The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future.

Although monotherapy with angiostatic drugs is still far from effective, there is abundant evidence that angiostatic therapy can improve the efficacy of conventional treatments like radiotherapy. This has instigated numerous efforts to optimize and clinically implement the combination of angiostatic drugs with radiation treatment. The results from past and present clinical trials that explored this combination therapy indeed show encouraging results. However, current findings also show that the combination has variable efficacy and is associated with increased toxicity. This indicates that combining radiotherapy with angiostatic drugs not only holds opportunities but also provides several challenges. In the current review, we provide an update of the most recent insights from clinical trials that evaluated the combination of angiostatic drugs with radiation treatment. In addition, we discuss the outstanding questions for future studies in order to improve the clinical benefit of combining angiostatic therapy with radiation therapy.

Biomaterials and biotechnology: from the discovery of the first angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering.

This paper describes the discovery of the first inhibitors of angiogenesis; the discoveries that led to the development of the first biocompatible controlled release systems for macromolecules, and findings that helped to create the field of tissue engineering. In addition, new paradigms for creating biomaterials, early work on nanotechnology in medicine and intelligent drug delivery systems are discussed.

A brief history of anti-VEGF for the treatment of ocular angiogenesis.

In 1994, The American Journal of Pathology published a key article reporting that hypoxic retina produces vascular endothelial growth factor (VEGF), suggesting a role for VEGF in ocular neovascularization. Subsequent developments in anti-VEGF treatment for neovascular eye disease have improved visual outcomes and changed the standard of care in retinal medicine and ophthalmology.

[The thalidomide experience: review of its effects 50 years later]. / Talidomida: 50 años después.

This year is the 50(th) anniversary of the discovery that the drug thalidomide causes birth defects and should therefore be considered as a teratogen. However, despite the existence of several other drugs that are also human teratogens, thalidomide continues to cause concern among health professionals as well as the general population. The objectives of this article are to make a short historical review of the discovery that this drug severely alters the embryo development, the critical period of gestation and the identification of the real effect of thalidomide. For the first time an analysis is provided to identify the type of malformations for which thalidomide really increases the risk. The proportions of the different types of malformations groups from the series of patients considered to be affected by thalidomide from the literature were compared with the proportions of the same malformations groups in non-exposed infants from the Spanish Collaborative Study of Congenital Malformation (ECEMC). The aim of the analysis was to calculate the relative frequencies of 13 groups of malformations observed in series of patients exposed to thalidomide, by comparison with the same groups of defects in 1,491 patients with limb malformations from the ECEMC consecutive newborn infants, non-exposed to thalidomide. The results showed that the groups with the most classical limb malformations attributed to thalidomide (phocomelia, thumb absence/hypoplasia) had a significantly very higher frequency in exposed cases than in the ECEMC's cases. However, cases presenting with only lower limb malformations were 3 times less frequent in thalidomide cases than in those of ECEMC. Finally, other groups presented the same frequency as those observed in the ECEMC's cases. The results of the 2 last groups, strongly suggests that they were not due to the effect of thalidomide. In addition to the short historical review of the teratogenicity risk of thalidomide, and their new therapeutic properties, it is documented that, as it happens with all other currently known human teratogens, not all malformations observed in infants prenatally exposed to thalidomide were caused by this drug. Finally, it is discussed the paradox that the «feared¼ thalidomide drug causing a great human drama affecting about 10,000 infants has led to a formidable contribution to the scientific knowledge, and large range of therapeutic applications.

From the discovery of vascular endothelial growth factor to the introduction of avastin in clinical trials - an interview with Napoleone Ferrara by Domenico Ribatti.

Napoleone Ferrara and his colleagues at Genentech were the first to isolate and clone vascular endothelial growth factor (VEGF) in 1989. His laboratory has investigated many aspects of VEGF biochemistry and molecular biology. In 1993, Ferrara reported that inhibition of VEGF-induced angiogenesis by specific monoclonal antibodies resulted in dramatic suppression of the growth of a variety of tumors in vivo. These findings provided an important evidence that inhibition of angiogenesis may suppress tumor growth and blocking VEGF action could have therapeutic value for a variety of malignancies. A further development was the design in a rational fashion in 1997 of a humanized anti-VEGF monoclonal antibody (Avastin), now in clinical trials as a treatment for several solid tumors and also outside of cancer, in the treatment of age-related macular degeneration (AMD). Ferrara's work is revolutionizing quality of life for many of the estimated 1.2 million individuals in the US who have wet AMD. Upwards of a million AMD patients worldwide have already received anti-VEGF antibody therapy.

Anti-angiogenesis in cancer; met and unmet goals - an interview with Robert Kerbel by Francesco Bertolini.

Robert Kerbel is one of the most influential scientists in the field of cancer-related angiogenesis and anti-angiogenic therapies. Along with the late Judah Folkman, Dr. Kerbel has also pioneered the use of continuous low dose chemotherapy for cancer treatment, an approach which is now widely used for many types of cancer and is a promising backbone to be associated with novel targeted therapies. In this interview, Dr. Kerbel describes the steps that moved his career towards the angiogenesis field, the already achieved biological and clinical results and the unmet goals.

Clinical application of therapies targeting VEGF.

This year's Lasker DeBakey Clinical Research Award goes to Napoleone Ferrara for the discovery of vascular endothelial growth factor (VEGF) as a major mediator of angiogenesis and for the development of an effective anti-VEGF therapy for wet macular degeneration, a leading cause of blindness in the elderly.

The scientific contributions of M. Judah Folkman to cancer research.

Dr Judah Folkman was frequently described as a highly compassionate physician who served his patients not only by performing surgery and offering them comfort and reassurance, but also by working tirelessly in the laboratory to find new approaches to the treatment of disease. His dedication to understanding the role of angiogenesis, the formation of new blood vessels, in human disease has given rise to new treatments for several diseases, including inflammatory diseases, vision-threatening diseases of the eye and, as will be emphasized in this Perspective, cancer.

Judah Folkman, a pioneer in the study of angiogenesis.

More than 30 years ago, Judah Folkman found a revolutionary new way to think about cancer. He postulated that in order to survive and grow, tumors require blood vessels, and that by cutting off that blood supply, a cancer could be starved into remission. What began as a revolutionary approach to cancer has evolved into one of the most exciting areas of scientific inquiry today. Over the years, Folkman and a growing team of researchers have isolated the proteins and unraveled the processes that regulate angiogenesis. Meanwhile, a new generation of angiogenesis research has emerged as well, widening the field into new areas of human disease and deepening it to examine the underlying biological processes responsible for those diseases.

Investigación desarrollada en retinopatía diabética, enfermedad cardiovascular y relación del virus de la hepatitis C y la diabetes / Research developed in diabetic retinopathy, cardiovascular disease and relationship between hepatitis C virus infection and diabetes mellitus

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