Hyperthermic Intraperitoneal Chemotherapy With Recombinant Mutant Human TNF-α And Raltitrexed In The Preclinical Model With Colorectal Peritoneal Carcinomatosis

Colorectal cancer(CRC)is one of the gastrointestinal malignancies with high mortality.Peritoneal metastasis often occurs in advanced colorectal cancer,which is an important marker of poor prognosis.The current standard treatment for colorectal peritoneal carcinomatosis is cytoreductive surgery and then hypertheimic intraperitoneal chemotherapy(HIPEC),which can benefit patients.While the drugs used for HIPEC are limited and the absolute advantage of any specific drug cannot be derived,we need to develop new chemotherapeutic drugs to provide patients with more and better options.Recombinant mutant human tumor necrosis factor-α(rmhTNF)was obtained by modifying TNF-α.rmhTNF has been used to treat malignant pleural effusions,non-Hodgkin’s lymphoma and non-small cell lung cancer in clinic.Raltitrexed(RTX)is an inhibitor of thymidylate synthetase,which is effective against a variety of cancers,especially advanced CRC.In this research,the effect of rmhTNF on human CRC cells,the synergistic effect of rmhTNF and hyperthermia(42℃,HT),and the therapeutic effect of rmh TNF and RTX with HIPEC on the mouse model with colorectal peritoneal carcinomatosis were studied by using in vitro and in vivo experimental methods.The results showed that rmhTNF could induce death in human CRC cells in a dose-dependent and time-dependent manner.In addition,HT enhanced rmhTNF-mediated cell death in human CRC cells,indicating that rmhTNF had synergistic effect with HT.Besides,rmhTNF combined with RTX could enhance the toxicity to human CRC cells,upregulate the expression of pro-apoptotic protein and promote cell apoptosis.A series of in vivo experimental methods were conducted in the mouse model with colorectal peritoneal carcinomatosis,and we found that HIPEC with rmhTNF and RTX could inhibit the growth and spread of tumor,upregulate the expression of pro-apoptotic protein in tumor tissue and enhance the apoptotic level of tumor tissue and cause irreversible cell damage without any serious toxic and side effects.Collectively,rmhTNF and RTX significantly inhibited the activity of colorectal cancer cells under the effect of HT in vitro,and HIPEC with rmhTNF and RTX had a great therapeutic effect on colorectal peritoneal carcinomatosis in mice,which could provide experimental data and basis for the clinical treatment of colorectal peritoneal carcinomatosis.