Vandetanib hydrochloride

Description: IC50 Value: 40 nM (VEGFR2) [1]; 500 nM (EGFR) [2] Vandetanib is an anti-cancer drug that is used for the treatment of certain tumours of thethyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase. in vitro: Vandetanib also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Vandetanib is not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM, while almost has no activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM. Vandetanib inhibits VEGF-, EGF- and bFGF-stimulated HUVEC proliferation with IC50 of 60 nM, 170 nM and 800 nM, with no effect on basal endothelial cell growth. Vandetanib inhibits tumor cell growth with IC50 of 2.7 μM (A549) to 13.5 μM (Calu-6) [2]. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib [3]. in vivo: In tumor-bearing mice, vandetanib suppressed phosphorylation of VEGFR-2 and EGFR in tumor tissues, significantly reduced tumor vessel density, enhanced tumor cell apoptosis, suppressed tumor growth, improved survival, reduced number of intrahepatic metastases, and upregulated VEGF, TGF-α, and EGF in tumor tissues [4]. Animals were treated for 28 days with 1 mg/kg/d (DTX1) or 6 mg/kg q4d (DTX6) docetaxel with or withoutvandetanib (15 mg/kg/d p.o.) in mice bearing UMSCC2 tumor xenografts. The DTX1 dosing scheme was adjusted to treatment for 10 days followed by 9 days off due to severe gastrointestinal toxicity [5]. Toxicity: Treatment with vandetanib was not associated with serious adverse events, including alanine aminotransferase abnormality, bone marrow suppression, or body weight loss [4]. Clinical trial: N/A

Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non-small-cell lung cancer: A meta-analysis of 15 phase II/III randomized trials.[Pubmed:25471638]

Int J Cancer. 2015 Jul 15;137(2):409-19.

The efficacy of combined vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibition in patients with advanced non-small-cell lung cancer (NSCLC) was well studied. However, few studies focused on the risk and adverse events (AEs) of combined targeted therapy. The aim of this meta-analysis was to evaluate the safety profile of combined targeted therapy against EFGR and VEGF in patients with advanced NSCLC. A comprehensive literature search in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts and ESMO Abstracts was conducted. Eligible studies were randomized clinical trials (RCTs) that compared safety profile of combined therapy inhibiting EFGR and VEGF pathways with control groups (placebo, single EGFR or VEGF inhibition therapy, chemotherapy or a combination of them) in patients with advanced NSCLC. The endpoints included treatment discontinuation, treatment-related deaths and AEs. The search identified 15 RCTs involving 6,919 patients. The outcomes showed that three of four pairwise comparisons detected more discontinuation due to AEs in combined targeted therapy, with odds ratio (OR) compared with the control groups ranged from 1.97 to 2.29. Treatment with combined inhibition therapy was associated with several all-grade and grade 3 or 4 AEs (e.g. rash, diarrhea and hypertension). Also, there was a significantly higher incidence of treatment-related deaths in combined inhibition using vandetanib versus single EGFR inhibition therapy (OR = 1.97, 95% CI 1.19-3.28). In conclusion, combined inhibition therapy against EGFR and VEGF in patients with advanced NSCLC was associated with increased toxicity. Increased AEs hinder patient compliance and reduce their quality of life, leading to dose reduction or discontinuation.

Validation of a high-performance liquid chromatographic ultraviolet detection method for the quantification of vandetanib in rat plasma and its application to pharmacokinetic studies.[Pubmed:24762492]

J Cancer Res Ther. 2014 Jan-Mar;10(1):84-8.

AIM: To develop a simple and sensitive high-performance liquid chromatography (HPLC) assay with ultraviolet detection method of vandetanib in rat plasma. MATERIALS AND METHODS: Samples were extracted with methanol and acetonitrile, evaporated, and then the residue was reconstituted in mobile phase. Vandetanib and the internal standard (I.S.) trazodone hydrochloride were separated with gradient elution (on a C18 Atlantis column using a mobile phase of acetonitrile/0.5% triethylamine, pH 3.0, with a flow rate of 1.0 ml/min), then detected at 341 nm. RESULTS: A linear curve over the concentration range of 80-4000 ng/ml (R(2) = 0.9998) was obtained. Intra- and inter-assay accuracy ranged from 98.80% to 103.08% and 95.32% to 98.40%, with high precision (R.S.D. % <5%), respectively. The mean absolute recovery was 96.65%. CONCLUSION: A simple and sensitive HPLC assay with ultraviolet detection method was developed for the determination of vandetanib in rat plasma. This method is sufficient for pharmacokinetic studies of vandetanib in small animals and may be applied to human pharmacokinetic studies.

Late epidermal growth factor receptor inhibitor-related papulopustular rash: a distinct clinical entity.[Pubmed:25959005]

Clin Exp Dermatol. 2016 Jan;41(1):34-7.

We report four patients developing a late form of papulopustular rash induced by epidermal growth factor receptor inhibitors. These patients presented an unusual presentation of acneiform rash, characterized by late development (several months after treatment commenced), localization to the limbs with sparing of the face, and association with severe pruritus and Staphylococcus aureus superinfection in all cases. These clinical symptoms may suggest a distinct mechanism from the early acne-like rash frequently observed with these targeted anticancer therapies. Clinicians should be aware of this delayed adverse event, and we suggest the term 'late acneiform toxicity of EGFR inhibitors (LATE) syndrome' to permit better characterization of this clinical picture.

Drug-eluting embolic microspheres for local drug delivery - State of the art.[Pubmed:28710006]

J Control Release. 2017 Sep 28;262:127-138.

Embolic microspheres or beads used in transarterial chemoembolization are an established treatment method for hepatocellular carcinoma patients. The occlusion of the tumor-feeding vessels by intra-arterial injection of the beads results in tumor necrosis and shrinkage. In this short review, we describe the utility of using these beads as devices for local drug delivery. We review the latest advances in the development of non-biodegradable and biodegradable drug-eluting beads for transarterial chemoembolization. Their capability to load different drugs, such as chemotherapeutics and anti-angiogenic compounds with different physicochemical properties, like charge and hydrophilicity/hydrophobicity, are discussed. We specifically address controlled and sustained drug release from the microspheres, and the resulting in vivo pharmacokinetics in the plasma vs. drug distribution in the targeted tissue.

Repositioning "old" drugs for new causes: identifying new inhibitors of prostate cancer cell migration and invasion.[Pubmed:26932199]

Clin Exp Metastasis. 2016 Apr;33(4):385-99.

The majority of prostate cancer (PCa) deaths occur due to the metastatic spread of tumor cells to distant organs. Currently, there is a lack of effective therapies once tumor cells have spread outside the prostate. It is therefore imperative to rapidly develop therapeutics to inhibit the metastatic spread of tumor cells. Gain of cell motility and invasive properties is the first step of metastasis and by inhibiting motility one can potentially inhibit metastasis. Using the drug repositioning strategy, we developed a cell-based multi-parameter primary screening assay to identify drugs that inhibit the migratory and invasive properties of metastatic PC-3 PCa cells. Following the completion of the primary screening assay, 33 drugs were identified from an FDA approved drug library that either inhibited migration or were cytotoxic to the PC-3 cells. Based on the data obtained from the subsequent validation studies, mitoxantrone hydrochloride, simvastatin, fluvastatin and vandetanib were identified as strong candidates that can inhibit both the migration and invasion of PC-3 cells without significantly affecting cell viability. By employing the drug repositioning strategy instead of a de novo drug discovery and development strategy, the identified drug candidates have the potential to be rapidly translated into the clinic for the management of men with aggressive forms of PCa.