Background:The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor, but promising effects of chemotherapies combined with interferon (IFN) have been reported.
Methods:To develop more effective combination therapies for HCC, we compared the antiproliferative effects of IFN-α and IFN-β in combination with various cytotoxic drugs on hepatoma cell lines using MTT assay and isobologram analysis.
Results:IFN-β was more potent than IFN-α in inhibiting the cell growth of all cell lines (P < .05, two-way ANOVA). PLC/PRF/5 was more sensitive to either IFN, than HLE and HuH7. Cell growth of all cell lines was inhibited in a dose-dependent manner by 5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX), but the sensitivities of these cells were considerably different. As for IFN-α, synergistic effects were observed when combined with 5-FU and DOX on PLC/PRF/5 cells only, whereas IFN-β showed synergistic effects with 5-FU and CDDP on HuH7 and PLC/PRF/5 cell lines.
Conclusion:The spectra of the antiproliferative activity and synergistic effect of IFN-β when combined with anticancer drugs are more potent than those of IFN-α. Combinations of IFN-β and anticancer drugs may provide a better treatment of HCC when combinations with IFN-α are ineffective.
Interferon Anticancer drug Cell proliferation HCC Combination therapy
Leung TW, Tang AM, Zee B, et al. Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-α, doxorubicin and 5-fluorouracil chemotherapy. Cancer 2002; 94: 421–7.PubMedCrossRefGoogle Scholar
Urabe T, Kaneko S, Matsushita E, Unoura M, Kobayashi K. Clinical pilot study of intrahepatic arterial chemotherapy with methotrexate, 5-fluorouracil, cisplatin and subcutaneous interferon-α-2b for patients with locally advanced hepatocellular carcinoma. Oncology 1998; 55: 39–47.PubMedCrossRefGoogle Scholar
Sakon M, Nagano H, Dono K, et al. Combined intraarterial 5-fluorouracil and subcutaneous interferon-α therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches. Cancer 2002; 94: 435–42.PubMedCrossRefGoogle Scholar
Stuart K, Tessitore J, Huberman M. 5-Fluorouracil and α-interferon in hepatocellular carcinoma. Am J Clin Oncol 1996; 19: 136–9.PubMedCrossRefGoogle Scholar
Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998; 67: 227–64.PubMedCrossRefGoogle Scholar
Berenbaum MC. Criteria for analyzing interactions between biologically active agents. Adv Cancer Res 1981; 35: 269–335.PubMedCrossRefGoogle Scholar
Von Hoff DD, Casper J, Bradley E, Sandbach J, Jones D, Makuch R. Association between human tumor colony-forming assay results and response of an individual patient’s tumor to chemotherapy. Am J Med 1981; 70: 1027–41.PubMedCrossRefGoogle Scholar
Horikoshi T, Fukuzawa K, Hanada N, et al. In vitro comparative study of the antitumor effects of human interferon-α, β and γ on the growth and invasive potential of human melanoma cells. J Dermatol 1995; 22: 631–6.PubMedGoogle Scholar
Giandomenico V, Vaccari G, Fiorucci G, et al. Apoptosis and growth inhibition of squamous carcinoma cells treated with interferon-α, IFN-β and retinoic acid are associated with induction of the cyclin-dependent kinase inhibitor p21. Eur Cytokine Netw 1998; 9: 619–31.PubMedGoogle Scholar
Coradini D, Biffi A, Pirronello E, Di Fronzo G. The effect of α-, β- and γ-interferon on the growth of breast cancer cell lines. Anticancer Res 1994; 14: 1779–84.PubMedGoogle Scholar
Shen H, Zhang M, Minuk GY, Gong Y. Different effects of rat interferon α, β and γ on rat hepatic stellate cell proliferation and activation. BMC Cell Biol 2002; 3: 9–16.PubMedCrossRefGoogle Scholar
Platanias LC, Uddin S, Domanski P, Colamonici OR. Differences in interferon alpha and beta signaling. Interferon beta selectively induces the interaction of the α and βL subunits of the type I interferon receptor. J Biol Chem 1996; 271: 23630–3.PubMedCrossRefGoogle Scholar
Russell-Harde D, Wagner TC, Perez HD, Croze E. Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation. Biochem Biophys Res Commun 1999; 255: 539–44.PubMedCrossRefGoogle Scholar
Chawla-Sarkar M, Leaman DW, Borden EC. Preferential induction of apoptosis by interferon (IFN)-beta compared with IFN-α2: correlation with TRAIL/Apo2L induction in melanoma cell lines. Clin Cancer Res 2001; 7: 1821–31.PubMedGoogle Scholar
Qin XQ, Runkel L, Deck C, DeDios C, Barsoum J. Interferon-beta induces S phase accumulation selectively in human transformed cells. J Interferon Cytokine Res 1997; 17: 355–67.PubMedCrossRefGoogle Scholar
Sangfelt O, Strander H. Apoptosis and cell growth inhibition as antitumor effector functions of interferons. Med Oncol 2001; 18: 3–14.PubMedCrossRefGoogle Scholar
Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 2001; 6: 34–55.PubMedCrossRefGoogle Scholar
Kreuser ED, Wadler S, Thiel E. Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Recent Results Cancer Res 1995; 139: 371–82.PubMedGoogle Scholar
Makower D, Wadler S. Interferons as biomodulators of fluoropyrimidines in the treatment of colorectal cancer. Seminin Oncol 1999; 26: 663–71.Google Scholar
Eguchi H, Nagano H, Yamamoto H, et al. Augmentation of antitumor activity of 5-fluorouracil by interferon alpha is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells. Clin Cancer Res 2000; 6: 2881–90.PubMedGoogle Scholar
Kondo M, Nagano H, Sakon M, et al. Expression of interferon alpha/beta receptor in human hepatocellular carcinoma. Int J Oncol 2000; 17: 83–8.PubMedGoogle Scholar