thymosin and Liver-Neoplasms

Liver fibrosis, a major characteristic of chronic liver disease, is inappropriate tissue remodeling caused by prolonged parenchymal cell injury and inflammation. During liver injury, hepatic stellate cells (HSCs) undergo transdifferentiation from quiescent HSCs into activated HSCs, which promote the deposition of extracellular matrix proteins, leading to liver fibrosis. Thymosin beta 4 (Tβ4), a major actin-sequestering protein, is the most abundant member of the highly conserved β-thymosin family and controls cell morphogenesis and motility by regulating the dynamics of the actin cytoskeleton. Tβ4 is known to be involved in various cellular responses, including antiinflammation, wound healing, angiogenesis, and cancer progression. Emerging evidence suggests that Tβ4 is expressed in the liver; however, its biological roles are poorly understood. Herein, we introduce liver fibrogenesis and recent findings regarding the function of Tβ4 in various tissues and discuss the potential role of Tβ4 in liver fibrosis with a special focus on the effects of exogenous and endogenous Tβ4. Recent studies have revealed that activated HSCs express Tβ4 in vivo and in vitro. Treatment with the exogenous Tβ4 peptide inhibits the proliferation and migration of activated HSCs and reduces liver fibrosis, indicating it has an antifibrotic action. Meanwhile, the endogenously expressed Tβ4 in activated HSCs is shown to promote HSCs activation. Although the role of Tβ4 has not been elucidated, it is apparent that Tβ4 is associated with HSC activation. Therefore, understanding the potential roles and regulatory mechanisms of Tβ4 in liver fibrosis may provide a novel treatment for patients.

Topics: Cell Physiological Phenomena; Cell Transdifferentiation; Gene Expression; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Signal Transduction; Thymosin

The hepatitis C virus (HCV) is a global public health problem, with chronic infection leading to development of cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Treatment of HCV is suboptimal with overall response rates of slightly greater than 50% when patients are treated with pegylated interferon alfa and ribavirin. Thymosin alpha 1 (Talpha1; TA-1) is an immunomodulatory peptide with intrinsic activities that might improve treatment outcomes for HCV by incorporation of this agent in current treatment paradigms. An extensive body of literature supports a possible role for this agent in difficult to treat populations. However, clinical trials to date have failed to conclusively support the role of TA-1 in combination interferon-based therapies. Therefore, the promise of TA-1 adjunctive therapy for HCV remains, but the proof will require investment in large randomized clinical trials of appropriate patient populations.

Topics: Carcinoma, Hepatocellular; Chronic Disease; Clinical Trials as Topic; Hepacivirus; Humans; Interferons; Liver Cirrhosis; Liver Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Ribavirin; Thymalfasin; Thymosin; Treatment Outcome

Treatment of chronic hepatitis B and C viruses (HBV and HCV) is still disappointing, and both are the major causes of liver cirrhosis and hepatocarcinoma. Interferon and lamivudine are the registered drugs for chronic HBV but are scarcely effective on HBeAg-negative patients, and resistance due to virus mutation is the rule with lamivudine. Interferon and ribavirine represent the standard treatment for chronic HCV but less than the half of the infected population is eligible for this treatment and less of the half of treated patients will experience a sustained response. No single new drug to date has shown the potential to overcome this dismal picture. Combined strategies are thus the currently most available approach to improve the response rate of chronic HBV and HCV infection, with a subsequent decrease in the number of patients developing hepatocellular carcinoma (HCC). Combination of thymosin alpha 1 with interferon or antiviral agents is currently the most promising option, but nontoxic immunomodulants, such as oral MIMP, should be explored. This review focuses on the difficulties with current therapy and the rationale for use of combination therapy with thymosin alpha 1 for both HBV and HCV therapies.

Topics: Adjuvants, Immunologic; Antiviral Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Therapy, Combination; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Viral, Human; Humans; Liver Neoplasms; Thymalfasin; Thymosin

Topics: Adolescent; Adult; Aged; Autophagy; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Humans; Leukocytes, Mononuclear; Liver Neoplasms; Male; Middle Aged; Thymalfasin; Thymosin; Young Adult

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is a disease of immune microenvironment. Chronic Hepatitis B virus (HBV) infection, also an immune-related disease, is the major etiological factor for HCC especially in Asia. As an immune regulator, which has pleiotropic activities on T cells, nature killer cells and dendritic cells and so on, the efficacy of thymalfasin on HCC patients has been proven by several pilot studies as an adjuvant therapy. Combination of thymalfasin significantly improved survival and prolonged the time to tumor recurrence in patients who received transcatheter arterial chemoembolization after tumor resection. An improvement in patients' immunity has also been demonstrated. However, there is no large-scale randomized controlled study so far in resectable HCC patients. To confirm the role of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection, a large-scale multicenter randomized controlled trial has been planned in China to investigate the effect of thymalfasin (1.6 mg twice a week for 12 months) on 2-year recurrence-free survival rate and tumor immune microenvironment. Here is the first announcement of the study protocol (ClinialTrials.gov Identifier: NCT02281266).

Topics: Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; China; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Research Design; Thymalfasin; Thymosin; Treatment Outcome

To observe the effect of postoperative anti-viral therapy using lamivudine and thymosin alpha1 on recurrence of hepatocellular carcinoma (HCC) coexisting with active hepatitis B.. From Jan. 2000 to Dec. 2002, 33 HCC patients with coexisting with active hepatitis B were randomized into two groups: Group I (n = 17) received hepatectomy only, and Group II (n = 16) received hepatectomy and postoperative therapy using lamivudine plus thymosin alpha1. The suppression of HBV-DNA, HBeAg seroconversion rate, tumor recurrence rate and median survival in the two groups were observed and compared.. In Group II and Group I, the 1-year HBV-DNA suppression rate was 100.0% vs 6.0% (P < 0.01), HBeAg seroconversion rate was 62.5% vs 5.9% (P < 0.05), tumor recurrence rate was 81.3% vs 95.5% (P > 0.05), the recurrence time was 7.0 vs 5.0 months (P < 0.01) and median survival 10.0 vs 7.0 months (P < 0.01).. Anti-viral therapy using lamivudine and thymosin alpha1 postoperatively may suppress the HBV reaction, delay the recurrence and prolong the survival for patients with HCC with coexisting active hepatitis B.

Topics: Adult; Aged; Carcinoma, Hepatocellular; DNA, Viral; Female; Hepatectomy; Hepatitis B; Humans; Lamivudine; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Period; Reverse Transcriptase Inhibitors; Survival Rate; Thymalfasin; Thymosin

To observe the effect of postoperative transcatheter hepatic arterial chemoembolization (TACE) and thymosin alpha(1) (T(alpha1)) treatment on recurrence of hepatocellular carcinoma (HCC).. From Jan 2000 to Dec 2002, 57 patients with HCC were randomly divided into three groups: group A (n = 18) received hepatectomy plus postoperative TACE and T(alpha1), group B (n = 23) received hepatectomy plus postoperative TACE and group C (n = 16) received hepatectomy only. The recurrence rate, the time to tumor recurrence and the median survival for the three groups were investigated.. For group A, B and C, the 1 year recurrence rate was 83.3%, 87.0% and 87.5% (P = 0.926), respectively. The time to tumor recurrence was 7.0, 5.0 and 4.0 months (P = 0.039), respectively. The median survival was 10.0, 7.0 and 8.0 months (P = 0.002), respectively.. Postoperative TACE plus Talpha(1) treatment for HCC patients does not decrease the recurrence rate but may delay its occurrence and prolong surviving time.

Topics: Adjuvants, Immunologic; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Carboplatin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Female; Hepatectomy; Humans; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Postoperative Period; Survival Rate; Thymalfasin; Thymosin

Thymosin β 10 (TMSB10) has been demonstrated to be overexpressed and function as an oncogene in most types of human cancer including hepatocellular carcinoma (HCC). In our study, we present more evidence about the clinical significance and biological function of TMSB10 in HCC. First, we observed levels of TMSB10 expression were obviously increased in HCC tissues compared with normal liver tissues at The Cancer Genome Atlas (TCGA) datasets. Furthermore, we confirmed that

Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Prognosis; RNA Interference; Thymosin

There is limited information available concerning the effect of thymalfasin (Tα1) as an adjuvant therapy in hepatocellular carcinoma (HCC) patient who received liver resection. The present study aimed to evaluate whether Tα1 can improve the prognosis of small HCC patients after liver resection.A total of 206 patients with small HCC who underwent liver resection were analyzed in our retrospective cohort study. Patients were divided into 2 groups: group A (resection + Tα1, n = 44) and group B (resection, n = 162). Clinical data, overall survival (OS), and recurrence-free survival (RFS) were compared. Prognostic factors were identified using multivariate analysis.After a median follow-up of 47.0 months, 134 patients (65%) had recurrence, and 62 patients (30.09%) died. The 1, 3, and 5-year OS rate of patients in group A was 97.7%, 90.6%, and 82.9%, respectively, and 95.1%, 80.5%, and 62.9%, respectively, for patients in group B (P = .014). The 1, 3, and 5-year RFS rate of patients in group A was 70.5%, 56.8%, and 53.3%, respectively, and 65.8%, 41.3%, and 32.1%, respectively, for patients in group B (P = .015). Multivariate analysis indicated that Tα1 was an independent prognostic factor for both OS (P = .015, hazard ratio 0.349, 95% confidence interval 0.149-0.816) and RFS (P = .019, hazard ratio 0.564, 95% confidence interval 0.349-0.910).Tα1 as an adjuvant therapy after liver resection may improve the prognosis of small HCC patients after liver resection.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Comorbidity; Disease-Free Survival; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Retrospective Studies; Sex Factors; Thymalfasin; Thymosin; Young Adult

Cisplatin is a potent chemotherapeutic drug widely used for the treatment of human cancer. However, its efficacy against hepatocellular carcinoma (HCC) is poor for reasons that remain unclear. We show here that prothymosin-alpha (PTMA) is overexpressed in HCC cell lines. Silencing PTMA using short-hairpin RNA sensitizes HCC cells to cisplatin, while ectopic expression of PTMA induces cell resistance to the drug. Cisplatin inhibits both the JNK pathway and PTMA in a dose-dependent manner. Treatment with a JNK inhibitor also reduces PTMA protein stability and sensitizes HCC cells to cisplatin. Notably, the effects of PTMA silencing and JNK inhibition can be reversed by ectopic expression of PTMA. We show that PTMA silencing induces translocation of proapoptotic Bax to mitochondria and enhances cisplatin-induced cytochrome c release and caspase-9 activation. Conversely, ectopic expression of PTMA reverses these effects. Our results indicate that PTMA is positively regulated by JNK and protects HCC cells against cisplatin-induced cell death. The JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC.

Topics: Antineoplastic Agents; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Caspase 9; Cell Line, Tumor; Cisplatin; Cytochromes c; Gene Silencing; Humans; Liver Neoplasms; MAP Kinase Kinase 4; Mitochondria; Protein Precursors; Protein Transport; Thymosin

Prothymosin alpha (PTMA) is overexpressed in various human tumors, including hepatocellular carcinoma (HCC). The significance of PTMA overexpression and its underlying mechanism remain unclear. We show here that silencing PTMA sensitizes HCC cells to the kinase inhibitor sorafenib. In contrast, ectopic expression of PTMA induces cell resistance to the drug. While inhibitors targeting JNK, ERK or PI3K reduce PTMA expression, only ERK activation is suppressed by sorafenib. In addition, inhibition of ERK produces a dramatic decrease in both endogenous PTMA level and promoter activation. Ectopic expression of active MKK1/2 considerably induces PTMA expression. We also identify a sorafenib-responsive segment lying 1000-1500-bp upstream of the PTMA transcription start site and observe that it is controlled by c-Myc and ERK. Mutation in the PTMA promoter at the predicted c-Myc binding site and silencing of c-Myc both abrogate sorafenib's effect on PTMA transcription. We also find that silencing PTMA potentiates Bax translocation to mitochondria in response to sorafenib and this is associated with increased cytochrome c release from mitochondria and enhanced caspase-9 activation. These results indicate that PTMA is positively regulated by the oncoprotein c-Myc and protects HCC cells against sorafenib-induced cell death, thus identifying PTMA as a new target for chemotherapy against HCC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; DNA-Binding Proteins; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Protein Precursors; Sorafenib; Thymosin; Transcription Factors

Prothymosin alpha (PTMA) is a nuclear oncoprotein-transcription factor essential for cell cycle progression and proliferation. PTMA was overexpressed in several human malignancies including hepatocellular carcinoma (HCC). However, the prognostic significance of PTMA protein expression in HCC remains unclear. In the present study, we evaluated PTMA protein expression by immunohistochemistry in order to elucidate the prognostic roles of PTMA in HCC patients.. By immunohistochemistry, we investigated the expression of PTMA protein in tumor tissue from 226 HCC patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 120 months.. PTMA expression was observed in 162 (71.7%) of the 226 HCC patients and was significantly associated with higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T-stage, and lower albumin level. PTMA expression was an independent predictor of early recurrence (P=0.001). PTMA expression showed an unfavorable influence on recurrence-free survival (RFS) (P<0.001). Subgroup analysis showed that among patients with tumor size ≤5.0 cm (140 patients), patients at AJCC T-stage 1 (95 patients) and patients with alpha-fetoprotein ≤20 ng/mL (83 patients), the differences in RFS between PTMA-positive and PTMA-negative groups were also statistically significant (P=0.017, P=0.002 and P=0.002, respectively). In addition, PTMA expression was an independent predictor of shorter RFS (P=0.011). PTMA expression showed an unfavorable influence on overall survival (P=0.014), but was not an independent predictor of shorter overall survival (P=0.161).. PTMA protein expression might be a novel predictor of early recurrence and RFS in HCC patients, even those at early stage or with alpha-fetoprotein-negative after curative hepatectomy. PTMA could be used as an immunohistochemical biomarker to detect patients with a high risk of recurrence.

Topics: alpha-Fetoproteins; Carcinoma, Hepatocellular; Disease-Free Survival; Female; Follow-Up Studies; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Predictive Value of Tests; Protein Precursors; Survival Rate; Thymosin; Tumor Burden

To explore the impact of triple anti-tumor therapy based on thymosin α1 (Tα1) combined with Huaier granule(HG) and sirolimus on the level of serum alpha-fetoprotein (AFP) in rat models of liver cancer.. Ninety Sprague-Dawley rats were randomly divided into triple anti-tumor therapy group, Tα1 group, HG group, sirolimus group, positive control and blank control groups, with 15 rats in each group. Except the blank control group, the rats in the other groups were induced using diethylnitrosamine (DEN) to establish liver cancer models. After DEN treatment, the triple therapy group underwent 0.8 mg/kg Tα1 subcutaneous injection (from once a day for two weeks to twice a week since the third week), 0.35 g/kg HG gavage (three times a day) and 1 mg/kg sirolimus gavage (once a day). The dose of the rest single drug groups were the same with that of the triple therapy group. The positive control and blank control groups were not treated with the drugs. The treatment lasted 20 weeks. Then, the behavior of the rats were observed at the different time points, and the level of serum AFP in the rats were detected at 6, 16, 18, 20 weeks, respectively.. The typical symptoms of liver cancer were seen in the DEN-induced rats at 16 weeks. Since the tenth week, 6 rats died one after another. Pathological section of rat liver tissue suggested that the rat models were established successfully. According to the incidence rate of liver cancer and the survival rate at 20 weeks, the triple anti-tumor therapy was significantly superior to the single drug treatments. In addition, the triple anti-tumor therapy significantly reduced the level of serum AFP in the rats.. The triple anti-tumor therapy can significantly prolong the survival time of rats with liver cancer, decrease the cancer incidence rate and the level of serum AFP.

Topics: alpha-Fetoproteins; Animals; Antineoplastic Combined Chemotherapy Protocols; Behavior, Animal; Carcinoma, Hepatocellular; Disease Models, Animal; Liver; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley; Sirolimus; Survival Analysis; Thymalfasin; Thymosin

Sorafenib is a kinase inhibitor used as anticancer drug against various human tumors, including advanced hepatocellular carcinoma (HCC). β-Catenin and prothymosin alpha (PTMA) are overexpressed in HCC and other tumors. Previous studies have shown that PTMA expression modulates the response of HCC cells to sorafenib. However, the underlying mechanism of PTMA activity in this context remains unclear. We show here that sorafenib inhibits both β-catenin and PTMA in a dose-dependent manner. Silencing β-catenin reduces PTMA level and sensitizes HCC cells to sorafenib. In contrast, ectopic expression of β-catenin induces PTMA expression and cell resistance to the drug. Sorafenib inhibits PTMA expression at the transcriptional level by inhibiting the β-catenin pathway. Nucleotide deletion analysis of the PTMA gene promoter reveals that a DNA segment lying 1,500-1,600 bp upstream of the PTMA transcription start site represents an AP-1-binding site that is critical for β-catenin modulation of gene transcription in response to sorafenib. In addition, chemical inhibitors that target JNK abrogate β-catenin/AP-1 binding to the endogenous PTMA gene and reduces PTMA transcription and protein expression. Silencing of β-catenin or c-Fos induces similar effects on gene regulation and these are reversed by ectopic expression of β-catenin. Mutations in the PTMA promoter at the predicted β-catenin/AP-1 binding site partly abrogate sorafenib's effects on PTMA transcription. These results indicate that PTMA is induced by the oncoprotein β-catenin and protects HCC cells against sorafenib-induced cell death. The β-catenin/JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC.

Topics: Antineoplastic Agents; Apoptosis; beta Catenin; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Liver Neoplasms; MAP Kinase Signaling System; Niacinamide; Phenylurea Compounds; Protein Precursors; Sorafenib; Thymosin; Transfection

Thymosin beta 4 (Tβ4) and thymosin beta 10 (Tβ10) are two members of the beta-thymosin family involved in many cellular processes such as cellular motility, angiogenesis, inflammation, cell survival and wound healing. Recently, a role for beta-thymosins has been proposed in the process of carcinogenesis as both peptides were detected in several types of cancer. The aim of the present study was to investigate the expression pattern of Tβ4 and Tβ10 in hepatocellular carcinoma (HCC). To this end, the expression pattern of both peptides was analyzed in liver samples obtained from 23 subjects diagnosed with HCC. Routinely formalin-fixed and paraffin-embedded liver samples were immunostained by indirect immunohistochemistry with polyclonal antibodies to Tβ4 and Tβ10. Immunoreactivity for Tβ4 and Tβ10 was detected in the liver parenchyma of the surrounding tumor area. Both peptides showed an increase in granular reactivity from the periportal to the periterminal hepatocytes. Regarding HCC, Tβ4 reactivity was detected in 7/23 cases (30%) and Tβ10 reactivity in 22/23 (97%) cases analyzed, adding HCC to human cancers that express these beta-thymosins. Intriguing finding was seen looking at the reactivity of both peptides in tumor cells infiltrating the surrounding liver. Where Tβ10 showed a strong homogeneous expression, was Tβ4 completely absent in cells undergoing stromal invasion. The current study shows expression of both beta-thymosins in HCC with marked differences in their degree of expression and frequency of immunoreactivity. The higher incidence of Tβ10 expression and its higher reactivity in tumor cells involved in stromal invasion indicate a possible major role for Tβ10 in HCC progression.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Thymosin

Thymosin beta 10 (Tbeta10) overexpression has been reported in a variety of human cancers. However, the role of Tbeta10 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to analyze Tbeta10 expression in tumor and matched non-tumorous tissues, and to assess its prognostic significance for HCC after hepatectomy.. The level of Tbeta10 mRNA and protein in tumor and matched non-tumorous tissues was evaluated in 26 fresh HCC cases by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Additionally, Tbeta10 protein expression in 196 HCC was analyzed by immunohistochemistry (IHC) and correlated with clinicopathological characteristics and survival.. Results from RT-PCR and western blot analysis show that the levels of Tbeta10 mRNA and protein were significantly higher in tumor tissues of HCC, compared to that in matched non-tumorous tissues (P = 0.01 and P < 0.001, respectively). IHC staining showed that high expression of Tbeta10 was detected in 58.2% (114/196) of HCC cases. High expression of Tbeta10 was significantly associated with advanced TNM stage (P < 0.001). Survival analysis demonstrated that high Tbeta10 was related to shorter overall survival (OS) (P = 0.000) and disease-free survival (DFS) (P = 0.000). Multivariate analysis showed that high expression of Tbeta10 was an independent prognostic factor for both OS (P = 0.001, HR = 4.135, 95% CI: 2.603 to 6.569) and DFS (P = 0.001, HR = 2.021, 95% CI: 1.442 to 2.832). Subgroup analysis revealed that high expression of Tbeta10 predicts poorer survival for early and advanced stage.. Tbeta10 protein abnormal expression might contribute to the malignant progression of HCC. High expression of Tbeta10 predicts poor prognosis in patients with HCC after hepatectomy.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Hepatocellular; Case-Control Studies; Disease Progression; Female; Follow-Up Studies; Hepatectomy; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Thymosin; Young Adult

To investigate the effects of different treatments for hepatocellular carcinoma (HCC) with tumor thrombus in the portal vein (PVTT).. From Jan. 2000 to Jan. 2003, a total of 84 HCC patients with PVTT were divided into five groups based on methed of treatment: Group A (n = 9), HCC resection + PVTT removal + postoperative TACE + thymosin alpha(1); Group B (n = 20), HCC resection + PVTT removal + postoperative TACE; Group C (n = 7), HCC resection + PVTT removal; Group D (n = 38), TACE only; Group E (n = 10), conservative treatment only.. The rate of PVTT shrinkage or disappearance of groups A, B, C, D and E was 66.7%, 70.0%, 57.1%, 7.9% and 0, respectively with respective median survival time of 10.0, 7.0, 8.0, 5.0 and 2.0 months. The one year survival rate was 44.4%, 15.0%, 14.3%, 10.5% and 0.. Resection of HCC and removal of tumor thrombus in the portal vein may have the tumor thrombus cleared in most of the patients and postoperative TACE and thymisin alpha(1) treatment may improve their survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Follow-Up Studies; Hepatectomy; Hepatic Artery; Humans; Liver Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Portal Vein; Survival Analysis; Thymalfasin; Thymosin

The immunomodulatory and antimetastatic/antitumor activity of thymosin alpha(1) (Talpha(1)) was evaluated in BALB/c-mice. Daily subcutaneous application (7 consecutive days, 0.01-10 microg of Talpha(1)/injection per mouse) upregulated the number of thymocytes and peripheral blood cells in tumor bearing mice. To check the influence of Talpha(1) treatment on growth of experimental metastases, RAW H10 lymphosarcoma cells or L-1 sarcoma cells were intravenously injected into BALB/c-mice to establish liver or lung metastases. Local tumor growth was induced by subcutaneous injection of L-1 sarcoma cells. Talpha(1) was subcutaneously administered daily for 7 consecutive days starting 24 h after tumor cell challenge. Organ colonization, as well as local tumor growth, were investigated on day 14 after tumor cell inoculation, and demonstrated a statistically significant (P<0.05) reduction of experimental liver and lung metastases and local tumor growth for Talpha(1) treated mice.

Topics: Adjuvants, Immunologic; Animals; Cell Count; Dose-Response Relationship, Drug; Immunity; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Organ Size; Thymalfasin; Thymosin; Thymus Gland; Tumor Cells, Cultured

Identification of gene products exclusively or abundantly expressed in cancer may yield novel tumour markers. We recently isolated a number of cDNA clones, including alpha-prothymosin, from rat hepatocellular carcinoma (HCC) using a subtraction-enhanced display technique. Alpha-Prothymosin is involved in cell proliferation and is regulated by the oncogene c-myc in vitro. In the present study, we analysed alpha-prothymosin gene expression and its correlation with c-myc in patients with HCC, cirrhosis and adenoma and in normal controls. Hepatic alpha-prothymosin messenger RNA (mRNA) levels were two- to 9.2-fold higher in tumoral tissues than in adjacent non-tumoral tissues in 14 of 17 patients with HCC, regardless of coexisting cirrhosis and viral hepatitis. No marked difference in alpha-prothymosin mRNA levels was present in patients with adenoma and hepatic cirrhosis and in healthy controls. The c-myc mRNA amounts were two- to fivefold increased in 11 of 17 patients with HCC and correlated significantly with those of alpha-prothymosin (P < 0.001). In situ hybridization revealed that increased alpha-prothymosin mRNA was localized in the tumour nodules of the patients with HCC. These data suggest that overexpression of alpha-prothymosin in HCC patients, correlated with c-myc, is possibly involved in the tumorigenic process and may be a novel molecular marker for human HCC.

Topics: Adenoma; Adult; Aged; Biomarkers, Tumor; Blotting, Northern; Carcinoma, Hepatocellular; Female; Hepatitis B; Hepatitis C; Humans; In Situ Hybridization; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Protein Precursors; Proto-Oncogene Proteins c-myc; Radioimmunoassay; RNA, Messenger; Thymosin

Thymosin-alpha 1 is a biological response modifier that has been used clinically, alone and in combination with interferon-alpha for the treatment of chronic hepatitis B viral infection. Both immunomodulatory and immediate intracellular mechanisms have been postulated to explain the effect of these two agents on HBV-infected hepatocytes.. In this study, hepatitis B transfected HepG2 hepatoblastoma cells (HepG2-Nu2), derived from 2.2.15 cells, were used as an in vitro model to determine the efficacy of thymosin-alpha 1 and interferon-alpha, individually and combined, as proliferation inhibitors of HBV-infected cells. For comparison, parental HepG2 cells and an SV40-transfected HepG2 cell line (HepG2P9T2) were also evaluated.. In a clonogenic soft agar assay, thymosin-alpha 1 inhibited the anchorage-independent growth of the HepG2-Nu2 cells by 40% compared with untreated controls, but did not inhibit parental HepG2 or HepG2P9T2 clonal growth. The response was dose dependent over concentrations spanning three log units. In comparison, 10000 units/ml of interferon-alpha inhibited parental HepG2, HepG2-N4Z and HepG2P9T2 by 33%, 41% and 87%, respectively. The combination of thymosin-alpha 1 and interferon-alpha consistently inhibited HepG2-Nu2 clonal growth more effectively than either treatment alone, reaching maximum inhibition levels of 51%.. Thymosin-alpha 1 specifically inhibits the tumorigenic growth of HBV-transfected HepG2 cells in contrast to the general inhibition displayed by interferon-alpha. This panel of cell lines may be an important resource for dissecting the mechanism by which thymosin, alone or in combination with other drugs, influences HBV-infected hepatocytes and/or HBV-associated carcinoma.

Topics: Adjuvants, Immunologic; Antiviral Agents; Cell Division; Cell Transformation, Viral; DNA, Viral; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Hepatitis B virus; Hepatoblastoma; Humans; Interferon-alpha; Liver Neoplasms; Thymalfasin; Thymosin; Transfection; Tumor Cells, Cultured; Virus Replication

We studied the effect of combined chemo-immunotherapy, 5-FU followed by thymosin alpha 1 (T alpha 1) and interleukin-2 (IL-2) at low doses, on liver metastases from colorectal cancer, induced by splenic injection of DHD/K12 cells (1,2-dimethylhydrazine-induced colon adenocarcinoma) in syngeneic BDIX rats. The presence of liver metastases was checked by laparotomy 14 days after tumor-cell injection. Evaluable rats were assigned randomly to 5 experimental groups designated as control, 5-FU, IL-2, 5-FU/IL-2 and 5-FU/T alpha 1/IL-2. 5-FU was administered i.v. as a continuous infusion for 7 days by an osmotic device implanted surgically. T alpha 1 and IL-2 were administered for 4 days and repeated after 11 days. Combined chemo-immunotherapy was shown both to significantly reduce the growth of liver metastases and to prevent extra-hepatic spread. 5-FU/T alpha 1/IL-2 also improved survival rate. Combined immunotherapy after 5-FU restored NK activity of the peripheral-blood-mononuclear-cell (PBMC) in tumor and/or 5-FU immunodepressed rats and enhanced PBMC cytotoxic activity against the DHD/K12 autologous cell line. This model was devised to mimic the clinical situation of unresectable liver metastases.

Topics: Animals; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Cytotoxicity, Immunologic; Fluorouracil; Immunotherapy; Interleukin-2; Killer Cells, Natural; Liver Neoplasms; Male; Rats; Rats, Inbred Strains; Survival Analysis; T-Lymphocytes, Cytotoxic; Thymalfasin; Thymosin

In the present paper we analysed the presence of prothymosin alpha (ProT) in human liver. In normal liver, ProT immunostaining was found in the nuclei of bile duct cells, but not in the hepatocytes. In contrast an intense immunoreactivity was observed in regenerative hepatocytes of chronic hepatitis, cirrhosis and in hepatocellular carcinomas. In all cases the immunostaining was restricted to the nuclei, but the nucleoli were always negative. Similar results were obtained for proliferating cell nuclear antigen. These findings confirm that ProT is related to cell proliferation and provides a new immunohistochemical proliferation marker for routinely processed samples.

Topics: Carcinoma, Hepatocellular; Cell Division; Hepatitis, Chronic; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Liver Neoplasms; Nuclear Proteins; Proliferating Cell Nuclear Antigen; Protein Precursors; Thymosin

Prothymosin alpha (PT-alpha) is a nuclear protein involved in cell proliferation. Transcription of PT-alpha has been reported to be regulated by the c-myc gene in vitro. We identified PT-alpha as being overexpressed in a human colon cancer minus normal mucosa subtraction cDNA library. Northern blot (messenger RNA) analysis showed that both PT-alpha and c-myc genes were overexpressed in human colorectal cancers compared with adjacent normal tissues. Immunohistochemical studies for PT-alpha and c-myc supported these findings. There was no correlation between PT-alpha or c-myc messenger RNA expression and Dukes' stage of colorectal cancer; or between either of these two and actin messenger RNA expression. There was, however, a significant correlation between the PT-alpha expression and c-myc expression (P < 0.001). These findings support the hypothesis that PT-alpha gene transcription may be associated with, and possibly under the control of, the c-myc gene in human colorectal cancers.

Topics: Blotting, Northern; Colon; Colonic Neoplasms; Humans; Liver Neoplasms; Protein Precursors; Proto-Oncogene Proteins c-myc; RNA, Messenger; Thymosin