Objective: To study the effect of interferon-alpha (IFN-alpha) on the recurrence and metastasis of hepatocellular carcinoma (HCC) in nude mice, and to clarify if there is synergistic effect treated by combination of IFN-alpha and all-trans retinoic acid (ATRA).
Methods: The effect of IFN-alpha and/or ATRA on the proliferation of HCC cell lines was measured in vitro. The metastatic model of human HCC in nude mice LCI-D20 was used in present study. Curative resection was performed at 10th day after implantation in 44 nude mice. Drugs were given at the next day after resection. IFN-alpha was administered subcutaneously at doses of 3+/-10(5) U/day, 6+/-10(5) U/day, respectively. ATRA was administered p.o. at a dose of 20 mg/kg/day, and IFN-alpha 6+/-10(5)U/day combined with ATRA 20 mg/kg/day. The mice were sacrificed 35 days after treatment. The recurrent tumor size was measured and the presence of intrahepatic dissemination and lung metastases were recorded.
Results: The effect of IFN-alpha and/or ATRA on the proliferation of HCC cells SMMC7721, BEL-7402, BEL-7405, and MHCC97 was not obvious. The combination of IFN-alpha and ATRA had no synergistic effect in vitro. The lung metastatic rate, the liver recurrent rate, the size of main recurrent lesions, the number of intrahepatic disseminating nodules and the largest disseminating nodule of the controlled group was 100%(12/12), 100%(12/12), (1346.3+/-4.2 ) mm(3), 8.2+/-4.4, 864 mm(3), respectively; whereas it was 0, 87.5%(7/8), (8.7+/-2.9) mm(3), 2.3+/-0.6, and 7.8mm(3), respectively in the IFN-alpha 3+/-10(5) U/day treated group(P<0.05); 0, 12.5%(1/8), 0.5mm(3), 2, 0.5 mm(3) in the IFN-alpha 6+/-10(5)U/day treated group(P<0.05); 0, 12.5%(1/8), 1 mm(3), 2.5+/-0.7, 8 mm(3) in the IFN-alpha 3+/-10(5) U/day and ATRA treated group(P<0.05); 87.5%, 100%, (1472.6+/-5.6) mm(3), 7.3+/-3.8, 768.5 mm(3) in the ATRA treated group (P>0.05).
Conclusions: IFN-alpha has an inhibitory effect on intrahepatic recurrence and lung metastasis of human HCC after curative resection in nude mice, and the effect is enhanced with increasing dose. IFN-alpha and ATRA have no synergistic effect according to in vivo and in vitro test. ATRA has no effect on recurrence and metastasis of HCC.