Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of B-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues,
BackgroundCombination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS).Patients and methodsPatients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m2 and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m2 twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m2 and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin.ResultBetween June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6–11.6) in the control group and 14.0 months (95% CI 12.4–15.5) in the experimental group (HR 0.84, 95% CI 0.70–1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher.ConclusionS-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment.Clinical trials numberUMIN000007834
(1) The mechanisms of tumor suppression are exerted by down-regulation or ablation of a variety of oncogene products including transactivaters such as nuclear factor-kappa B (NF-κB), growth signal transducers such as the Wnt signal molecule, β-catenin, and several growth factors and their receptors, and so on.(2) Curcumin also has anti-invasion, antimetastasis, and antiangiogenesis potential. (3,4) This potential is desirable for new cancer therapeutic agents. β-Catenin is a key molecule of APC (adenomatous polyposis coli)-derived colorectal carcinogenesis (5) that can be phosphorylated as a result of its association with APC, glycogen synthase kinase (GSK)-3β, and then degraded in the ubiquitination pathway. Accumulated β-catenin in the cytoplasm is transferred into the nucleus and acts together with lymphoid enhancer binding factor-1/T-cell-factor family proteins as a transactivator of other oncogenes, including c-myc and cyclin D1.(7-9) The low toxicity of curcumin is also advantageous for clinical use; however, its hydrophobicity, low absorption, and easy degradation are disadvantageous.(1) Recent clinical and preclinical studies of colorectal cancer patients and animals have suggested that curcumin bioavailability is limited. (10)(11)(12) To improve this low bioavailability, we synthesized a series of curcumin analogs and successfully screened an analog named bearing a 30-to 50-fold enhanced tumor suppressive potential against various types of cancers in vitro.(13) The molecular mechanisms of the tumor suppressive effects of GO-Y030 were similar to those of curcumin, including cell cycle arrest, down-regulation of oncogene activities such as NF-κB and Wnt signal transactivation, and induction of caspase 3 activity. The familial adenomatous polyposis (FAP) mouse is a very good model, because it develops adenomas through the same molecular mechanism as in human colorectal carcinogenesis, including the APC tumor suppressor gene. The chemopreventive ability of curcumin was assessed in an FAP model mouse, Min, harboring a truncation mutation at codon 850 with the potential to prevent adenoma formation. (12,14) To examine the bioavailability of synthesized analog and its toxicity, the FAP mouse model was applied. In this study, oral administration of GO-Y030 improved chemopreventive ability in FAP mouse without apparent toxicities in vivo. Materials and MethodsAnimal experiment. Genotyping of Apc 580D/+ mice were carried out by the polymerase chain reaction method as described previously.(15) Apc 580D/+ mice were fed either the basal diet (HFD32; CLEA Japan, Tokyo, Japan) basal diet containing 0.1% (weight/weight) curcumin, or basal diet containing 0.1% or 0.5% GO-Y030. All animal experiments were conducted in accordance with the guidelines set by Tohoku University.Compound. GO-Y030 was synthesized as previously described.Immunohistochemistry. The deparaffinized 4-μm specimens were heated in 1 mM ethylenediaminetetraacetic acid (EDTA)/ 10 mM Tris buffer (pH = 9.0) at 95°C for 40 min. After washing the specimens ...
LBA1 Background: PARADIGM is the first prospective trial to test the superiority of PAN vs. BEV in combination with standard doublet first-line chemotherapy for patients (pts) with RAS WT mCRC and left-sided primary tumors. Methods: This open-label, multicenter trial in Japan (NCT02394795) randomly selected pts with chemotherapy-naive RAS WT mCRC to PAN + mFOLFOX6 or BEV + mFOLFOX6. Overall survival (OS) as primary endpoint was hierarchically tested in patients with left-sided tumors, followed by those in the full-analysis set (FAS) population. Key secondary endpoints included progression-free survival (PFS), response rate (RR), and curative resection (R0) rate. Results: From May 2015 to June 2017, 823 pts were randomized; 12 did not receive protocol treatment and 9 were excluded due to major deviation of inclusion criteria. A total of 400 pts received PAN and 402 pts received BEV as FAS; 312 and 292 pts had left-sided primary tumors, respectively. OS was analyzed after 448 OS events in left-sided pts with a median follow-up of 61 months. PAN significantly improved OS vs. BEV in both populations: left-sided (HR, 0.82; 95.798% CI, 0.68-0.99, p = .031, which crossed the boundary of significance [0.042]), and FAS (HR, 0.84; 95% CI, 0.72-0.98; p = .030, with < 0.05 as the boundary). Although PFS was comparable between treatment groups, RR and R0 resection rates were higher with PAN compared with BEV (Table). HR for OS in the right-sided population was 1.09. No new safety signal was observed. Conclusions: PAN significantly improved OS vs. BEV in combination with mFOLFOX6 in pts with RAS WT and left-sided mCRC, establishing a standard first-line combination regimen for this population. Clinical trial information: NCT02394795. [Table: see text]
BackgroundCurcumin is known to possess many anti-tumor properties such as inhibition of tumor growth and induction of apotosis. However, limited bioavailability of curcumin prevents its clinical application. A synthesized curcumin analog, 1,5-diaryl-3-oxo-1,4-pentadiene such as GO-Y030, has the improved anti-tumor potential in vitro as well as in mouse model of colorectal carcinogenesis.ResultsThese compounds were divided into two groups; one is the higher anti-proliferative group, in which 79.7% of 1,5-diaryl-3-oxo-1,4-pentadienes were clustered. One of the 1,5-diaryl-3-oxo-1,4-pentadiene analogs, GO-Y078 has the most enhanced growth inhibition, and its solubility was improved, compared with curcumin. GO-Y078 inhibits NF-κB transactivation, as well as expression of TP53 and DR5 more effectively than curcumin. In a mouse model, GO-Y078 presented 1.4 fold more survival elongation that was not achieved by curcumin and GO-Y030.ConclusionsThe 1,5-diaryl-3-oxo-1,4-pentadiene analogs can yield good lead compounds for cancer chemotherapy, to overcome low bioavailability of curcumin.
Curcumin is a dietary constituent with tumor‐suppressing potential, inhibiting various pathways involved in carcinogenesis. However, because of its low bioavailability, the use of curcumin in in vivo trials has been limited. To overcome this problem, we synthesized more than 50 analogs and identified a monoketone analog, GO‐Y030, which has a 30‐fold higher potential to suppress tumor cell growth compared with curcumin. We investigated the inhibitory effect of GO‐Y030 on NF‐κB activation. In thyroid, pancreatic cancers and cholangiocarcinoma cells, in which NF‐κB is activated, NF‐κB activation was suppressed to 8–62% of the control value following treatment with 1 μM GO‐Y030, an effect comparable to that of 10 μM curcumin. Direct inhibition of IKKβ kinase activity and suppression of nuclear translocation of the NF‐κB p65 subunit were observed. The 50% growth inhibition concentrations of GO‐Y030 ranged from one‐11th to one‐14th of those of curcumin. GO‐Y030 also induced cell death comparable to that induced by curcumin but at a 10‐fold lower concentration. In pancreatic and thyroid cancer cells, the growth‐inhibitory effect of GO‐Y030 was 4‐ and 15‐fold greater, respectively, than that of curcumin. GO‐Y030 was a much stronger inducer of apoptosis compared with curcumin. The enhanced potency of GO‐Y030 may make it more useful than curcumin, which suffers from low bioavailability. GO‐Y030 is a good lead compound for the development of useful compounds for practical cancer chemotherapy. (Cancer Sci 2011; 102: 1045–1051)
PURPOSE Several trials have evaluated the efficacy of rechallenge treatment with anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.
The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or S-1 and cisplatin (SP) are regarded as a standard therapy against unresectable, recurrent, or advanced gastric cancer (AGC). Especially, SP is the most common regimen against AGC in Japan. For patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC, trastuzumab, a monoclonal antibody targeting HER2 antibody, is additionally used in combination. Although trastuzumab in combination with XP (trastuzumab-XP) have been widely accepted, the efficacy of trastuzumab in combination with SP (trastuzumab-SP) lacks sufficient verification. The aim of the present study is to validate the comparability of trastuzumab-SP to trastuzumab-XP. Patients with HER2-positive AGC were assigned to the trastuzumab-XP or trastuzumab-SP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or SP was administered to 58 patients: 28 with trastuzumab-XP and 30 with trastuzumab-SP. In the trastuzumab-XP group, response rate (RR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were 39.3%, 89.3%, 7.9 months, and 20.0 months, respectively. In the trastuzumab-SP group, RR, DCR, mPFS and mOS were 50.0%, 86.7%, 6.9 months, and 16.7 months, respectively. No significant difference in efficacy was observed between both groups. Severe hand-foot syndrome was observed more frequently in the trastuzumab-XP group than in the trastuzumab-SP group (14.3% vs. 0%, p = 0.05). Trastuzumab in combination with SP is a potential first-line therapeutic option for patients with HER2-positive AGC.
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