Beyond Anti-VEGF: Dual-Targeting Antiangiogenic and Antiproliferative Therapy.

Beyond anti-VEGF: dual-targeting antiangiogenic and antiproliferative therapy.

Am J Transl Res. 2013; 5(4): 393-403
Chen CT, Hung MC

Antiangiogenesis is a promising antitumor strategy that inhibits tumor vascular formation to suppress tumor growth. Specifically, targeting VEGF has shown therapeutic benefits in many cancer types, leading to its approval as the first antiangiogenic drug by the Food and Drug Administration in the United States. It is known, however, that patients will experience unfavorable side effects as the VEGF and/or VEGF receptor signaling pathway is also required for homeostasis in normal tissues. Moreover, due to the cytostatic nature of antiangiogenic, cancer cells that are not killed by these drugs later develop an even more malignant phenotype, resulting in tumor invasion and metastasis. Although there have been many attempts to reduce drug resistance and increase therapeutic efficacy by combining antiangiogenic drugs with chemotherapy, the cumulative toxicity of antiangiogenic combinations limits their feasibility as treatments, as chronic angiogenesis inhibition typically reduces the antitumor effect of the co-administered chemotherapeutics. To overcome these problems, it is critical to explore new strategies that limit tumor resistance and side effects and also increase the exposure of chemotherapy drugs at the tumor site. Here, we review current understanding of antiangiogenic drugs and introduce a new combination strategy that links direct antiangiogenic protein and enzyme prodrug system with dual-targeting antiangiogenic and antiproliferative therapeutic effect in tumor microenvironment. This strategy has the potential to overcome these clinical hindrances and may serve as a paradigm for the next generation of antiangiogenic drugs. HubMed – drug


Unresectable hepatocellular carcinoma treated with transarterial chemoembolization: clinical data from a single teaching hospital.

Int J Clin Exp Med. 2013; 6(5): 367-71
Wang Y, Shen Y

The aim of this study is to evaluate the survival rates of patients with unresectable hepatocellular carcinoma (HCC) following transarterial chemoembolization (TACE) performed in a single teaching hospital. This study retrospectively assessed the electronic medical records of 217 patients in whom HCC was newly diagnosed from January 2009 to February 2013 at a single medical center. Hepatic artery infusion chemotherapy was performed using one drug or combinations of oxaliplatin, fluorouracil and doxorubicin. The primary endpoint of the study was overall survival (OS). Survival rates were calculated using Kaplan-Meier method. A total of 217 HCC patients (173 men and 44 women; mean age, 56.3 years; age range, 36.1-84.3 years) were treated with TACE in a single center. The overall survival rates at 1 and 2 years were 64% and 40%, respectively. The overall median survival time from the start of TACE treatment was 13 months. Our results indicated that TACE is an effective minimally invasive therapy option for palliative treatment of HCC patients. HubMed – drug


Influence of preoperative diastolic dysfunction on hemodynamics and outcomes of patients undergoing orthotopic liver transplantation.

Int J Clin Exp Med. 2013; 6(5): 351-7
Xu ZD, Xu HT, Li WW, Zou Z, Shi XY

Left ventricular diastolic dysfunction is receiving more attention in patients with end-stage liver diseases. The importance of diastolic dysfunction observed before orthotopic liver transplantation (OLT) and its adverse effects on hemodynamics and outcomes of OLT patients, have not been fully explored. We carried a retrospective study to investigate the influence of diastolic dysfunction on OLT patients.Included in this retrospective study were 330 consecutive patients scheduled for cadaveric OLT over a 5-year period. According to preoperative Doppler echocardiogram (ECHO) findings, patients were divided into two groups: DD group (patients with diastolic dysfunction) and control group (patients with normal ECHO). Patient characteristics, operation variables, hemodynamic course, blood products and drug requirements, postoperative courses and outcomes were evaluated.306 patients met the study entry criteria and 100 had preoperative diastolic dysfunction. Mean artery blood pressure was significantly lower in DD group after graft reperfusion than that in control group (P<0.01). More patients in DD group required epinephrine, and the mean dose of epinephrine was higher in DD group than that in control group (P<0.01). There was no significant difference in postoperative ventilation time, duration of ICU and hospital stay, renal failure and postoperative mortality between the two groups.Diastolic dysfunction is common in liver transplant recipients. Patients with diastolic dysfunction may be associated with substantial hemodynamic alterations after graft reperfusion and need more inotropic support during OLT. Diastolic dysfunction was not associated with significant adverse postoperative outcomes. HubMed – drug


Recombinant human Acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer.

PLoS One. 2013; 8(5): e65620
Savi? R, He X, Fiel I, Schuchman EH

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third leading cause of cancer death worldwide. The only approved systemic treatment for unresectable HCC is the oral kinase inhibitor, sorafenib. Recombinant human acid sphingomyelinase (rhASM), which hydrolyzes sphingomyelin to ceramide, is an orphan drug under development for the treatment of Type B Niemann-Pick disease (NPD). Due to the hepatotropic nature of rhASM and its ability to generate pro-apoptotic ceramide, this study evaluated the use of rhASM as an adjuvant treatment with sorafenib in experimental models of HCC. METHODOLOGYPRINCIPAL FINDINGS: In vitro, rhASM/sorafenib treatment reduced the viability of Huh7 liver cancer cells more than sorafenib. In vivo, using a subcutaneous Huh7 tumor model, mouse survival was increased and proliferation in the tumors decreased to a similar extent in both sorafenib and rhASM/sorafenib treatment groups. However, combined rhASM/sorafenib treatment significantly lowered tumor volume, increased tumor necrosis, and decreased tumor blood vessel density compared to sorafenib. These results were obtained despite poor delivery of rhASM to the tumors. A second (orthotopic) model of Huh7 tumors also was established, but modest ASM activity was similarly detected in these tumors compared to healthy mouse livers. Importantly, no chronic liver toxicity or weight loss was observed from rhASM therapy in either model. CONCLUSIONSSIGNIFICANCE: The rhASM/sorafenib combination exhibited a synergistic effect on reducing the tumor volume and blood vessel density in Huh7 xenografts, despite modest activity of rhASM in these tumors. No significant increases in survival were observed from the rhASM/sorafenib treatment. The poor delivery of rhASM to Huh7 tumors may be due, at least in part, to low expression of mannose receptors. The safety and efficacy of this approach, together with the novel findings regarding enzyme targeting, merits further investigation. HubMed – drug