PDF(Pubmed)
Abstract：
OBJECTIVE: Colorectal cancer (CRC) is the third-leading cause of death in the world. Although the prognosis has improved due to improvement of chemotherapy, metastatic CRC is still a recalcitrant disease, with a 5-year survival of only 13%. Irinotecan (IRN) is used as first-line chemotherapy for patients with unresectable CRC. However, there are severe side effects, such as neutropenia and diarrhea, which are dose-limiting. We have previously shown that methionine restriction (MR), effected by recombinant methioninase (rMETase), lowered the effective dose of IRN of colon-cancer cells in vitro. The aim of the present study was to evaluate the efficacy of the combination of low-dose IRN and MR on colon-cancer in nude mice.
METHODS: HCT-116 colon-cancer cells were cultured and subcutaneously injected into the flank of nude mice. After the tumor size reached approximately 100 mm3, 18 mice were randomized into three groups; Group 1: untreated control on a normal diet; Group 2: high-dose IRN on a normal diet (2 mg/kg, i.p.); Group 3: low-dose IRN (1 mg/kg i.p.) on MR effected by a methionine-depleted diet.
RESULTS: There was no significant difference between the control mice and the mice treated with high-dose IRN, without MR. However, low-dose IRN combined with MR was significantly more effective than the control and arrested colon-cancer growth (p=0.03). Body weight loss was reversible in the mice treated by low-dose IRN combined with MR.
CONCLUSIONS: The combination of low-dose IRN and MR acted synergistically in arresting HCT-116 colon-cancer grown in nude mice. The present study indicates the MR has the potential to reduce the effective dose of IRN in the clinic.
METHODS: HCT-116 colon-cancer cells were cultured and subcutaneously injected into the flank of nude mice. After the tumor size reached approximately 100 mm3, 18 mice were randomized into three groups; Group 1: untreated control on a normal diet; Group 2: high-dose IRN on a normal diet (2 mg/kg, i.p.); Group 3: low-dose IRN (1 mg/kg i.p.) on MR effected by a methionine-depleted diet.
RESULTS: There was no significant difference between the control mice and the mice treated with high-dose IRN, without MR. However, low-dose IRN combined with MR was significantly more effective than the control and arrested colon-cancer growth (p=0.03). Body weight loss was reversible in the mice treated by low-dose IRN combined with MR.
CONCLUSIONS: The combination of low-dose IRN and MR acted synergistically in arresting HCT-116 colon-cancer grown in nude mice. The present study indicates the MR has the potential to reduce the effective dose of IRN in the clinic.
摘要：
目的：结直肠癌（CRC）是世界上第三大死亡原因。尽管由于化疗的改善，预后有所改善，转移性CRC仍然是一种顽固性疾病，5年生存率仅为13%。伊立替康（IRN）被用作不可切除的CRC患者的一线化疗。然而,有严重的副作用，比如中性粒细胞减少症和腹泻,这是剂量限制。我们之前已经证明蛋氨酸限制(MR)，受重组蛋氨酸酶(rMETase)影响，降低了体外结肠癌细胞IRN的有效剂量。本研究的目的是评估低剂量IRN和MR组合对裸鼠结肠癌的疗效。
方法：培养HCT-116结肠癌细胞，并皮下注射到裸鼠腹侧。肿瘤大小达到约100mm3后，将18只小鼠随机分为三组；第1组：正常饮食的未经处理的对照；第2组：正常饮食的高剂量IRN（2mg/kg，i.p.）；第3组：低剂量IRN（1mg/kgi.p.）对甲硫氨酸耗尽的饮食影响的MR。
结果：对照小鼠与高剂量IRN治疗小鼠之间没有显着差异，没有先生。然而,低剂量IRN联合MR的治疗效果明显优于对照组,并且抑制了结肠癌的生长(p=0.03).在低剂量IRN联合MR治疗的小鼠中，体重减轻是可逆的。
结论：低剂量IRN和MR的组合在阻止裸鼠中生长的HCT-116结肠癌方面起协同作用。本研究表明，MR具有降低临床IRN有效剂量的潜力。
方法：培养HCT-116结肠癌细胞，并皮下注射到裸鼠腹侧。肿瘤大小达到约100mm3后，将18只小鼠随机分为三组；第1组：正常饮食的未经处理的对照；第2组：正常饮食的高剂量IRN（2mg/kg，i.p.）；第3组：低剂量IRN（1mg/kgi.p.）对甲硫氨酸耗尽的饮食影响的MR。
结果：对照小鼠与高剂量IRN治疗小鼠之间没有显着差异，没有先生。然而,低剂量IRN联合MR的治疗效果明显优于对照组,并且抑制了结肠癌的生长(p=0.03).在低剂量IRN联合MR治疗的小鼠中，体重减轻是可逆的。
结论：低剂量IRN和MR的组合在阻止裸鼠中生长的HCT-116结肠癌方面起协同作用。本研究表明，MR具有降低临床IRN有效剂量的潜力。
