Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS
Jiao WuSai‐Ching J. YeungSicheng LiuAiham QdaisatDewei JiangWenli LiuZhuo ChengWenjing LiuHaixia WangLu LiZhongmei ZhouRong LiuChuanyu YangCeshi ChenRunxiang Yang
36
Citation
51
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Weight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival ( P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.Abstract Background: The use of oxaliplatin is increasing in colorectal cancer both in the metastatic and adjuvant setting. There is an increased recognition of hypersensitivity reactions (HSR) to oxaliplatin which is a potential barrier to the continued use of this drug in patients in whom benefits are observed. The aim of this retrospective review is to identify the incidence of HSR and the results of rechallenging patients with oxaliplatin. Methods and results: In 97 patients, we identified six patients with HSR (an incidence of 6.2%) There was a spectrum of reported symptoms with most occurring within minutes of infusion after a median of six doses of oxaliplatin. All these patients were rechallenged with oxaliplatin. Success was noted when oxaliplatin was administered over a prolonged rate of 6 h. The use of maximal premedications did not influence the outcome. Conclusions: Our experience confirms the need to be vigilant of HSR to oxaliplatin and to recognize idiosyncratic reactions. A feasible method to prevent the recurrence of HSR is to prolong the infusion rate without delaying or stopping effective treatment with oxaliplatin.
Hypersensitivity reaction
Cite
Citations (2)
Premedication
Hypersensitivity reaction
Cite
Citations (4)
背景・目的: oxaliplatin base の化学療法が大腸癌腹膜播種症例に与える影響について検討した。対象・方法: 2006 年1月～2012 年11 月の間に，腹膜播種陽性Stage IV 大腸癌と診断され，oxaliplatin base の化学療法を導入した49 例（oxaliplatin施行群）と，それ以前に5─FU 系の全身化学療法を施行した26 例（control 群）を対象。oxaliplatin 導入前後のoverall survival（OS）を比較。また，oxaliplatin 施行群のOS に関して臨床病理学的因子を共変量とし，単変量，多変量解析を行い，予後因子を検討した。結果: oxalplatin 施行群はcontrol 群より有意に生存期間が延長していた（中央値 20.5 か月 vs 11.7 か月，p＝0.04）。oxaliplatin 施行群におけるOS に対するfavorable factor として，70 歳以下（p＝0.03），原発巣切除（p＝0.02）が同定された。結語: oxaliplatin base の化学療法は大腸癌腹膜播種症例においても生存期間を改善させた。腹膜播種の程度に関係なく原発巣切除を70 歳以下の症例に行い，速やかにoxaliplatin base の化学療法を導入することが予後向上につながることが示唆された。
Base (topology)
Cite
Citations (0)
Cite
Citations (0)
OBJECTIVE To investigate the efficacy and safity of the domestic vs.imported oxaliplatin applied in advanced colon cancer.METHODS A total of 68 patients with advanced colon cancer were randomly divided into 2 groups : domestic oxaliplatin(50 mg) treatment group(the Ai Heng group,n=35) and imported oxaliplatin(50 mg) treatment group(Eloxatin group,n=33).All patients in both groups was adopted FOLFOX4 program(oxaliplatin combined with 5-fluorouracil and folinic acid).The adverse reactions and recent clinical efficacy were observed and a statistical analysis was conducted.RESULTS There were no significant difference in the recent clinical efficacy and chemotherapy-related adverse reactions between the two groups(P0.05).CONCLUSION Domestic oxaliplatin and the imported oxaliplatin are similar in anti-tumor efficacy and adverse reactions.Domestic oxaliplatin is safe and effective for advanced colon cancer.
Folinic acid
Clinical efficacy
Cite
Citations (0)
Background: Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear. Patients and Methods: In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined. Results: The median age was 67 years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. An initial dose of 130 or 100 mg/m2 of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33%, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m2, the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m2. A total of 10 patients (18%) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14% and the mPFS was 6.1 months. Conclusion: An initial oxaliplatin dose of 130 mg/m2 resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance.
Cite
Citations (18)
瞄准：在回顾的案例系列分析在变形 colorectal 癌症调查导致 oxaliplatin 的严重过敏反应的反应(SAR ) 并且进行全身的文学评论。方法：在在高雄老手医院将军的从 2006 ～ 2011 的 6 年的经期期间，暴露于 oxaliplatin 相关的化疗的 412 个病人的一个总数回顾地被考察。关于威胁生活的 SAR 后面的 oxaliplatin 的相关英语语言的研究也在 MEDLINE 被考察吗？并且 PubMed？搜索。结果：八个病人(1.9% ， 412 个案例中的 8 个) 被识别。七个病人是成功的没有任何 sequelae，复活了，一个病人到期了。我们在病人 3 在五个病人和重新质问的 oxaliplatin 使用改变了化疗政体。与 66 个病人一起的 23 相关英语语言的研究被报导。接待的病人一 oxaliplatin 的 10 个周期中部(变化， 2 ～ 29 ) 。最普通的症状是呼吸的悲痛(60%) ，发烧(55%) ，和低血压(54%) 。三个致命的事件被报导(4.5%) 。66 个案例的十一个病人(16%) 被 oxaliplatin 重新质问。结论：SAR 必须重重地在收到 oxaliplatin 相关的化疗的病人被考虑，在特别 pretreated 病人。oxaliplatin 相关的 SAR 的机制，预言者，预防方法和管理上的进一步的研究被推荐。
Cite
Citations (0)
Colorectal cancer is one of the leading causes of cancer death. The mainstay of chemotherapy in colorectal cancer patients for the past 40 years has been fluorouracil (5-FU). Oxaliplatin (Eloxatin) is a novel platinum compound with promising activity in colorectal cancer. As a single agent, oxaliplatin has produced response rates of 12% to 24% in patients with previously untreated advanced colorectal cancer, and 10% to 11% in patients with relapsed or refractory advanced colorectal cancer. In phase II trials, oxaliplatin combined with 5-FU, with or without leucovorin, was associated with response rates of 60% and higher when used as front-line therapy, and when used in patients with relapsed or refractory advanced colorectal cancer, response rates ranged from 25% to 50%. In the front-line setting, two randomized trials of 5-FU and leucovorin, with or without oxaliplatin, demonstrated that the addition of oxaliplatin significantly increases response rate and time to tumor progression, but not survival, over 5-FU plus leucovorin alone. The reasons for this discrepancy are unclear, and several possibilities are being considered. Additional phase III trials are underway to clarify the contribution of oxaliplatin in the treatment of patients with locally advanced and metastatic colorectal cancer.
Refractory (planetary science)
Cite
Citations (47)
oxaliplatin を含む化学療法により肝類洞障害が生じ，その結果，門脈圧が亢進し脾腫が生じる例があることが知られている。今回われわれは，oxaliplatin を含む化学療法により脾臓が増大し，oxaliplatin の休薬により縮小した大腸癌の2 例を報告する。なお脾臓体積の測定には医用画像処理ワークステーションZIOSTATION を用いた。ZIOSTATION 上で脾臓の3D 画像を作成し，その体積を測定した。症例1: 治療開始前137.82 mL であった脾臓はmFOLFOX6/bevacizumab による治療開始2 か月後160.96 mL に増大した。6 コース終了後神経障害のためoxaliplatin のみを休薬したところ151.58 mLに縮小した。神経障害改善後にoxaliplatin を再導入したところ脾臓は177.48 mL に増大したものの，再びoxaliplatin のみを休薬したところ158.52 mLに縮小した。症例2: 治療開始前105.84 mL であった脾臓はmFOLFOX6/bevacizumabによる治療開始10 か月後に228.54 mL に増大した。その後sLV5FU2/bevacizumab，さらにirinotecan 単剤へと移行したところ197.06 mL に縮小した。oxaliplatin 投与によって脾臓は増大するものの，oxaliplatin を休薬すれば脾臓の増大は可逆的である可能性がある。
Cite
Citations (0)
Aim: Cisplatin plus 5-fluorouracil (5-FU) or S-1 is a standard therapy for gastric cancer (GC). However, cisplatin is emetic and potentially nephrotoxic. Oxaliplatin may be less toxic, but few basic data are available for this setting. Here, we evaluated oxaliplatin for GC, by testing surgical specimens. Materials and Methods: We evaluated effects of oxaliplatin and 5-FU, alone and in combination, on surgical specimens from 11 patients with GC, using collagen gel droplet embedded culture drug tests. Results: Oxaliplatin was less efficacious than 5-FU, and its synergistic effect was less in tumors highly sensitive to 5-FU than in those with low sensitivity. Tumor differentiation and drug sensitivity were not correlated. Conclusion: Although oxaliplatin monotherapy had little effect on GC, we saw a limited synergistic effect of oxaliplatin with 5-FU in 5-FU-sensitive patients. Collagen gel droplet embedded culture drug tests may predict this synergistic effect, and help select candidates for this or other regimens.
Nephrotoxicity
Cite
Citations (7)