Two bifunctional ruthenium(II)-p-cymene complexes with perfluorinated side chains, attached via pyridine ligands, have been evaluated in a series of in vitro and in vivo assays. Their effects on human endothelial (ECRF24 and HUVEC) cells, noncancerous human embryonic kidney (HEK-293) cells, and various human tumor cells were investigated. The complex with the shorter chain, 1, inhibits the proliferation of the tumor cell lines and ECRF24, whereas 2 selectively inhibits ECRF24 and HUVEC proliferation. Neither inhibits the migration of ECRF24 cells whereas both compounds inhibit sprout formation in HUVEC cells. Using three preclinical models, i.e., vasculature formation in the chorioallantoic membrane (CAM) of the chicken embryo, human A2780 ovarian carcinoma tumors xenografted on the CAM, and human LS174T colorectal adenocarcinoma tumors grown in athymic mice, the angiostatic and anticancer activities of these two complexes were studied. Overall, 1 inhibited tumor growth predominantly through an anticancer effect whereas 2 inhibited tumor growth predominately via an antiangiogenic mechanism.

Cancer cells are often dependent on epigenetic pathways for their survival. Consequently, drugs that target the epigenome, rather than the underlying DNA sequence, are currently attracting considerable attention. In recent years, the first epigenetic drugs have been approved for cancer chemotherapy, mainly for hematological applications. Limitations in single-drug efficacies have thus far limited their application in the treatment of solid tumors. Nevertheless, promising activity for these compounds has been suggested when combined with other, distinctly targeted agents. In this review, we discuss the anti-angiogenic activity of histone deacetylase and DNA methyltransferase inhibitors and their combinations with other targeted (anti-angiogenic) therapeutics in treatment of solid tumors. The role that these inhibitors play in the inhibition of tumor angiogenesis, particularly in combination with other targeted agents, and the advantages they present over broad acting anticancer agents, are critically discussed.

Angiostatic therapies are now routinely embedded in the daily clinical management of cancer. Although these agents clearly benefit patient survival rates, the effect is only moderate with sometimes considerable side effects. A major cause of failure in this respect is the induction of resistance and tolerability against these drugs. Most angiostatic drugs are tyrosine kinase inhibitors that aim to inhibit or neutralize the activity of tumour-produced growth factors. Frustrating the tumour cells in this way results in genetic adaptations in the cells, turning them into mutants that are dependent on other growth mechanisms. It may therefore be necessary to shift to another class of drugs that directly target the tumour vasculature. It is evident that improvement of future angiogenesis inhibitors can only arise from two efforts. First, through the identification of better targets, preferably specifically expressed in the tumour vasculature. Secondly, through the development of combination therapies. The present review highlights the current efforts and challenges in trying to develop effective angiostatic combination therapies.

BackgroundPersonal continuity – having a GP who knows his or her patients and keeps track of them -is an important dimension of continuity of care andis associated with lower mortality rates, higher quality of life and reduced healthcare costs. In the last decades, it has become more challenging for general practitioners (GPs) to provide personal continuity due to changes in society and healthcare.AimTo investigate GPs’ and older patients’ views on personal continuity andhow personal continuity can be improved.Design and SettingCross-sectional survey study in the NetherlandsMethodA digital and postal survey was send to 499 GPs and 1599 patients aged 65 or aboveResults were analysed using descriptive statistics for quantitative data and thematic analysis for open questions.Results249 GPs and 582 patients completed the surveys. A large majority of GPs (92–99%) and patients(91–98%) felt it was important for patients to see their own GP for life events or psychosocial issues.GPs and patients provided suggestions on how personal continuity can be improved.The thematic analysis of these suggestions identified nine themes1: personal connection,2GP accessibility and availability,3communication about (dis)continuity,4GP responsibility,5triage,6time for the patient,7actions by third parties,8team continuity and9GP vocational training.Discussion/conclusionBoth GPs andolder patients still place high value on personal continuity in the context of a changing society. GPs and patients provided a wide range of suggestions for improving personal continuity. We will use these suggestions to develop interventionsfor optimising personal continuity in general practice.