Oncolytic viral gene therapy for prostate cancer using two attenuated,replication-competent,genetically engineered herpes simplex viruses

BACKGROUND: Attenuated, replication-competent herpes simplex virus mutants offer an exciting new modality in cancer therapy through their ability to selectively replicate within and kill malignant cells with minimal harm to normal tissues. METHODS: This study investigates the efficacy of two such viruses, G207 and NV1020, in human prostatic carcinoma. In vitro studies were performed on four human prostatic carcinoma cell lines, and in vivo single/multiple dose studies were undertaken on mice by using two human cell types. Tumor volume, histopathology at necropsy, and serum prostate specific antigen (PSA) were used as measures of antiproliferative effect in the in vivo experiments. RESULTS: Both viruses were effective in producing cytolytic effects in vitro at various multiplicities of infection in all cell lines tested. Both viruses demonstrated antitumor effects in vivo with a statistically significant decrease in serum PSA and inhibition of growth of both PC-3 and C4-2 subcutaneous xenografts. Tumor-free animals at necropsy were observed in the treated groups but not in control animals. CONCLUSION: These results display impressive activity against human prostate cancer and offer promise for the use of this modality in the future.     

G207, modified herpes simplex virus type 1, kills human pancreatic cancer cells in vitro

Pancreatic cancer is often fetal, and farther effective therapeutic options are needed. This study was designed to assess whether the replication-restricted herpes simplex virus, G207, was effective in killing human pancreatic cancer cells in vitro. G207, a multimutated strain of herpes simplex virus type 1 carrying lacZ reporter gene, is capable of efficient cytolytic growth in many dividing cells, including certain tumor cells, but not in nondividing cells. Three human pancreatic cell lines, AsPC-1, MIA PaCa-2, and BxPC-3, were infected with G207 at different multiplicities of infection. After 24 hours, expression of the lacZ reporter gene was tested using a histochemical X-gal assay. In addition, cell lines were infected with G207 for 24 to 48 hours; then the virus obtained from cell pellets and media supernatant was used to infect Vero cells to obtain G207 titers by plaque assay. To assess whether increasing viral immediate early gene expression would improve cytolysis and virus production, similar experiments were performed with the addition of 0.5 mmol/L of hexamethylene bisacetamide (HMBA) 1 hour after viral infection. Finally, MTS cell viability assays were performed to measure viable cells at 24 to 96 hours post infection. The X-gal assay data revealed a viral dose-dependent β-galactosidase expression, indicating G207 infectivity and expression of the lacZ reporter gene. Plaque assays demonstrated a viral dose-dependent increase in plaque formation, indicating viral production from all three cell lines. In addition, HMBA data indicated a modest increase in viral production. The MTS assay data indicated a dose-dependent cytotoxicity for G207 in the cell lines tested. G207 infects, replicates in, and is cytotoxic to the above-listed human pancreatic cell lines in vitro and warrants therapeutic evaluation in models of pancreatic cancer. Supported by the Wilmot Cancer Research Fellowship Program funded by the James P. Wilmot Foundation. Presented at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20,1998.     

Effective treatment of pancreatic tumors with two multimutated herpes simplex oncolytic viruses

Pancreatic cancer is an aggressive, rapidly fatal disease against which current nonsurgical therapy has minimal impact. This study evaluates the efficacy of two novel, replication-competent, multimutated herpes viruses (G207 and NV1020) in an experimental model of pancreatic cancer. Four human pancreatic carcinoma cell lines were exposed to G207 or NV1020, and cell survival and viral progeny production were determined. Flank tumors in athymic mice were subjected to single or multiple injections of 1 X 10⁷ G207 or NV1020, and tumor volume was evaluated over time. For all of the cell lines, G207 and NV1020 produced infection, viral replication, and cell lysis (P <0.05). NV1020 resulted in a higher production of viral progeny compared to G207. The efficacy of viral tumor cell kill was greatest in those cells with the shortest in vitro doubling time. For flank tumors derived from hs766t, single or multiple injections of both viruses were equally effective and significantly reduced flank tumor burden (P <0.05). Complete hs766t flank tumor eradication was achieved in 25% (5 of 20) of animals treated with G207 and 40% (8 of 20) of animals treated with NV1020. In vivo efficacy correlated with in vivo tumor doubling time. There were no adverse effects related to viral administration observed in any animal. NV1020 and G2O7 effectively infect and kill human pancreatic cancer cells in vitro and in vivo. Given the lack of effective nonoperative treatments for pancreatic cancer, oncolytic herpes viruses should be considered for clinical evaluation. Presented in part at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

Effect of gene therapy with the herpes simplex virus-thymidine kinase gene on hepatic metastasis in murine colon cancer

Hepatic metastasis of colon cancer is an important prognostic factor for survival. In this study, we examined the effect of gene therapy using the herpes simplex virus-thymidine kinase (HS-tk) gene with short-course ganciclovir (GCV) treatment for multiple hepatic metastases of murine colon cancer. Colon26 cells transfected with the (HS-tk) gene were found to be sensitive to GCV in a concentration-dependent way. On the other hand, induction of theHS-tk gene in the cells had no influence on cell growth in vitro. However, multiple hepatic metastases of Colon26 cells transfected withHS-tk gene were significantly suppressed by the GCV treatment. These results thus suggest thatHS-tk gene therapy is useful for the treatment of hepatic metastasis in colon cancer.     

腺病毒介导的胸苷激酶基因治疗肝癌的研究进展

肝癌是我国常见的恶性肿瘤,针对肝癌的传统治疗方法疗效欠佳、患者预后较差.近10余年来,随着分子生物学技术的发展,肝癌的基因治疗成为该领域新的研究方向和热点,其中以腺病毒为载体的单纯疱疹病毒胸苷激酶自杀基因系统（ADV-tk）对肝癌的治疗研究开展得最早也最为广泛.其原理是把单纯疱疹病毒胸苷激酶基因通过腺病毒导入细胞内,利用其产生的酶将无毒的药物前体更昔洛韦（GCV）转变成细胞毒性产物,从而杀死肝癌细胞.多项动物实验和临床研究结果表明：ADV-tk/GCV系统是治疗肝癌的有效方法.本文总结近年来ADV-tk/GCV系统在肝癌治疗中取得的研究进展,分别从载体的发展过程、基因的作用机制、导入方式、增强杀伤效力、降低肝毒性以及相关动物模型的改进等几个方面进行综述.     

Microwave coagulation therapy for hepatocellular carcinoma

The efficacy and safety of microwave coagulation therapy (MCT) in patients with hepatocellular carcinoma (HCC) and impaired hepatic reserve were studied. Preoperative background factors, postoperative results, and prognostic factors were compared in 51 patients who underwent hepatic resection (HR group) and 38 patients who underwent microwave coagulation therapy (MCT group). Before surgery, measures of hepatic function, including level of albumin (P = 0.0072), prothrombin time (P < 0.0001), hepaplastin test (P = 0.0088), and the radioactivity of technetium-99m galactosyl-human serum albumin 15 min in the liver after injection divided by that in both liver and heart (P < 0.0001) were significantly lower in the MCT group than in the HR group. The indocyanine green dye retention rate at 15 min was significantly greater (P < 0.0001) in the MCT group than in the HR group, and a significant difference was noted in Child-Pugh grade between the groups (P < 0.0001). Operative time (P = 0.0014) and blood loss during surgery (P = 0.0005) were significantly lower in the MCT group than in the HR group. In contrast, no significant differences were recognized between the groups in the changes in postoperative liver function, or in the rates of morbidity, mortality, local recurrence, and survival. Moreover, the type of treatment (HR or MCT) was not a prognostic factor. The results indicate that MCT can be used safely as an alternative to hepatic resection in patients with poor liver function without reducing the efficacy of local control. Received for publication on Jan. 17, 2000; accepted on April 1, 2000     

Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinoma

Tumor hypoxia induces vascular endothelial growth factor (VEGF) expression, which stimulates tumor angiogenesis. The VEGF pathway is inhibited by soluble VEGF receptors (soluble fetal liver kinase-1 [sFlk-1]) that bind VEGF and block its interaction with endothelial cells. Herpes simplex virus (HSV)-derived amplicons are replication-incompetent viruses used for gene delivery. We attempt to attenuate angiogenesis and inhibit hepatoma growth through amplicon-mediated expression of sFlk-1 under hypoxic control. A multimerized hypoxia-responsive enhancer (10xHRE) was cloned upstream of the sFlk-1 gene (10xHRE/sFlk-1). An amplicon expressing 10xHRE/sFlk-1 was genetically engineered (HSV10xHRE/sFlk-1). SK-HEP-1 human hepatoma cells were transduced with HSV10xHRE/sFlk-1 and incubated in normoxia (21% O₂) or hypoxia (1% O₂). Human umbilical vein endothelial cell assay evaluated capillary inhibition. Western blot assessed sFlk-1 expression. SK-HEP-1 flank tumors (n = 24) in athymic mice were treated with HSV10xHRE/sFlk-1. Media from hypoxic SK-HEP-1 transduced with HSV10xHRE/sFlk-1 yielded an 80% reduction in capillary formation (P < 0.005), whereas normoxic SK-HEP-1 yielded a 25% reduction (P < 0.05). Western blot of SK-HEP-1 transduced with HSV10xHRE/sFlk-1 demonstrated greater sFlk-1 expression in hypoxia vs. normoxia. SK-HEP-1 tumors treated with HSV10xHRE/sFlk-1 yielded a 72% reduction in volume vs. the control group (P < 0.000001). HSV amplicon-mediated delivery of a hypoxia-inducible soluble VEGF receptor substantially reduces new vessel formation and tumor growth in hepatoma. Presented at the Forty-Fifth Annual Meeting of the Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 15–19, 2004 (oral presentation). Supported in part by grants RO1 CA 76416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant MBC-99366 (Y.F.) from the American Cancer Society, and grant BC024118 from the US Army and Rochester Nathan Shock Center.     

乙型肝炎病毒相关肝细胞癌抗病毒治疗的作用和意义

肝细胞癌(hepatocellular carcinoma,HCC)为我国常见恶性肿瘤,虽然肝脏外科技术飞速发展,但近30年来肝癌病人预后无明显改善,大家往往重视局部治疗,对肝癌病人的全身综合治疗关注不够,尤其是忽视了对我国肝癌的最主要致病因素乙型肝炎病毒(hepatitis B virus,HBV)的研究和有效治疗。结合我们自己在这一方面前期的研究结果以及国内外近年来发表的相关文献,系统阐述了HBV相关HCC抗病毒治疗的作用和意义。抗病毒治疗可有效预防肝癌病人HBV再激活,改善HCC病人肝脏炎症、肝纤维化,显著降低肝癌术后复发率,提高生存率。并讨论核苷类抗病毒治疗的适应证、药物选择以及治疗疗程等相关问题。研究结果还显示抗病毒应答时间快慢、病毒耐药变异等均是影响HCC术后复发的危险因素,因此选择速效、低耐药核苷类药物。并主张长期抗病毒治疗,以最大限度改善HBV相关HCC病人预后。积极有效的抗病毒治疗应该成为HBV相关HCC病人综合治疗的重要组成部分。     

单纯疱疹Ⅰ型病毒载体与慢性疼痛基因治疗的研究现状和进展

慢性疼痛是一个巨大的医疗难题,目前传统的治疗方法都存在一定局限性,疼痛基因治疗是一种全新的治疗方式,HSV-Ⅰ具有天然嗜神经性,适合神经系统转基因治疗,现就HSV-Ⅰ载体及其转前脑啡肽原基因在炎性疼痛、神经病理性疼痛、癌性疼痛中的应用作一综述.     

经肝动脉或瘤体注射单纯疱疹病毒-胸苷激酶基因治疗兔肝癌

目的　观察瘤体内直接注射或经肝动脉注射载有单纯疱疹病毒胸苷激酶 (HSV TK)基因的EB病毒表达质粒 pDR2 /TK、丙氧鸟苷 (GCV )对原位兔肝癌的治疗效果。 方法　制作兔原位肝癌模型 (VX2 ) ,瘤体注射或经肝动脉注射质粒 pDR2 /TK ,腹腔注射GCV连续 10d。RT PCR检测肝癌HSV TK表达 ;螺旋CT监测肝癌大小 ,并观察兔存活时间。结果TK基因导入 10d后 ,直接注射组TK在肝癌组织强表达 ,癌旁组织弱表达 ,正常肝组织不表达 ;肝动脉注射组TK基因在肝癌表达稍强于癌旁及正常肝组织。直接注射组肿瘤大小 ( 3 .5 5± 0 .3 9)cm ,与经肝动脉注射+肝动脉结扎组肿瘤大小 ( 3 .70± 0 .3 7)cm无明显差别 (P >0 .0 5 ) ,但均明显小于对照组。瘤体直接注射TK基因 +GCV治疗组动物平均存活时间 ( 5 9.8± 3 .3 )d、肝动脉注射组 +肝动脉结扎组( 5 4.8± 4.5 )d明显长于各对照组 (P均 <0 .0 1)。结论　对实验性兔肝癌 ,瘤体内直接注射或经肝动脉注射导入治疗基因后 ,HSV TK/GCV系统具有较好的治疗效果。     

肝动脉灌注化疗在肝癌转化治疗中的作用

根治性切除是肝癌病人得以长期生存的主要治疗手段,然而我国肝癌诊断时大部分为中晚期,可行根治性切除者＜30％.众多学者尝试利用多种方式对初始不可切除肝癌进行转化治疗,力争缩小肿瘤或使肝癌降期,以创造更多手术切除机会.近年来,奥沙利铂/亚叶酸钙/5-氟尿嘧啶(FOLFOX)方案肝动脉灌注化疗在不可切除肝癌病人中呈现出明显优...     

免疫联合靶向治疗在晚期肝癌转化治疗中的研究进展

随着肝细胞癌(HCC)发病机制研究的深入,晚期肝癌已经进入到了多种方式、多种药物联合使用的综合治疗时代,尤其是免疫治疗、免疫联合抗血管靶向治疗以及肝动脉灌注化疗等降期转化治疗取得了显著的疗效,给晚期肝癌患者带来了希望。目前免疫联合靶向药物治疗晚期肝癌已经成为了国内外研究的热点之一,阿特利珠单抗联合贝伐珠单抗(T+A)方案更是作为一线治疗方案正式写入了多个指南之中。本文就免疫联合靶向治疗研究进展、适用人群、疗效监测方面进行讨论。     

免疫联合靶向治疗在晚期肝癌转化治疗中的研究进展

随着肝细胞癌(HCC)发病机制研究的深入,晚期肝癌已经进入到了多种方式、多种药物联合使用的综合治疗时代,尤其是免疫治疗、免疫联合抗血管靶向治疗以及肝动脉灌注化疗等降期转化治疗取得了显著的疗效,给晚期肝癌患者带来了希望。目前免疫联合靶向药物治疗晚期肝癌已经成为了国内外研究的热点之一,阿特利珠单抗联合贝伐珠单抗(T+A)方案更是作为一线治疗方案正式写入了多个指南之中。本文就免疫联合靶向治疗研究进展、适用人群、疗效监测方面进行讨论。     

5-Fluorouracil and gemcitabine potentiate the efficacy of oncolytic herpes viral gene therapy in the treatment of pancreatic cancer

Oncolytic herpes viruses are attenuated, replication-competent viruses that selectively infect, replicate within, and lyse cancer cells and are highly efficacious in the treatment of a wide variety of experimental cancers. The current study seeks to define the pharmacologic interactions between chemotherapeutic drugs and the oncolytic herpes viral strain NV1066 in the treatment of pancreatic cancer cell lines. The human pancreatic cancer cell lines Hs 700T, PANC-1, and MIA P_aC_a-2 were treated in vitro with NV1066 at multiplicities of infection (MOI; ratio of the number of viral particles per tumor cell) ranging from 0.01 to 1.0 with or without 5-fluorouracil (5-FU) or gemcitabine. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Viral replication was measured using a standard plaque assay. Six days after combination therapy, 76% of Hs 700T cells were killed compared with 43% with NV1066 infection alone (MOI = 0.1) or 0% with 5-FU alone (2 βmol/L) (P < .01). Isobologram and combination-index analyses confirmed a strongly synergistic pharmacologic interaction between the agents at all viral and drug combinations tested (LD5 to LD95) in the three cell lines. Dose reductions up to 6- and 78-fold may be achieved with combination therapy for NV1066 and 5-FU, respectively, without compromising cell kill. 5-FU increased viral replication up to 19-fold compared with cells treated with virus alone. Similar results were observed by combining gemcitabine and NV1066. We have demonstrated that 5-FU and gemcitabine potentiate oncolytic herpes viral replication and cytotoxicity across a range of clinically achievable doses in the treatment of human pancreatic cancer cell lines. The potential clinical implications of this synergistic interaction include improvements in efficacy, treatment-associated toxicity, tolerability of therapeutic regimens, and quality of life. These data provide the cellular basis for the clinical investigation of combined oncolytic herpes virus therapy and chemotherapy in the treatment of pancreatic cancer. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 141-18, 2005 (oral presentation). Supported in part by training grant T 32 CA09501 (D.P.E. and K.J.H.), AACR-AstraZeneca Cancer Research and Prevention fellowship (P.S.A), grants RO1 CA 76416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant BC024118 from the U.S. Army (Y.F.), grant IMG0402501 from the Susan G. Komen Foundation (Y.F.), and grant 032047 from Flight Attendant Medical Research Institute (Y.F.).     

Repeat hepatectomy is the most useful treatment for recurrent hepatocellular carcinoma

Hepatic resection has been regarded as a curative treatment for primary hepatocellular carcinoma (HCC), but a high incidence of postoperative recurrence is general. Thus it is important to predict the patterns of recurrence and select the appropriate treatment for recurrence for a better long-term prognosis of patients with HCC. Clinicopathological studies on 80 patients with intrahepatic recurrence after curative hepatectomy suggested that nodular-type recurrence with up to three nodules is mainly due to metachronous multicentric hepatocarcinogenesis rather than intrahepatic metastases. We reviewed 300 patients with recurrent HCC, and repeat hepatectomy was done in 78 cases (26.0%). The 3- and 5-year survival rates after repeat hepatectomy were 82.8% and 47.5%, respectively, showing better prognosis than those for other treatments. Repeat hepatectomy is the preferred treatment offering a hope of long-term survival for patients with recurrent HCC as long as liver function is sufficient; thus early detection of recurrence should be ensured. Received: February 14, 2001 / Accepted: March 24, 2001     

规范化抗乙肝病毒治疗在肝癌肝切除术后癌症复发的回顾性研究

目的研究抗病毒治疗对乙型肝炎相关肝细胞性肝癌切除后复发的影响。方法利用2010年2月至2011年1月在我中心接受部分肝切除治疗的87例乙肝表面抗原阳性的肝癌患者(其中62例接受规范化抗病毒治疗,25例未进行抗病毒治疗)的详细临床资料以及3年的随访资料进行回顾性分析,研究抗乙肝病毒治疗对于患者肝癌切除后复发以及总体生存的影响。结果 87例HBs Ag阳性患者全部具有完整的随访资料。患者3年随访资料表明,抗病毒治疗可以明显降低术后1个月之后的血清转氨酶水平,提供对肝脏的保护。同时,回顾性研究也证实,抗病毒治疗组相对于对照组的3年癌症复发率有明显改善(50%与64%),3年总体生存率也获得显著提高(66.6%与48.7%)。结论针对HBV-DNA大于104/ml的患者进行围手术期和术后规范化抗病毒治疗是一项安全、有效的治疗手段,与手术切除联合,定期复查,严格防控耐药性病毒株的产生,可以明显延缓患者术后肝脏功能,减少肝癌复发、改善患者预后。     

Delay of alternative antiviral therapy and poor outcomes of acyclovir‐resistant herpes simplex virus infections in recipients of allogeneic stem cell transplant – a retrospective study

Acyclovir is commonly used to prevent and treat herpes simplex virus (HSV) reactivation after hematopoietic cell transplant (HCT), and only few reports have been published on acyclovir‐resistant HSV in HCT recipients. We reviewed the medical records of patients with a microbiologic diagnosis of acyclovir‐resistant HSV by plaque reduction test who received an HCT from 2002 through 2014. A total of 4 028 HCTs were performed during the study period, and 18 of the recipients met the diagnostic criteria for acyclovir‐resistant HSV. All cases had undergone allogeneic HCTs. Most patients were in the pre‐engraftment period or on systemic corticosteroid therapy for graft‐versus‐host disease (GVHD). The median time between diagnosis and susceptibility testing was 15 days, and antiviral therapy was changed at a median of 27 days. Patients required prolonged therapy (~80 days), and many had serious complications including renal failure and hospitalization. In conclusion, acyclovir‐resistant HSV infection is more likely during the period of profound deficit in T‐cell‐mediated immunity and is associated with significant morbidities. Higher doses of acyclovir prophylaxis might be needed for patients with history of HSV during pre‐engraftment or GVHD treatment. In patients who do not respond or progress after 1 week of acyclovir therapy, testing for drug‐resistant HSV, and early switch to an alternative antiviral should be considered.     

Hes1在肝细胞癌中的表达及意义

目的：检测Hes1基因在人肝细胞癌、癌旁、肝硬化和正常肝组织中的表达情况,分析其与乙肝病毒（HBV）的关系和临床意义,探讨Hes1通路在HBV致癌过程中发挥的作用。方法通过免疫组化技术检测60例人肝细胞癌标本（癌、癌旁组织）,20例肝硬化组织和20例正常肝组织标本中Hes1蛋白的表达情况;同时利用蛋白质印迹技术（Western-Blot）技术对组化结果进行验证（分别检测10例标本）。比较Hes1在四种组织中的表达差异,分析其与HBV的相关性和与分化程度的关系。结果免疫组化显示,Hes1蛋白在肝癌组织中呈强阳性表达,癌旁和肝硬化组织中呈中度阳性表达,而正常肝组织中呈阴性表达;Hes1在肝癌、癌旁、肝硬化和正常肝组织中的阳性率分别为65．12％、40．23％、32．23％和15．00％,差异有统计学意义（P＜0．05）。Hes1在癌旁和肝硬化组织中表达无差别（P＞0．05）。在HBsAg阳性和HBsAg阴性肝组织中,前者的阳性率显著高于后者（P＜0．05）,Hes1的表达与HBV呈显著正相关（r＝0．787,P＝0．001）。低分化肝细胞癌中Hes1的表达明显强于高分化肝细胞癌（P＜0．05）。结论 Hes1在肝癌组织中表达升高与肝癌的发生发展有关,Hes1在HBV相关性肝癌的发病机制中可能起重要作用,Hes1高表达可能意味着预后较差。     

MAGE-1基因在肝细胞肝癌中的表达及临床意义

目的:研究MAGE-1基因在肝细胞肝癌组织中的表达,结合临床资料分析,探讨MAGE-1基因与肝细胞肝癌(HCC)患者临床指标及转移与复发的关系,为MAGE-1基因编码蛋白用于HCC患者免疫治疗提供依据。方法:用RT-PCR的方法对31例HCC患者癌组织及相应癌旁组织MAGE-1基因表达进行检测,随机对6例RT-PCR扩增产物中目的基因片段进行DNA测序以证实其为MAGE-1基因,所有患者均测定并统计AFP、AFU、抗HCV、HBsAAg、AFPmRNA、肿瘤直径等临床指标。结果:31例HCC患者肝癌组织中MAGE-1基因表达的阳性率64.5％(20/31)明显高于癌旁组织2％(1/31),P<0.01。HCC患者肝癌组织中MAGE-1基因表达的阳性率与患者AFP、AFU、抗HCV、乙肝标志物、AFPmRNA、肿瘤直径等临床指标均无关,P>0.05。结论:MAGE-1基因在HCC患者肝癌组织中特异高表达,HCC患者肝癌组织中MAGE-1基因表达的阳性率与HCC患者AFP、AFU、AFPmRNA肿瘤转移、复发均无关。     

干扰素在肝细胞癌治疗中的应用及其作用机制的研究进展

干扰素（Interferons,IFNs）是一种具有抗病毒、抗细胞增殖和免疫调节作用的细胞因子,在临床上已广泛应用于抗病毒和抗肿瘤治疗。INFs已被认为是对慢性病毒性肝炎最有效的抗病毒药之一,近年来,大量研究显示IFNs可以预防慢性病毒性肝炎患者中肝细胞癌（hepatocellular carcinoma,HCC）的发生,以及具有预防HCC术后复发和抗HCC侵袭和转移的作用。