice using human colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55-79% inhibition of tumor growth among 11 types of colorectal tumor xenograft, whereas UFT alone showed 23-67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in tumors. To investigate the reason for the higher efficacy of UFT/LV on colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated tumors were noted. Our results indicate that a combined therapy of UFT with LV may contribute to the treatment of colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT.
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http://dx.doi.org/10.3892/ol.2010.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412464PMC
November 2010

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo.

Oncol Rep 2010 Nov;24(5):1307-13

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi, Tokushima 771-0194, Japan.

Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dose-dependent manner. Furthermore, we observed decreased expression of γ-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.
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http://dx.doi.org/10.3892/or_00000987DOI Listing
November 2010

Irinotecan overcomes the resistance to 5-fluorouracil in human colon cancer xenografts by down-regulation of intratumoral thymidylate synthase.

Oncol Rep 2010 Oct;24(4):835-42

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi, Tokushima 771-0194, Japan.

To clarify the molecular interaction of irinotecan (CPT-11) and oxaliplatin (l-OHP) in combination with 5-fluorouracil (5-FU), the antitumor effects of CPT-11 and l-OHP combined with the oral 5-FU prodrug, S-1 composed by tegafur, gimeracil and potassium oteracil, were investigated on human colon cancer KM12C xenografts sensitive or resistant to 5-FU in nude mice. In parental KM12C tumor xenografts, combined treatment of CPT-11 with oral S-1 significantly augmented the antitumor activity compared with those of CPT-11 and S-1 alone. Interestingly, combined therapy of CPT-11 with S-1 was markedly effective with almost 90% of inhibition of tumor growth on 5-FU-resistant tumors (KM12C/ 5-FU), and its potency likely corresponded to that in parental tumors. In contrast, combined administration of l-OHP with S-1 did not shown an effect on KM12C/5-FU tumor xenografts. To investigate why only CPT-11 potentiated the anti-tumor activity in combination with 5-FU pro-drugs against 5-FU-resistant colon tumors, the activities or expression levels of thymidylate synthase (TS), ribonucleotide reductase (RNR) and other enzymes in 5-FU-metabolism in both tumors were measured following administration of CPT-11 and/or l-OHP. CPT-11, but not l-OHP, induced a decrease in activities and protein levels of TS and an increase in those of RNR in KM12C/5-FU tumors only, which was likely related to decreased expressions of several proteins in G1/S phase of the cells including CDK4, pRB, and E2F1 in these tumors. These findings suggest that CPT-11, but not l-OHP, would overcome the resistance to 5-FU in combination with 5-FU pro-drugs on 5-FU-resistant colon tumors.
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http://dx.doi.org/10.3892/or.2010.835DOI Listing
October 2010

Oral fluoropyrimidine may augment the efficacy of aromatase inhibitor via the down-regulation of estrogen receptor in estrogen-responsive breast cancer xenografts.

Breast Cancer Res Treat 2011 Jul 31;128(2):381-90. Epub 2010 Aug 31.

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno Hiraishi, Kawauchi-Cho, Tokushima-Shi, Tokushima 771-0194, Japan.

The present preclinical study was designed to evaluate a new combination therapy comprised of the aromatase inhibitor anastrozole (ANA) and the oral fluoropyrimidines, UFT and S-1 against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7/Arom 14, which was stably transfected with the cDNA of human aromatase. MCF-7/Arom 14 cells showed a high aromatase activity and notably were able to grow in the presence of testosterone and estradiol (E(2)) in vitro. ANA and 5-fluorouracil (5-FU) inhibited cell growth at concentrations of 0.005-10 and 0.2-5 μM, respectively, and the combination of both drugs additively inhibited cell growth. The growth of MCF-7/Arom 14 tumors was significantly inhibited by ANA and S-1 or UFT in vivo. The combination of ANA with S-1 or UFT administered using a 21-day consecutive, metronomic-like regimen significantly enhanced the antitumor efficacy, suppressing tumor growth for 2-4 times longer than monotherapy. To investigate the mechanisms by which S-1 enhances the antitumor activity of ANA, the protein and mRNA expression levels of ER-α in tumor tissue after treatment with S-1, ANA, and the typical chemotherapeutic agents doxorubicin (ADM) or paclitaxel (TXL) were analyzed. The protein and mRNA expression levels of ER-α in the tumor tissue were markedly decreased after treatment with S-1 or S-1 + ANA, but not after treatment with either ADM or TXL. The reduced ER-α level after S-1 treatment might contribute to the increased antitumor activity of ANA by reducing ER-α-induced growth signaling in addition to the decrease in estrogen production induced by ANA. Based on these results, the combination of ANA and S-1 might yield a greater benefit than other chemotherapeutic agents in postmenopausal women with ER-positive breast cancer.
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http://dx.doi.org/10.1007/s10549-010-1141-3DOI Listing
July 2011