Serum TGF-alpha Levels Research Articles

Clinical efficacy of erlotinib in patients previously treated for advanced non‐small cell lung cancer

Erlotinib is one of the standard second/third line treatments for patients with advanced non-small cell lung cancer (NSCLC). This study investigated the efficacy of erlotinib in a Chinese population with advanced NSCLC and compared the predictive value of serum vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-alpha for the efficacy of erlotinib. Patients with advanced, previously treated NSCLC received 150 mg of erlotinib once daily orally until disease progression or intolerable toxicity. Serum levels of VEGF and TGF-alpha were measured by ELISA at baseline and 1 month after treatment commenced. There were 112 patients enrolled during the period October 2005 to February 2008 and followed until July 2008. Serum samples were available in 50 patients. Tumour response to erlotinib was partial in 35.7% of patients and 41.1% of patients had stable disease. The severity of skin rash (P < 0.001) had a significant positive correlation with the response to erlotinib. Median progression-free survival (PFS) and overall survival were 6.3 months and 12.5 months, respectively. After erlotinib treatment, serum VEGF levels did not change significantly, while serum TGF-alpha levels increased in patients who had partial response (P = 0.075) or stable disease (P = 0.055), but not in patients with progressive disease (P = 0.155). In patients with measurable serum TGF-alpha levels at baseline the PFS and median survival were 5 and 9.9 months respectively, and in patients with no measurable TGF-alpha at baseline the PFS and median survival were 11 and 21 months, respectively. Overall survival was significantly longer in patients with negative baseline serum TGF-alpha (P = 0.002). Oral erlotinib was effective as a second/third line treatment for patients with advanced NSCLC. Baseline serum TGF-alpha levels may be a predictor for the efficacy of erlotinib treatment.

Impaired liver regeneration in acute liver failure: the significance of cross‐communication of growth associated factors in liver regeneration

Liver regeneration is considered to be retarded or suppressed in patients with acute liver failure. However, the mechanisms for this suppression remain to be elucidated. In order to evaluate deficiencies in liver regeneration in patients with acute liver failure, we focused on the cross-communication of growth-associated factors in experimental models. In primary cultured rat hepatocytes, the levels of cellular p53 and transforming growth factor-alpha (TGF-alpha), as well as DNA synthesis increased by the addition of hepatocyte growth factor (HGF). When p53 activity was suppressed, TGF-alpha expression and DNA synthesis were reduced. DNA synthesis was also reduced when TGF-alpha activity was suppressed. In rats after partial hepatectomy, hepatic HGF and p53 protein levels increased, followed by an increase of hepatic TGF-alpha levels and hepatocyte proliferation. Circulating levels of HGF and TGF-alpha correlated with changes in the hepatic levels. The suppression of TGF-alpha activity reduced the proliferation of hepatocytes in these rats. In patients suffering from acute hepatitis, serum HGF levels increased followed by an increase of serum TGF-alpha levels. In contrast, in patients with acute liver failure, the increase of serum TGF-alpha levels was suppressed depending on the severity of hepatic failure, even though serum HGF levels markedly increased. The patients' hepatic levels were consistent with serum levels. Cross-communication of growth associated factors may be important in the progression of liver regeneration, and impaired regenerative capacity in patients with acute liver failure may be attributable, at least in part, to a disruption of communication of growth-associated factors.

Phase I study of epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and vascular endothelial growth factor monoclonal antibody, bevacizumab, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN)

5539 Background: Studies of EGFR inhibitors in SCCHN have demonstrated reproducible activity. Preclinical studies have implicated angiogenesis as a mechanism of resistance to these agents. Furthermore, angiogenesis has been linked with tumor progression and worse outcome in SCCHN. This phase I multi-institutional trial was undertaken to assess the feasibility and toxicity of adding bevacizumab, an anti-VEGF monoclonal antibody to erlotinib, an EGFR tyrosine kinase inhibitor. Methods: Eligible patients were required to have performance status 2 or better, measurable disease, intact organ function, no more than one prior therapy for recurrent/metastatic disease, and no prior EGFR or VEGF based therapy. Escalating doses of bevacizumab (5, 10, and 15 mg/kg IV q3 weeks) were administered with a fixed dose of erlotinib (150 mg PO QD) to consecutive patient cohorts to establish a phase II dose. Plasma VEGF and serum TGF-alpha levels were drawn prior to therapy, after 2 weeks, and after 8 weeks of therapy. Results: 10 patients have been enrolled with 4, 3, and 3 patients in each cohort. Grade 3 toxicity consisted of diarrhea (1 patient), skin rash (1 patient), lymphopenia (1 patient). One patient experienced grade 4 hemorrhage from a tongue tumor after 6 treatment cycles that was felt to be therapy related. Common grade 1/2 toxicities observed included dermatologic (70%), fatigue (70%), and diarrhea (50%). Dose limiting toxicity, as defined by the protocol, was not observed at any dose level. Of 9 patients evaluated after 2 cycles, we have observed 1 PR, 7 SD, and 1 PD. 6 patients have had stable disease for greater than 12 weeks. Conclusions: Administration of bevacizumab 15mg/kg q3 weeks with erlotinib 150mg QD is feasible and well tolerated in recurrent/metastatic SCCHN. Assessment of regimen efficacy is underway in the phase II segment of this trial. Supported by NCI grant # N01-CM-17102. No significant financial relationships to disclose.

The Mitogenic Activity of Hepatocyte Growth Factor on Rat Hepatocytes Is Dependent upon Endogenous Transforming Growth Factor-α

Both transforming growth factor-alpha (TGF-alpha) and hepatocyte growth factor (HGF) induce DNA synthesis in hepatocytes in vitro and in vivo. Hepatic and circulating levels of HGF have been reported to increase before an increase in TGF-alpha levels in several rat models of liver regeneration. In addition, serum TGF-alpha levels increase after an increase in serum HGF levels in patients with either partial hepatectomy or acute hepatitis. In this study, we investigate the significance of TGF-alpha in hepatocyte proliferation. TGF-alpha contents and DNA synthesis in cultured rat hepatocytes increased in response to HGF addition to the culture medium in a dose-related manner. These increases were suppressed by the addition of anti-sense TGF-alpha mRNA oligonucleotide. Furthermore, the addition of anti-TGF-alpha rabbit IgG suppressed the increase in DNA synthesis. When the anti-TGF-alpha antibody was administered to rats after partial hepatectomy, the number of mitotic hepatocytes was reduced in comparison to rats treated with normal rabbit IgG. These results were observed even though hepatic HGF levels were increased equally in rats given either anti-TGF-alpha antibody or normal rabbit IgG. Our results suggest that HGF stimulates TGF-alpha production in rat hepatocytes, and that the mitogenic activity of HGF depends on endogenous TGF-alpha activity.

Transforming Growth Factor α Levels in Liver and Blood Correlate Better than Hepatocyte Growth Factor with Hepatocyte Proliferation during Liver Regeneration

Transforming growth factor alpha (TGFalpha) and hepatocyte growth factor (HGF) are mitogens for hepatocytes in vitro and in vivo, produced by hepatocytes or nonparenchymal cells such as stellate cells in the liver. It is still uncertain whether TGFalpha and HGF are essential for liver regeneration. To assess the role of these growth factors in liver regeneration, their circulating and hepatic levels were studied in various rat models of liver regeneration. Hepatic and plasma HGF levels were increased with increased number of mitotic hepatocytes in rats after partial hepatectomy or carbon tetrachloride intoxication. However, hepatic HGF levels were decreased despite an increased number of mitotic hepatocytes and increased or unchanged plasma HGF levels in rats given phenobarbital and in rats after dimethylnitrosamine intoxication, which can induce hepatic necrosis after apoptosis of hepatic stellate cells. In contrast, hepatic and serum TGFalpha levels were increased in all of the models. In sham-operated rats with no increased number of mitotic hepatocytes, hepatic and circulating levels of HGF were increased, whereas those levels of TGFalpha were unchanged. The results indicate that TGFalpha levels in liver and blood more closely correlate with hepatocyte mitogenesis than HGF levels.

Serum transforming growth factor alpha level as a marker of hepatocellular carcinoma complicating cirrhosis.

Transforming growth factor alpha (TGF alpha) is alleged to play a role in malignant progression as well as normal cell growth in an autocrine manner and its serum levels have been reported to increase during this progression. Most hepatocellular carcinomas (HCC) develop in cirrhotic livers in which hepatocyte necrosis and regeneration prevail. The significance of serum TGF alpha levels in the diagnosis of HCC complicating cirrhosis should be clarified. One hundred twenty-four patients with cirrhosis were studied, 80 with HCC (HCC) patients and 44 without (LC) patients. There was no difference in clinical features between the two groups. One hundred eighty-two healthy adults were also studied as controls. Serum TGF alpha levels were measured by enzyme-linked immunosorbent diffusion assay (ELISA). Serum TGF alpha levels were significantly higher in HCC patients than in healthy adults or LC patients (mean +/- SD: 45 +/- 40 vs. 21 +/- 15 or 25 +/- 19 pg/ml, respectively). In LC patients, serum TGF alpha levels were significantly correlated with serum albumin and total bilirubin levels (r = -0.44 and 0.32, respectively). When the cutoff level was defined as 25 pg/ml from receiver operating characteristic curve, sensitivity and specificity for the diagnosis of HCC in the presence of cirrhosis were 69% and 66%, respectively. Serum TGF alpha levels were decreased after successful treatment for HCC in 60% of the HCC patients. Serum TGF alpha levels showed no correlation with serum alpha-fetoprotein levels; the levels were greater than 25 pg/ml in 67% of the HCC patients whose serum alpha-fetoprotein levels were within 20 ng/ml. Serum TGF alpha levels may provide useful information for the diagnosis of HCC developing in the presence of cirrhosis.

Liver regeneration in fulminant hepatitis as evaluated by serum transforming growth factor alpha levels

Transforming growth factor alpha (TGF alpha) is supposed to act as a mitogen for hepatocytes in an autocrine manner in vitro and in vivo. Retarded liver regeneration is a possible reason for poor prognosis of fulminant hepatitis (FH). We analyzed serum TGF alpha levels in patients with FH and patients with acute nonfulminant hepatitis (AH). Also, the relation of those levels to serum hepatocyte growth factor (HGF) levels and their changes after glucagon-insulin (G-I) therapy were studied. Maximal serum TGF alpha levels achieved in each case after admission until recovery from disease or death were correlated positively with maximal serum alanine transaminase (ALT) and total bilirubin levels in patients with AH, but negatively with maximal total bilirubin levels in patients with FH. Maximal serum TGF alpha levels in patients with FH were significantly higher in survivors than in nonsurvivors. Maximal serum HGF levels were positively correlated with maximal serum TGF alpha levels in patients with AH, but not in patients with FH. Multiple regression analysis indicated that G-I therapy was related to the increment of serum TGF alpha levels in patients with FH. These results suggest that serum TGF alpha levels are increased in accordance with liver regeneration after necrosis in patients with AH, but such liver regeneration may be retarded, depending on the extent of liver damage in patients with FH. G-I therapy seems to stimulate liver regeneration after liver damage. The possible contribution of TGF alpha and HGF to liver regeneration merits consideration for recovery from AH. (Hepatology 1996 Feb;23(2):253-7)

Elevated serum levels of transforming growth factor-alpha in breast cancer patients.

Previous studies suggest that transforming growth factor-alpha (TGF alpha) may have the potential of a tumor marker. Since the levels of serum TGF alpha in cancer patients and healthy individuals have not been reported, we determined the serum TGF alpha levels of 83 breast cancer patients and 74 healthy individuals by using a TGF alpha radioimmunoassay kit. All of the cancer patients' sera were positive for TGF alpha; their TGF alpha concentrations ranged from 210 to 740 pg/ml, with a mean of 353 +/- 98 pg/ml. Sixty-seven percent (50 cases) of normal sera were positive for TGF alpha; the levels ranged from 120 to 207 pg/ml, with a mean of 144 +/- 17 pg/ml. The difference in serum TGF alpha levels between cancer patients of different disease stages and healthy individuals was found to be statistically significant by Student t-test and the Mann-Whitney test. No correlation was found between serum carcinoembryonic antigen and TGF alpha levels. The potential of serum immunoreactive TGF alpha as a marker for breast cancer warrants further investigation.