Biomedical subjects

Hiroshi Wada

Publications and source records attributed to Hiroshi Wada.

At least 19 recordsLinked to original sources

PubMed2007

Stronger growth-inhibitory effect of interferon (IFN)-beta compared to IFN-alpha is mediated by IFN signaling pathway in hepatocellular carcinoma cells.

Interferon (IFN) is a promising drug for prevention and treatment of hepatocellular carcinoma (HCC) in combination with chemotherapeutic agents. We previously reported that the spectra of antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha in HCC cells. However, the mechanism of the diverse antitumor effects of the IFNs is not understood yet. We studied the expression of IFN alpha receptor 2 (IFNAR2), STATs, and IFN-alpha, IFN-beta's growth-inhibitory effect, signal transduction and binding to IFNAR2 on three HCC cell lines and a tumor xenografted mouse model (12 animals/group). From the results, IFN-beta showed a significantly stronger growth-inhibitory effect than IFN-alpha on the HuH7 cell line (expressing low IFNAR2), however it was similarly high on PLC/PRF/5 and weak on HLE. In the nude mouse tumor xenograft model, IFN-beta injection significantly suppressed tumor volume relative to vehicle injection, while IFN-alpha showed weaker growth-inhibition. IFN signal transduction (phosphorylated-STAT1, 3) induced by IFN-beta was higher than that by IFN-alpha in HuH7 and tumor xenografts. Pretreatment of hepatoma cells with anti-IFNAR2 antibody blocked the IFN signaling, more for IFN-alpha. IFN-alpha's antiproliferative effect was reduced by the antibody in lower concentrations compared to that of IFN-beta. Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha.

Antineoplastic Agents↗

PubMed2006

A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chemotherapy with the novel oral DPD-inhibiting chemotherapeutic drug S-1 and interferon-alpha.

A 54-year-old man was admitted Osaka University Hospital for hepatocellular carcinoma (HCC) with portal vein thrombus and multiple intrahepatic metastases that extended to the bilateral lobes of the liver. He underwent multimodal therapy, including extended left lobectomy followed by intra-arterial 5-fluorourcil (5-FU) infusion chemotherapy combined with subcutaneous interferon-alpha (IFN-alpha) to treat the lesions in the residual liver. Seven months after the initial resection, recurrent tumors in the spleen, lung, and residual liver were detected by follow-up examination. We started a new regimen of per oral administration of S-1 and subcutaneous IFN-alpha injection, because the combined therapy with intra-arterial 5-FU infusion was not considered effective for distant metastases. After two cycles of S-1 and IFN-alpha, the metastatic tumor in the spleen and the recurrence in the residual liver had disappeared, and the diagnosis was complete remission with no adverse effect; the pulmonary metastasis showed a partial response, and was finally resected. This patient is still alive with no recurrence 32 months after initial hepatic resection. This outcome suggests that combination therapy with S-1 and IFN-alpha may be a promising treatment modality against advanced HCC with distant metastasis.

Administration, Oral↗

PubMed2006

Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro.

BACKGROUND/AIMS: Several studies have reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the mechanism underlying the clinical anti-tumor effects of this treatment is not well understood. The aim of this study was to determine the role of Fas/FasL signaling in the anti-tumor effect of this combination therapy. METHODS AND RESULTS: We used six human hepatoma cell lines, three of which are known Fas-expressing cells. Growth of Fas-positive hepatoma cell lines was inhibited by an agonistic anti-Fas antibody in a dose-dependent manner, and these effects were enhanced by IFNalpha or 5-FU alone, but even more so by combination therapy using both agents. Annexin-V assay implicated apoptosis as the main mechanism underlying these growth inhibitory effects, although changes in Fas expression regulated by IFNalpha and/or 5-FU did not correlate with increased apoptosis. Caspase-3 activation was exclusively increased by IFNalpha/5-FU combination treatment, which was compatible with enhancement of the synergistic apoptotic effect, and other caspases and apoptotic factors (FLIP, BCL-xl, and Bax) were also regulated by IFNalpha/5-FU. 51Cr-release assay revealed that pretreatment with IFN activated cytotoxicity of peripheral blood mononuclear cells (PBMCs) against HCC cells. The largest interaction was observed when both PBMC and HCC cells were pretreated with the combination of IFNalpha/5-FU. These cytotoxicities were markedly inhibited by a neutralizing anti-Fas antibody. CONCLUSIONS: Our results indicated that IFNalpha/5-FU combination treatment enhances the induction of apoptosis and the cytotoxic effect of PBMCs via the Fas/FasL pathway. The Fas/FasL pathway seems, at least in part, to contribute to the anti-tumor effects of IFNalpha/5-FU against HCCs.

Antibodies↗

PubMed2006

Effects of heat stress on Young's modulus of outer hair cells in mice.

Intense sound exposure causes permanent hearing loss due to hair cell and cochlear damage. Prior conditioning with sublethal stressors, such as nontraumatic sound, heat stress and restraint protects the ear from acoustic injury. However, the mechanisms underlying conditioning-related cochlear protection remain unknown. In this paper, Young's modulus and the amount of filamentous actin (F-actin) of outer hair cells (OHCs) with/without heat stress were investigated by atomic force microscopy and confocal laser scanning microscopy, respectively. Conditioning with heat stress resulted in a statistically significant increase in Young's modulus of OHCs at 3-6 h after application, and such modulus then began to decrease by 12 h and returned to pre-conditioning level at 48 h after heat stress. The amount of F-actin began to increase by 3 h after heat stress and peaked at 12 h. It then began to decrease by 24 h and returned to the pre-conditioning level by 48-96 h after heat stress. These time courses are consistent with a previous report in which heat stress was shown to suppress permanent threshold shift (PTS). In addition, distortion product otoacoustic emissions (DPOAEs) were confirmed to be enhanced by heat stress. These results suggest that conditioning with heat stress structurally modifies OHCs so that they become stiffer due to an increase in the amount of F-actin. As a consequence, OHCs possibly experience less strain when they are exposed to loud noise, resulting in protection of mammalian hearing from traumatic noise exposure.

Acoustic Stimulation↗

PubMed2006

Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-alpha and fluorouracil in vitro.

Several studies have recently reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the clinical effect of this treatment was not complete. The new therapeutic modality should be necessary to rise up this clinical response rate. Recently, the anti-tumor effect of Vitamin K2 has been reported in terms of decreased recurrence rate of HCC patients. The aim of this study was to explore the additive or synergistic effect of Vitamin K2 to combined therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) against hepatocellular carcinoma (HCCs). The study was conducted using three hepatoma cell lines (PLC/PRF/5, Hep3B and HepG2). The 3-(4-5-dimethylthiazol-2-yl)-2, 5-dyphenyl tetrazolium bromide (MTT) assay (48h) revealed anti-tumor effect of IFNalpha and 5-FU. Cell growth assay (3-7 days) showed growth inhibitory effect of Vitamin K2 on three cell lines after day 5. But additional effect of combination treatment of Vitamin K2 and IFNalpha/5-FU was not observed in any time course from 48h to 7 days. Cell cycles were assessed with flowcytometry. Although either Vitamin K2 or IFNalpha/5-FU alone has the influence to the cell cycles, no significant change was shown in the combination of Vitamin K2 and IFNalpha/5-FU. In conclusion, Vitamin K2 itself has potentially growth inhibitory effect for HCC cell lines, but does not enhance the anti-tumor effect of IFNalpha and 5-FU.

Journal Article↗

PubMed2006

Imaging by atomic force microscopy of the plasma membrane of prestin-transfected Chinese hamster ovary cells.

The high sensitivity of mammalian hearing is achieved by amplification of the motion of the cochlear partition. This cochlear amplification is thought to be generated by the elongation and contraction of outer hair cells (OHCs) in response to acoustical stimulation. This motility is made possible by a membrane protein embedded in the lateral membrane of OHCs. Although a fructose transporter, GLUT-5, was initially proposed to be this protein, a later study identified the gene of the motor protein distributed throughout the OHC plasma membrane. This protein has been named "prestin." However, although previous morphological studies by electron microscopy and atomic force microscopy (AFM) found the lateral wall of OHCs to be covered with 10-nm particles, believed to be motor proteins, it is unknown whether such particles consist only of prestin or are a complex of GLUT-5 and prestin molecules. To determine if the 10-nm particles are indeed constituted only of prestin, plasma membranes of prestin-transfected and untransfected Chinese hamster ovary (CHO) cells, which do not express GLUT-5, were observed by AFM. First, the cells attached to a substrate were sonicated so that only the plasma membrane remained on the substrate. The cytoplasmic face of the cell was observed by the tapping mode of the AFM in liquid. As a result, particle-like structures were recognized on the plasma membranes of both the prestin-transfected and untransfected CHO cells. Comparison of the difference in the frequency distribution of these structures between those two cells showed approximately 75% of the particle-like structures with a diameter of 8-12 nm in the prestin-transfected CHO cells to be possibly constituted only by prestin molecules. Our data suggest that the densely packed 10-nm particles observed on the OHC lateral wall are likely to be constituted only of prestin molecules.

Animals↗

PubMed2006

Genome duplications of early vertebrates as a possible chronicle of the evolutionary history of the neural crest.

It is now accepted that ancestral vertebrates underwent two rounds of genome duplication. Here we test the possible utility of these genome duplication events as a reference time for the evolutionary history of vertebrates, by tracing the molecular evolutionary history of the genes involved in vertebrate neural crest development. For most transcription factors that are involved in neural crest specification, more than two paralogs are involved in that process. These were likely involved in the specification of the neural crest before the genome duplications occurred in ancestral vertebrates, although FoxD3 may have acquired that role after the genome duplications. By contrast, the epithelial-mesenchymal transition of neural crest cells is controlled by genes that evolved after the genome duplications, such as cadherin6, cadherin7, cadherin11, and rhoB. This suggests that primitive neural crest cells control their delamination by using a small or distinct set of cell adhesion molecules. Alternatively, these observations suggest that delamination of the neural crest evolved after the genome duplications. In that case, the neural crest might have evolved in sequential steps; the specification of the neural crest occurred before the genome duplications, and the neural crest acquired a new cell migration property after the genome duplications.

Animals↗

PubMed2006

Local mechanical properties of mouse outer hair cells: atomic force microscopic study.

OBJECTIVES: Outer hair cells (OHCs) are capable of altering their cell length in response to changes in membrane potential. Due to this electromotility, OHCs probably subject the basilar membrane to force, resulting in cochlear amplification. To understand the mechanism of such amplification, knowledge of the mechanical properties of OHCs is required since the force produced by OHC electromotility is thought to depend on such properties. Various studies have been conducted to investigate the mechanical properties of guinea pig OHCs. With regard to mice, however, although various kinds of transgenic and knockout mice possess great potential as research models, the mechanical properties of mouse OHCs have not as yet been reported since the cells and/or tissues in the mouse hearing organ are relatively small and vulnerable to external stimuli, rendering sample preparation difficult. In this study, therefore, to establish indicators of the mechanical properties of OHCs in mice, such properties were measured by atomic force microscopy (AFM). METHODS: CBA/JNCrj strain male mice aged 10-12 weeks (25-30 g) were used. Cochleae were dissected out from the animal and both the basilar membrane and the organ of Corti were simultaneously unwrapped from the modiolus with forceps. Dissected coiled tissue was then incubated with an enzymatic digestion medium for 15 min. After digestion, OHCs were isolated by gently triturating the coiled tissue. Local mechanical properties of the OHCs were then measured by an indentation test using an AFM. RESULTS: Young's modulus and stiffness of the OHC in the apical turn of the mouse cochlea were 2.1+/-0.5 kPa and 4.4+/-1.2 mN/m, respectively. CONCLUSIONS: Young's modulus of the OHC in the apical turn of the cochlea in mice was roughly the same as that in the apical turn of the cochlea in guinea pigs; however, the stiffness of the former was about two times greater than that of the latter because the cell length of the former was shorter than that of the latter.

Animals↗

PubMed2006

Conserved RARE localization in amphioxus Hox clusters and implications for Hox code evolution in the vertebrate neural crest.

The Hox code in the neural crest cells plays an important role in the development of the complex craniofacial structures that are characteristic of vertebrates. Previously, 3' AmphiHox1 flanking region has been shown to drive gene expression in neural tubes and neural crest cells in a retinoic acid (RA)-dependent manner. In the present study, we found that the DR5-type RA response elements located at the 3' AmphiHox1 flanking region of Branchiostoma floridae are necessary and sufficient to express reporter genes in both the neural tube and neural crest cells of chick embryos, specifically at the post-otic level. The DR5 at the 3' flanking region of chick Hoxb1 is also capable of driving the same expression in chick embryos. We found that AmphiHox3 possesses a DR5-type RARE in its 5' flanking region, and this drives an expression pattern similar to the RARE element found in the 3' flanking region of AmphiHox1. Therefore, the location of these DR5-type RAREs is conserved in amphioxus and vertebrate Hox clusters. Our findings demonstrate that conserved RAREs mediate RA-dependent regulation of Hox genes in amphioxus and vertebrates, and in vertebrates this drives expression of Hox genes in both neural crest and neural tube. This suggests that Hox expression in vertebrate neural crest cells has evolved via the co-option of a pre-existing regulatory pathway that primitively regulated neural tube (and possibly epidermal) Hox expression.

Animals↗

PubMed2006

An apparatus for diagnosis of ossicular chain mobility in humans.

Confirmation of the conditions of the ossicles is essential for tympanoplasty. However, at present, ossicular mobility is experimentally estimated with palpation by a surgeon, and the results depend on the surgeon's skill. In this study, a new apparatus for quantitatively measuring ossicular mobility was developed. With this apparatus, the ossicles were displaced and the reaction force from the ossicles, (i.e. the load applied to the ossicles) was simultaneously detected. Ossicular mobility of three patients with otosclerosis or chronic otitis media was measured to evaluate the usability of the apparatus. The apparatus can distinguish the differences in ossicular mobility between normal and fixed ossicles, and it makes estimating the change of mobility between pre- and posttreatments for ossicular fixation possible. Positive correlation was seen between ossicular mobility and hearing level.

Acoustic Impedance Tests↗

PubMed2006

Autophony in patients with patulous eustachian tube: experimental investigation using an artificial middle ear.

OBJECTIVE: To investigate the contribution of anatomical factors, such as the caliber of the patent eustachian tube (ET) and the volume of the middle ear cavity, on vocalized sound transmission to the inner ear. METHODS: Model experiment using artificial middle ear. RESULTS: In the present model experiment, sound transmission from the pharynx to the inner ear under patulous conditions was affected by the caliber of the ET and by the mastoid volume, especially in the low-frequency region, that is, a larger caliber of the ET and smaller mastoid volume resulted in greater sound transmission from the pharyngeal space to the inner ear. CONCLUSION: Patulous symptoms may be more distressful in patients with poorly developed mastoid cavity than in those with well-aerated mastoid under similar conditions of patulous ET.

Adult↗

PubMed2006

Sox genes regulate type 2 collagen expression in avian neural crest cells.

Neural crest cells give rise to a wide variety of cell types, including cartilage cells in the cranium and neurons and glial cells in the peripheral nervous system. To examine the relationship of cartilage differentiation and neural crest differentiation, we examined the expression of Col2a1, which encodes type 2 collagen often used as a cartilage marker, and compared it with the expression of Sox transcription factor genes, which are involved in neural crest development and chondrogenesis. We found that Col2a1 is expressed in many neural crest-derived cell types along with combinations of Sox9, Sox10 and LSox5. Overexpression studies reveal the activation of Col2a1 expression by Sox9 and Sox10, and cross-regulation of these Sox genes. Luciferase assay indicates a direct activation of the Col2a1 enhancer/promoter both by Sox9 and Sox10, and this activation is further enhanced by cAMP-dependent kinase (PKA) signaling. Our study suggests that the regulatory mechanisms are similar in cartilage and neural crest differentiation.

Animals↗

PubMed2006

Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1 alpha.

BACKGROUND: Hepatocellular carcinoma (HCC) is a hypervascular tumor and angiogenesis plays an important role in its progression. Angiogenesis is regulated by a balance between pro and antiangiogenic molecules. The aim of this study was to investigate the expressions of angiogenic factors and elucidate their roles in angiogenesis in HCC. METHODS: We investigated immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), hypoxia-induced factor-1alpha (HIF-1alpha) and thrombospondin-1 (TSP-1) in 60 specimens of surgically resected HCC. We investigated the relationship between their expressions and clinicopathological factors or prognosis. RESULTS: Ang-2 staining had a significant correlation with the grade of differentiation of HCC cells (P=0.0082). VEGF and Ang-2 expression correlated positively with microvessel density (MVD) (P=0.0061 and 0.0374, respectively). MVD of well-differentiated HCC were significantly lower than those of moderately and poorly differentiated HCC. The disease-free survival time of patients with high Ang-2 and/or HIF-1alpha expression was significantly shorter than that of the low expression group (P=0.0278 and 0.0374, respectively). CONCLUSION: Our study showed that the expression of VEGF and Ang-2 correlated with MVD. Strong Ang-2 expression and/or high nuclear expression of HIF-1alpha is a significant predictive factor for recurrence after curative resection in HCC patients.

Adult↗

PubMed2006

Evolutionary embryology resurrected in Japan with a new molecular basis: Nori Satoh and the history of ascidian studies originating in Kyoto during the 20th century.

This article briefly summarizes the scientific contributions of Nori Satoh, the winner of the 2005 edition of the Kowalevsky Medal, to Developmental Biology and especially to Evo-Devo with his 30 years of research on tunicates - a primitive chordate species. His research began with his pure developmental interest in the clock mechanism of cell differentiation and later expanded into various aspects of evolutionary and developmental phenomena. He is not only known as a founder of molecular biology-based tunicate studies, but also for his world-wide service to education and his prestigious publications in international scientific journals.

Animals↗

PubMed2006

TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.

Transforming growth factor beta 1 (TGF-beta1) is a proposed regulator of Ids (inhibitors of DNA binding/differentiation) gene expression in epithelial cells. We previously reported that Id proteins are variously expressed in human hepatocellular carcinomas (HCC). However, the mechanism of regulation of Ids in HCC remains obscure. Here, we examined the relationship between Id1 and TGF-beta1 in four HCC cell lines, and studied the changes in cell proliferation, cell cycle and differentiation. The four HCC cell lines expressed Id1, TGF-beta1 and their receptors at various levels. TGF-beta1 strongly inhibited the growth of HuH7 cells, while the growth inhibition was moderate in PLC/PRF/5, and was not observed in HLE and HLF cell lines. TGF-beta1-induced growth inhibition in HuH7 cells was associated with cell accumulation in the G1 phase and partial induction of differentiation (with reduction of AFP and AFP-L3). Induction by TGF-beta1 dose-dependently suppressed Id1 expression in HuH7 cells; 1 ng/ml TGF-beta1 inhibited Id1 by 84.0 and 78.6% that of the untreated control at transcriptional and protein levels, respectively. HLE and HLF cells, which did not exhibit a TGF-beta1 growth inhibitory effect, lacked TGF-beta receptors and Id1 expression was not altered. In PLC/PRF/5 cells, Id1 augmentation was not observed in response to TGF-beta1, indicating that TGF-beta1-induced growth inhibition was not related to Id1 in this cell line. Our results suggest that, in some HCC cells, the pathway of suppression of Id1 by TGF-beta1 may be important in TGF-beta1-induced growth inhibition and partial differentiation.

Blotting, Western↗

PubMed2006

Angiogenesis in cholangiocellular carcinoma: expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance.

Angiogenesis in cholangiocellular carcinoma (CCC) has rarely been investigated. The aim of this study was to determine the angiogenesis status of CCC and assess its relationship with angiogenic factors and clinicopathological characteristics. We examined 33 surgically resected CCC specimens. Tumor angiogenesis was assessed by microvessel density (MVD) using the anti-CD34 antibody, and the expression of VEGF, Ang-1, Ang-2, and TSP-1 was determined by immunohistochemistry. The mean (+/- SD) MVD was 87.2+/-52.6/mm2 (range, 0-229/mm2). A total of 75.6% cases were positive for VEGF expression, 36% for Ang-1, 57.6% for Ang-2 and 45.5% for TSP-1. VEGF and Ang-2 expression was associated with a significantly higher level of MVD (p=0.004 and 0.015, respectively). TSP-1 expression was associated with a significantly lower level of MVD (p=0.005) and a higher level of intrahepatic metastasis (46.7% vs. 5.6%, p=0.012). There was no significant correlation between VEGF, Ang-1, Ang-2, and TSP-1 expression and tumor size, capsule formation, infiltration of capsule, portal vein invasion, intrahepatic metastasis or CCC differentiation. There was no significant correlation between MVD levels, VEGF, Ang-1, Ang-2, and TSP-1 expression and postoperative survival. A considerable degree of angiogenesis, comparable to that of other solid tumors, was observed in CCC. VEGF and Ang-2 might play a proangiogenic role, and TSP-1 may play an inhibitory role in CCC. Although TSP-1 may increase intrahepatic CCC metastases, neither MVD levels nor the expression of VEGF, Ang-1, or Ang-2 was associated with clinicopathological factors and prognosis.

Adult↗

PubMed2006

Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers.

Interferon (IFN) is used in the treatment of many malignancies and viral disorders. We recently reported a significant correlation between the efficacy of IFN-alpha combined with chemotherapy in the treatment of advanced hepatocellular carcinoma (HCC) and IFN-alpha/type I IFN receptor (IFNAR2) expression. It is possible that the expression of IFNAR2 in gastrointestinal cancerous tissue, apart from HCC, may predict the efficacy of IFN-alpha combination therapy. We investigated the expression of IFNAR2 in 100 gastrointestinal cancerous tissues. IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples). The expression rate of IFNAR2 was 35.0% (7/20), 25.0% (5/20), 20.0% (4/20), 45.0% (9/20), and 25.0% (5/20) in esophageal, gastric cancer, colorectal, cholangiocarcinoma and pancreatic cancer samples, respectively. In our previous report, the expression rate of IFNAR2 in HCC samples was 64.8% (59/91). Thus, the expression rates of IFNAR2 in the five types of gastrointestinal cancers tested here were low, compared with HCC. The clinical efficacy of IFN-alpha mono- or combination therapies in patients with gastrointestinal neoplasms is expected to be lower than in patients with HCC based on the expression level of IFNAR2.

Gastrointestinal Neoplasms↗

PubMed2006

[The progress of hepatic arterial infusion chemotherapy for hepatocellular carcinoma].

Hepatic arterial infusion (HAI) chemotherapy has been selected as a therapeutic option for highly advanced hepatocellular carcinoma (HCC) with tumor thrombi in major portal branches or intrahepatic metastases. Conventional therapies have no clinical effect on highly advanced HCC. Recent advances of an implanted portcatheter system have facilitated repeated arterial infusion of chemotherapeutic agents, and HAI chemotherapy with several anticancer drugs provides a useful choice for advanced HCC. In various regimens of HAI chemotherapy, low-dose cisplatin and 5-fluorouracil (5-FU) therapy or combination therapy of interferon (IFN)-alpha/5-FU have been reported to improve the response rates for advanced HCC. However, the survival benefit of HAI chemotherapy may be affected by liver function. None of these regimens have been proved to be the standard for HAI chemotherapy. We previously reported that the beneficial effects of combination therapy of IFN-alpha/5-FU for advanced HCC. IFN-alpha/5-FU combination therapy may be a promising treatment modality for advanced HCC.

Antineoplastic Combined Chemotherapy Protocols↗