Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

Purpose

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo.

Methods

MTS was for NSCLC cell (PC9, 11–18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography.

Results

Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts.

Conclusions

These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein.     

Gentisic acid, an aspirin metabolite, inhibits oxidation of low-density lipoprotein and the formation of cholesterol ester hydroperoxides in human plasma

Gentisic acid, an aspirin metabolite, has an antioxidant effect, although its detailed mechanism remains elusive. The present study was designed to determine whether it inhibits low-density lipoprotein (LDL) oxidation and the formation of lipid hydroperoxides in human plasma. The susceptibility of LDL oxidative modification was investigated by a method using 2,2'-azobis or Cu2+. To study the effect of gentisic acid on free radical-induced damage to plasma lipids, cholesterol ester hydroperoxides generated by incubating human fresh plasma with Cu2+ and gentisic acid was analyzed. Gentisic acid inhibited LDL oxidation in a concentration-dependent manner. It significantly inhibited the formation of cholesterol ester hydroperoxides in plasma, and was consumed after the depletion of ascorbic acid and reduced form of coenzyme Q-10 (CoQH2-10), whereas concentrations of other antioxidants remained unchanged. Gentisic acid had a potent free radical scavenging activity with a minimal chelating effect. The potent antioxidant property of gentisic acid may partly account for the anti-atherogenic effects of aspirin.     

Hepatocellular carcinoma occurring in a Crohn��s disease patient

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn’s disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the non-neoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.     

Familial unilateral deafness and delayed endolymphatic hydrops

Delayed endolymphatic hydrops (DEH) is a unique disorder characterized by fluctuating otologic symptoms in the setting of preexisting unilateral deafness. The symptoms include aural fullness, fluctuating hearing, and/or episodes of vertigo similar to those observed in Meniere disease and may occur ipsilateral or contralateral to the previously deafened ear. In most reported cases, the unilateral deafness has been a profound sensorineural hearing loss with a sudden onset that has been variously attributed to bacterial or viral labyrinthitis, acoustic or cranial trauma, otosclerosis, and congenital CMV infection. Familial occurrence of the syndrome has not previously been reported in the literature. In this report, we describe two possible familial instances of delayed DEH. These patients raise the possibility that genetic factors may sometimes be the cause of this unusual syndrome.     

Squamous cell carcinomas of the mandibular alveolus: analysis of prognostic factors.

BACKGROUND: To assess the effect of clinicopathologic factors on local tumor control and survival in patients with mandibular alveolar carcinoma. METHODS: Fifty patients with mandibular alveolar carcinoma treated surgically were included in this study. There were 3 patients with T1, 25 with T2, 5 with T3, and 17 with T4 disease. Clinical evidence of bone invasion was noted in 47 patients. A hemi- or segmental mandibulectomy was performed on 37 patients, whereas 10 patients had a marginal mandibulectomy. The impact of clinicopathologic variables on local tumor control and patient survival was assessed by univariate analysis. Variables included T and N stage, dental extraction, treatment modality, tumor differentiation, nodal status, surgical margin, and bone invasion. RESULTS: Eleven patients (22%) develop recurrent disease, including 8 local recurrences, 1 neck, and 2 distant metastases. Overall, the 5-year actuarial rates of local control and disease-specific survival were 85 and 73%, respectively. Most local recurrences after surgical treatment were caused by inadequate resection margins. When resection margins were negative, the survival and local control rate were significantly better than when there were positive resection margins (survival, 91 vs. 11%; local control, 100 vs. 49%; p < 0.01). Neither T and N stages, clinical stage, tumor differentiation, dental extraction, bone invasion, extent of bone resection, nor treatment modality influenced outcome. CONCLUSIONS: The status of surgical margins was of major importance for the outcome of patients with gingival carcinoma of the mandible.     

The Effect of Overall Treatment Time of Radiation Therapy on Local Control of T1-Stage Squamous Call Carcinoma of the Glottis

From 1975 to 1990, 72 patients with T1 glottic cancer, excluding a verrucous type of carcinoma, were treated with radiation therapy (RT). All treatments were given with a standard fractionation of 2 Gy per day. The total dose to the tumor ranged from 60 to 70 Gy. Six patients received a split-course RT. The overall local control rate was 87% at 5 years. Forty-one patients who completed RT in 45 days or less had a 5-year local control rate of 95%. Sixteen patients who completed a treatment course in 46 to 49 days had a local control rate of 81%. Fifteen patients with a treatment course of more than 50 days had a local control rate of 73%. There was a statistically significant difference in local control rates among the three groups (P<.05). The split-course RT group had a 5-year local control rate of 50%; that rate was statistically significantly inferior to that of the continuous course group (P<.001). Multivariate analysis also showed that an interruption of the treatment course was an important parameter in relation to the local control. The prolongation of standard RT schedules adversely affected local control of T1 glottic carcinoma and, therefore, should be avoided whenever possible.     

Extracellular-added ADP-ribose increases intracellular free Ca2+ concentration through Ca2+ release from stores, but not through TRPM2-mediated Ca2+ entry, in rat beta-cell line RIN-5F

Intracellular ADP-ribose is an activator of TRPM2, which is a Ca2+-permeable channel and mediates H2O2-induced cell death, in the TRPM2-expressing rat beta-cell line RIN-5F. We examined the effect of extracellular-added ADP-ribose on intracellular Ca2+ concentration in RIN-5F cells. ADP-ribose induced Ca2+ release from the thapsigargin-sensitive Ca2+ store, but not Ca2+ entry across the plasma membrane. A phospholipase C (PLC) inhibitor and a non-specific IP3 receptor inhibitor blocked its Ca2+ release. H2O2-induced Ca2+ entry through TRPM2 was not affected by extracellular ADP-ribose. These findings suggest that extracellular-added ADP-ribose induces Ca2+ release through the PLC-IP3 pathway and does not act as a TRPM2 activator.