A Systematic Review of Clinical Studies Using VEGF Inhibitors in the Treatment of Macular Edema from Diabetic Retinopathy

Purpose: To synthesize the present clinical evidence of efficacy and adverse events of commonly used anti-VEGF drugs for Diabetic Macular Edema. Methods: A systematic review was undertaken from the Medline, Biosis, CINAHL, Cochrane and Web of Science databases. Grey literature that consisted of lectures, seminars and conferences was also retrieved. The cut-off date was January 1 2014. A two-stage screening process was undertaken followed by a data extraction stage using the systematic review software EPPI. These were done by two reviewers. Heterogeneous meta-analysis was performed on the primary outcome which was change in macular thickness from baseline after injection. Side effects were tabulated. Results: From 846 articles that were initially screened, 18 papers were included in the data extraction stage. For all anti-VEGF treatments, the average decrease in macular thickness was 114.4 microns (95% CI: 66.8 - 162 μM). The average decrease in thickness from Lucentis (161.9 μM) was larger than that for Avastin (96.5 μM) but this was not statistically significant (p = 0.23). The most common complications were vitreous hemorrhage, endophthalmitis and retinal detachment. Vision threatening complications were rare but were reported regularly. Conclusions: The synthesized clinical evidence to date supports both of these treatments as efficacious and safe for diabetic macular edema (DME). There is a trend toward greater efficacy for Lucentis over Avastin but this is not statistically significant and will need a head-to-head RCT to assess accurately.

Design and semisynthesis of oleanolic acid derivatives as VEGF inhibitors:Inhibition of VEGF-induced proliferation,angiogenesis,and VEGFR2 activation in HUVECs

Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases,such as cancer,rheumatoid arthritis,and age-related macular degeneration.Recent studies have revealed that oleanolic acid(OA),a natural pentacyclic triterpenoid,inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs,which may represent an attractive VEGF inhibitor.In this paper,rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential.As a result,a series of novel OA derivatives,possessingα,β-unsat-urated ketone system in ring A and amide functional group at C-28,were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs.The results showed that two promising derivatives,OA-1 and OA-16,exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs,compared with OA.The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VE-GFR2 activation.Furthermore,small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2.Thus,the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors,which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.

Deciphering resistancemechanisms and novel strategies to overcome drug resistance in ovarian cancer:a comprehensive review

Ovarian cancer is among the most lethal gynecological cancers,primarily due to the lack of specific symptoms leading to an advanced-stage diagnosis and resistance to chemotherapy.Drug resistance(DR)poses the most significant challenge in treating patients with existing drugs.The Food and Drug Administration(FDA)has recently approved three new therapeutic drugs,including two poly(ADP-ribose)polymerase(PARP)inhibitors(olaparib and niraparib)and one vascular endothelial growth factor(VEGF)inhibitor(bevacizumab)for maintenance therapy.However,resistance to these new drugs has emerged.Therefore,understanding the mechanisms of DR and exploring new approaches to overcome them is crucial for effective management.In this review,we summarize the major molecular mechanisms of DR and discuss novel strategies to combat DR.

Ovarian cancer recurrence:is the definition of platinum resistance modified by PARPi and other intervening treatments?The evolving landscape in the management of platinum-resistant ovarian cancer

Definitions of platinum resistance have been questioned and changed over the last five years,even though no predictive biomarker of resistance exists.These have sculpted how we approach platinum retreatment and,consequently,how we devise new treatment strategies for those patients with tumour progression on platinum therapy.Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs.When bevacizumab can be added to chemotherapy,progression-free survival improves significantly.For patients with a BRCA mutation,PARP inhibitor monotherapy is an option compared to chemotherapy.There is currently no clearly identified role for immune-checkpoint inhibition in this patient population.This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response,angiogenesis or immune modulation.It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.