Mechanism of IFN- α combinedwith ATRA in liver cancer therapy in perioperative phase of intervention

Abstract

：Objective To study aadjunctive treatment that has a better curative effect and fewer side effects inperioperative phase of interventional therapy.Method An animal model of HCC CBRH7919 wasestablished by implanting 22 Wistar rats with tumor tissue.The hepatic artery was tied offon week 3 after formation of tumor.The rats were divided into 2 groups:(1)control group(n= 12): peritoneal injection with normal saline;(2)interferon-α(IFN-α)+all-transretinoic acid(ATRA)large dose group(n= 10): peritoneal injection with IFN-α(1million U/Kg qod)andATRA(10 mg/Kg qd).After the hepatic artery being tied off,the ratswere treated on the 1st day and sacrificed on 9th day.The levels of expression of tumormetastasis associated gene,protein,tumor mirovessel density,and tumor cells apoptosis weredetermined.Results The mRNA of tumor metastasis associated gene VEGF and bFGF weredetected by RT-PCR.bFGF and VEGF gene in tumor tissue of IFN-α+RA group reducedsignificantly as compared with control group(P＜0.05).The result of bF-GF andVEGF protein in tumor tissue analyzed by immunohistochemistry was accordant with theRT-PCR.The levels of bFGF and VEGF in IFN-α+RA group decreasedsignificantly: a few bFGF and little VEGF.The expression of VEGF in serum was detected byELISA.The level of VEGF was different significantly between control group and IFN-α+RAgroups(92.5 ±13.9 pg/ml vs 69.8 ±20.4 pg/ml,P＜0.05).Mirovesseldensity(MVD)was detected by immunohistochemistry.More new vessels were found in tumortissue of the control group.However,new vessels in the IFN-α+RA groups reducedsignificantly.The level of MVD in control group was 114 ± 18/HP vs 66 ± 5/HP in IFN-α+RAgroups(P＜0.05).In the detection of tumor cells apoptosis,more necrotic areawas found in tumor tissue of IFN-α+RA group.An significant increase inthe necrosis cells(Annexin V-Pi+)was analyzed by flow cytometer.Cell nucleus was dyed toindigo through TUNEL method,and unevenly distributional chromatin was observed bymicroscopy.Apoptotic index was(3.715 ±1.57)in control groups vs(12.34±4.78)% in IFN-α+RAgroup(P＜0.05).Conclusion Inhibition of tumor angiogenesis through IFN-α combined with RA therapy can stop growth and metastasize of livercancer.The early and combined treatment with two anti-tumor angiogenesis drugs inperioperative phase of intervention plays an important role in prevention of recurrenceand metastasis of liver cancer after surgery.