Identification and targeting of tumor escape mechanisms: a new hope for cancer therapy?

Conventional cancer therapy is administered in the form of surgery, radiotherapy or chemotherapy. Immunotherapy is the latest asset to the panel of anti-cancer treatments. This approach appears favorable over the other more conventional methods for various reasons: (1) it is highly specific for cancer cells and, therefore, low toxicity should be expected; (2) it recognizes and eliminates cancer cells regardless of their phase in the cell cycle; (3) tumors that developed drug resistances would still be a suitable target for immunotherapy. (4) Immunotherapy offers the possibility of preventive immunization of high-risk patients. Due to the diverse mechanisms that result in the transformation of cells and subsequent tumor development, not all cancers respond similarly to treatment. Significant effort is currently invested in the characterization of the underlying regulatory network in individual cancers responsible for tumorigenesis. Understanding tumors better allows on one hand the identification of essential pathways that can be intercepted to kill the transformed cells more specifically. On the other hand, these insights also allow us to exclude therapeutic strategies with little chance of success when dealing with tumor escape mutants thus saving valuable time and resources. Any tumor therapy puts selective pressure on tumors thus favoring the outgrowth of therapy-resistant variants. This review summarizes current knowledge on tumor escape mechanisms and some of the efforts to overcome these mechanisms.     

European Commission-supported development of targeted nanomedicines: did MediTrans make a difference?

Nanotechnology-inspired approaches to particle design and formulation, an improved understanding of (patho) physiological processes and biological barriers to drug targeting, as well as the limited input of new chemical entities in the 'pipeline' of pharmaceutical companies, suggest a bright future for targeted nanomedicines as pharmaceuticals. There is an increased consensus to the view that a major limitation hampering the entry of targeted delivery systems into the clinic is that new concepts and innovative research ideas within academia are not being developed and exploited in close collaboration with the pharmaceutical industry. Thus, an integrated 'bench-to-clinic' approach realized within a structural collaboration between industry and academia, will facilitate and promote the progression of targeted nanomedicines towards clinical application. The MediTrans project performed under the EU Framework Program 6, was designed to contribute to this ambition. The objectives of this collaborative initiative were: to apply nanotechnology for development of innovative targeted drug-delivery systems; to optimize targeted nanomedicines by using imaging guidance; to promote structural collaboration between industry and academia; and to forward targeted nanomedicines towards the clinic and the market. In this article, we will briefly address the research content, outcome and impact of the MediTrans project.     

The impact of topiramate (Topamax®) therapy on the development of aggressive and/or agitated behavior

The use of topiramate therapy to control the neuropsychiatric and behavioral disturbances in individuals with mental and/or developmental disabilities with co-occurring psychiatric disturbances has become a standard of practice in many long-term care assisted living facilities. With increased utilization of this anticonvulsant, there has been a rise in the number documented cases of agitation and/or aggressive behavior associated with topiramate therapy. It is the purpose of this article to explore the current literature documenting the connection between topiramate utilization and the development of aggressive and/or agitated behavior.     

Growth hormone therapy in heart failure: a novel therapy worthy of further consideration?

Despite the improvements in survival with angiotensin-converting enzyme inhibitors and beta-blockers, the clinical events for patients with heart failure remain elevated. New therapies for heart failure are required to improve the functional capacity, quality of life and prognosis. Growth hormone exerts both direct and indirect effects on cardiac structure and function. Experimental models of heart failure and small studies have demonstrated significant improvements in cardiac function, haemodynamical parameters, functional capacity and quality of life. The results from randomised controlled studies have been mixed with others showing benefit and some that do not. The randomised studies showing benefit consistently used growth hormone every other day. Further studies are needed to assess the potential role of this adjuvant therapy in patients with heart failure.     

Treatment of lichen planopilaris: methotrexate or cyclosporine a therapy?

Background: Because of irreversible outcome of the lichen planopilaris (LPP), systemic therapy should be used in early inflammatory stages of the disease, without allowing the irreversible scar formation and permanent hair loss.

Objective: We assessed the efficacy and safety of methotrexate (MTX) and cyclosporine A (CsA) in the management of recalcitrant, extensive LPP and compared their efficacy and safety profile.

Methods: We retrospectively analysed the 16 LPP cases treated with either CsA or MTX therapy. Clinical improvement was defined as the absence of reported symptoms, lack of progression and reduction in erythema and follicular hyperkeratosis found in SIAscopic images.

Results: A total of 16 patients received either CsA (six cases) or MTX (10 cases) therapy. The dosage of CsA was between 3 and 5?mg/kg/day. The initial dosage of MTX was 10–15?mg/wk and tapered gradually. The clinical improvement was demonstrated significantly at SIAscopic images taken at the third months of therapy.

Conclusions: Our observations suggest that both MTX and CsA therapies provide similar clinical efficacy at the end of first month of therapy with dosages used in psoriasis therapy. MTX was found to be better tolerated in this study.     

Antidepressants and violence: cause for concern or media hype?

No Abstract     

L-Arginine: a novel therapy for coronary artery disease?

Coronary artery disease (CAD) is a significant cause of morbidity and mortality today. The treatment of CAD is improving, but its prevalence is increasing: both primary and secondary prevention measures are of vital importance. Atherosclerosis starts at an early age; it is initiated at the vascular endothelium level, a single layer entity that modulates vascular function. Modulation of vascular function is carried out through the L-arginine/nitric oxide (NO) pathway. Normal endothelial function requires an intact L-arginine/NO pathway and endothelium. Endothelial dysfunction may be a precursor to overt CAD. CAD risk factors have been shown to influence endothelial function, and the treatment of these risk factors can restore endothelial function. L-Arginine is a safe, novel, semiessential amino acid that increases NO production, thereby improving endothelial function. L-Arginine/NO has numerous beneficial neurohormonal modulating properties. Numerous animal model and human studies have been carried out to assess L-arginine in CAD and other related disorders such as congestive heart failure (CHF), peripheral vascular disease (PVD) and acute myocardial infarction (AMI). Prospective clinical trials are required to assess the promising role of L-arginine in CAD and related disorders     

Enhancing the cytotoxic activity of novel targeted therapies--is there a role for a combinatorial approach?

The increased understanding of the pathogenetic and oncogenic pathways underlying cancer has allowed the successful development of novel approaches to treating the disease. The use of drugs to correct specific genetic defects responsible for the biological behaviour of cancer cells has been successfully applied to the clinic. These have included agents that interfere with cell proliferation and cell cycle signalling, neo-vascularisation, and DNA integrity. As a number of these processes also determine cellular survival, these novel agents can work to lower the cytotoxic threshold for conventional drugs. Consequently, a combinatorial drug approach could potentially be a valuable strategy for improving therapy. Unfortunately, targeting and inactivating a single pathway can adversely promote redundant parallel signalling pathways, which then maintain the aberrant status quo. Indeed, the intrinsic heterogeneity of tumours can preclude the successful application of a single targeted therapy. However, combinatorial drug approaches can be employed to surmount this multi-faceted characteristic of cancer. This article will highlight a number of novel targeted therapies that have been developed, some of which are currently undergoing clinical evaluation, and will also appraise the potential beneficial interactions that they may have with conventional cytotoxic drugs.     

First platinum(II)-based metal-organic linker technology (Lx®) for a plug-and-play development of antibody-drug conjugates (ADCs)

ABSTRACT

Introduction: Compared to the antibody and drug components of an ADC, the linker part has been somewhat neglected. However, its importance for the reduction of failures in ADC approvals is increasingly recognized. Next of being a stable glue between drug and antibody, an ideal linker should improve the manufacturability and widen the therapeutic window of ADCs.

Areas covered: The biopharmaceutical company LinXis started an ADC development program in which platinum(II) is the key element of the first metal-organic linker. The cationic complex [ethylenediamineplatinum(II)]²⁺, herein called ‘Lx®’, is used successfully for conjugation of drugs to antibodies.

Expert opinion: Based on lessons learned from ADC development, Lx linker technology fulfills most of the desirable linker characteristics. Lx allows large-scale cost-effective manufacturing of ADCs via a straightforward two-step ‘plug-and-play’ process. First clinical candidate trastuzumab-Lx-auristatin F shows favorable preclinical safety as well as outstanding in vivo tumor targeting performance and therapeutic efficacy.     

Effect of RANKL-specific denosumab on osteoclast number and function: a potential friend or foe?

The antiresorptive effect of a single 60-mg injection of the RANKL (receptor activator of NFkappaB ligand)-specific mAb, denosumab, substantially exceeds the effects of alendronic acid (70 mg weekly) yet increases in bone mass at the lumbar spine are identical for both agents. Important experimental and clinical observations illustrating some of the potential consequences of osteoclast deficiency and low-rate bone resorption for osteoblast function, bone mineralization, bone quality and related mechanical properties are summarized. This review also discusses whether the benefits for bone health can be improved when aggressively pushing the limits with novel antiresorptive medications.