Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. In vitro, we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. In vivo, we established xenograft models of CRC-PC and assessed the antitumor effect by in vivo imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly in vitro, and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited in vivo. Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application.
Impact statement
Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both in vitro and vivo. The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.
BrayFFerlayJSoerjomataramISiegelRLTorreLAJemalA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin2018;
68:394–424
2.
TiwariAKLaird-FickHSWaliRKRoyHK.Surveillance for gastrointestinal malignancies. World J Gastroenterol2012;
18:4507–16
3.
CoccoliniFGhezaFLottiMVirziSIuscoDGhermandiCMelottiRBaiocchiGGiuliniSMAnsaloniLCatenaF.Peritoneal carcinomatosis. World J Gastroenterol2013;
19:6979–94
4.
PelzJOChuaTCEsquivelJStojadinovicADoerferJMorrisDLMaederUGermerCTKerscherAG.Evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective peritoneal surface disease severity score (PSDSS) for peritoneal carcinomatosis of colorectal origin. BMC Cancer2010;
10:689–90
5.
HuangYAlzahraniNAChuaTCLiauwWMorrisDL.Impacts of low peritoneal cancer index on the survival outcomes of patient with peritoneal carcinomatosis of colorectal origin. Int J Surg2015;
23:181–5
6.
BhandareMPatilPPaiVBhamreREngineerROstwalVSaklaniA.Peritoneal carcinomatosis in colorectal cancers – management perspective needs a change. Clin Colorectal Cancer2017;
16:e1–e6
7.
VallicelliCCavaliereDCatenaFCoccoliniFAnsaloniLPoiasinaEAbongwaHKSimoneBDAlbericiLFramariniMVerdecchiaGM.Management of peritoneal carcinomatosis from colorectal cancer: review of the literature. Int J Colorectal Dis2014;
29:895–8
8.
HeldermanRLokeDRKokHPOeiALTanisPJFrankenNCrezeeJ.Variation in clinical application of hyperthermic intraperitoneal chemotherapy: a review. Cancers2019;
11:78–96
9.
VerwaalVJRuthSWitkampABootHSlootenGZoetmulderF.Long-term survival of peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol2005;
12:65–71
10.
VerwaalVJBruinSBootHSlootenG.Tinteren Hv. 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol2008;
15:2426–32
11.
QiuCLiYLiangXQiYChenYMengXZhengHXuYCaiSCaiGLiuJ.A study of peritoneal metastatic xenograft model of colorectal cancer in the treatment of hyperthermic intraperitoneal chemotherapy with raltitrexed. Biomed Pharmacother2017;
92:149–56
12.
JungH.Interaction of thermotolerance and thermosensitization induced in CHO cells by combined hyperthermic treatments at 40 and 43°C.Radiat Res1982;
91:433–46
13.
SugarbakerPIhemelanduCBijelicL.Cytoreductive surgery and HIPEC as a treatment option for laparoscopic resection of uterine leiomyosarcoma with morcellation: early results. Ann Surg Oncol2015;
23:1501–7
14.
NeuwirthMGAlexanderHRKarakousisGC.Then and now: cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), a historical perspective. J Gastrointest Oncol2016;
7:18–28
15.
QuenetFEliasDRocaLGoereDGhoutiLPocardMFacyO.A UNICANCER phase III trial of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis. Eur J Surg Oncol2019;
45:e17
16.
ShanLBaiBLvYXieBHuangXZhuH.Lobaplatin suppresses proliferation and peritoneal metastasis of colorectal cancer in a preclinical model. Biomed Pharmacother2018;
108:486–91
17.
HaranakaKSatomiNSakuraiA.Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice.Int J Cancer1984;
34:263–7
18.
RobertsNJZhouSJr.LADHoldhoffM.Systemic use of tumor necrosis factor alpha as an anticancer agent (review. Oncotarget2011;
2:739–51
19.
LejeuneFJRueggCLienardD.Clinical applications of TNF-α in cancer.Curr Opin Immunol1998;
10:573–80
20.
YanZZhaoNWangZLiBBaoCShiJHanWZhangY.A mutated human tumor necrosis factor-alpha improves the therapeutic index in vitro and in vivo.Cytotherapy2006;
8:415–23
21.
LiMXuTZhangZXueXZhangCQinXLiWHaoQZhangWZhangY.Phase II multicenter, randomized, double-blind study of recombinant mutated human tumor necrosis factor-alpha in combination with chemotherapies in cancer patients. Cancer Sci2012;
103:288–95
22.
JiangCNiuJLiMTengYWangHZhangY.Tumor vasculature-targeted recombinant mutated human TNF-α enhanced the antitumor activity of doxorubicin by increasing tumor vessel permeability in mouse xenograft models.PLoS One2014;
9:e87036
23.
JiWYuanMZhangLZhangHJiaoJGaoZ.Effect of p53beta on human gastric cancer cells treated with recombinant mutated human TNF and cisplatin. Mol Med Rep2017;
15:3865–70
24.
XueSChenYQinSYangAWangLXuHGengH.Raltitrexed induces mitochondrialmediated apoptosis in SGC7901 human gastric cancer cells. Mol Med Rep2014;
10:1927–34
DingWLiuSMaJPuJWangHZhangSSunX.Raltitrexed increases radiation sensitivity of esophageal squamous carcinoma cells. Cancer Cell Int2019;
19:36–47
27.
RansomDWilsonKFournierMSimesRJGebskiVYipDTebbuttNKarapetisCSFerryDGordonSPriceTJ.Final results of Australasian gastrointestinal trials group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines. Ann Oncol2014;
25:117–21
28.
ChenYWuJChengKLiZLuoDQiuMGouHYiCLiQWangX.S-1 plus raltitrexed for refractory metastatic colorectal cancer: a phase II trial. Oncologist2019;
24:591–e165
29.
LiYChenYQiuCMaXLeiKCaiGLiangXLiuJ.17-allylamino-17-demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species-induced cell death. J Cell Biochem2018;
120:1560–76
30.
WangHYanZShiJHanWZhangY.Expression, purification, and characterization of a neovasculature targeted rmhTNF-alpha in Escherichia coli. Protein Expr Purif2006;
45:60–5
31.
XiaLZhouY.rmhTNF-α combined with cisplatin inhibits proliferation of A549 cell line in vitro. Chin Med Sci J2014;
29:185–7
32.
ZhangAZhengYQueZZhangLLinSLeVLiuJTianJ.Astragaloside IV inhibits progression of lung cancer by mediating immune function of tregs and CTLs by interfering with IDO. J Cancer Res Clin Oncol2014;
140:1883–90
33.
AartsFHendriksTBoermanOCKoppeMJOyenWJGBleichrodtRP.A comparison between radioimmunotherapy and hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis of colonic origin in rats. Ann Surg Oncol2007;
14:3274–82
34.
MaoRZouFYangLLinSLiYMaMYinPLiangXLiuJ.The loss of MiR-139-5p promotes colitis-associated tumorigenesis by mediating PI3K/AKT/wnt signaling. Int J Biochem Cell Biol2015;
69:153–61
35.
JayneDGFookSLoiCSeow-ChoenF.Peritoneal carcinomatosis from colorectal cancer. Br J Surg2002;
89:1545–50
36.
KuramochiHAndoMItabashiMNakajimaGKawakamiKHamanoMHiraiEYokomizoHOkuyamaRAraidaTYoshimatsuKKameokaSHayashiK.Phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, and bevacizumab. Cancer Chemother Pharmacol2017;
79:579–85
KrieglerMPerezCDeFayKAlbertILuSD.A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell1988;
53:45–53
39.
SchillerJHStorerBEWittPLAlbertiDTombesMBArzoomanianR.Biological and clinical effects of intravenous tumor-necrosis-factor-alpha administered 3 times weekly. Cancer Res1991;
51:1651–8
40.
SpacekMMitasPVockaMLacinaLHodkovaGSpundaR.Isolated perfusion of the upper extremity with TNF-alpha – double venous cannulation. Klin Onkol2017;
30:213–9
41.
YeHLuCZhengS.Drug selection in isolated hepatic perfusion for nonresectable liver tumors: recent trends and perspectives. World Chinese J Digestol2008;
23:2621–5
42.
SantoroARimassaLSobreroAFCitterioGSclafaniFCarnaghiCPessinoACaprioniF.Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy. Eur J Cancer2010;
46:2746–52
43.
ZeeJGonzalezDGRhoonGCvDijkJPuttenWHartA.Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Lancet2000;
355:1119–25
44.
RotiJ.Cellular responses to hyperthermia (40-46 degrees C): cell killing and molecular events. Int J Hyperthermia2008;
24:3–15
45.
LiuXZhangXZhengZLuHWuXHuangCWangCGuangG.The effect of chemotherapy combined with recombination mutant human tumor necrosis factor on advanced cancer. J Transl Med2004;
2:33–40
46.
ShangZMTangJDJiangQQGuoAZhangNGaoZXJiWS.Role of Δ133p53 in tumor necrosis factor-induced survival of p53 functions in MKN45 gastric cancer cell line. Eur Rev Med Pharmacol Sci2015;
19:2416–22
47.
GuoJZhangHGaoSZhangPLiXChenHWangXZhuX.Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis. World J Gastroenterol2017;
23:1406–11
48.
LiGDongSQuJSunZHuangZYeLLiangHAiXZhangWChenX.Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumour necrosis factor-alpha in chemotherapy of multidrug-resistant hepatocellular carcinoma. Liver Int2010;
30:585–92
49.
LiMQinXXueXZhangCYanZHanWKomarckCWangTDZhangY.Safety evaluation and pharmacokinetics of a novel human tumor necrosis factor-alpha exhibited a higher antitumor activity and a lower systemic toxicity. Anticancer Drugs2010;
21:243–51
