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Therapeutic Advances: May 15th
Added: 05/23/2002

Oncology generally features heavily in Therapeutic Advances, however this week there is a distinct cardiovascular feel to selected publications. The field of angiogenesis has gained much attention over the previous two decades and has formed an interface between cardiovascular and oncology research. This interface now seems to be expanding as a result of a growing body of evidence suggesting that key cells (eg platelets) and molecules (eg alpha-thrombin) involved in the thrombotic cascade play an important role in metastasis, angiogenesis and proliferation.

Due the emergence of this field our "Target of the Month" section features a review that describes the potential use of hemostasis modulators as the next generation of anticancer molecules. A second publication featured in our "Focus on Angiogenesis" section approaches oncology from the opposite direction, based on the concept that selective hemostasis may block the vascular supply to tumors. Harvard researchers have thus demonstrated that photodynamic activation of Miravant's novel photosensitizer MV6401 can produce tumor specific thrombosis. This was shown to shut down the microvasculature in a mammary tumor leading to impressive anti-cancer activity.

Continuing on the cancer theme, key articles have recently been published relating to metastasis. Up until now treatments have often been palliative - the bisphosphonates offer an excellent example. This group of molecules has been shown to prevent painful fractures associated with bone metastases. More recently, an increasing number of publications have emerged suggesting that this therapeutic class is able to prevent metastatic progression as well as the damage that it causes. This week, one such publication has been singled out in our "Focus on Oncology" section. A second approach to metastasis - immunotherapy - is featured in "Focus on Targeted Cancer Therapy" which highlights the advent of camel antibody fragments as a means of improving this therapeutic area.
The fields of metastasis and apoptosis frequently overlap. One such example is highlighted in our "Focus on Metastasis" section. FTY720, a molecule that was originally developed as an immunosupressive agent, has recently been reported to be both pro-apoptotic and anti-metastatic. This profile was related to cytoskeletal changes, reduction of adhesion and chemotaxis, and markedly reduced tumor integrin expression. Researchers at Case Western Reserve University have also been involved in the identification of molecules able to stimulate apoptosis. This group has recently published an article (see our "Focus on Cell Death" section) reporting KChAP, a K+ channel modulatory protein that increases K+ currents and the expression of pro-apoptotic proteins including p53.

Targeting KChAP increases apoptosis in prostate cancer cells even in DU145 cells that express mutant p53. KChAP transfection prevented growth of DU145 and LNCaP tumor xenografts in nude mice indicating that targeting KChAP might represent a novel method of cancer treatment. One of the most well-known apoptosis strategies focuses on the use of toposiomerases. This enzyme occurs in at least two isoforms, toposiomerase I and toposiomerase II, and there are many examples of inhibitors of each of these enzymes. In the past few years dual toposiomerase inhibitors have emerged as therapeutic candidates. One such molecule, Xenova's XR11576, leads this field and has been the subject of a recent publication featured in our "Focus on Industrial Development" section. This molecule is of particular interest since it appears to avoid the problem of multi-drug resistance associated with molecules that target only one isoform.
Control of ion channels also features in our "Licensing Opportunities" section. Perhaps one of the most well known ion channel related conditions is cystic fibrosis. This condition has long been know to involve the defective control of the CFTR chloride channel and consequently considerable efforts have been expended in order to identify agents able to open these channels. Bristol University researchers have identified a series of molecules with this property.
Arthritis is very common, debilitating and difficult to treat inflammatory condition. The field of angiogenesis is receiving growing attention especially amongst oncology groups - the indications of this pharmacological class are however expanding with arthritis patients representing one patient cohort that stand to profit from advances. Given the growth of this area our "Focus on Immunology and Inflammatory Disease" section features a review of this field. Our editorial panel is always on the hunt for new indication for established targets and immunology is our port of call this week in this respect, particularly HIV-1. Control of this disease has improved dramatically since the mid-1990's following the advent of HAART. Patients are now living longer, which has in turn presented a problem relating to drug resistance. Consequently second line or adjunct therapies are now being sought to control HIV-1 infection. A small but convincing body of evidence suggests that kappa opioid ligands may be useful in this respect. This therapeutic class is able to reduce infection of host cells with HIV-1 as well as reducing the neurotoxic effects observed when microglia become infected - a cause of AIDs dementia. Like arthritis, COPD (emphysema and obstructive bronchitis) is another therapeutic area much in the news recently.

Indeed due to public demand we have just published an analysis of developing targets relating to this condition. This review included an analysis of specific phosphodiesterase inhibitors. The growth of this field is evidenced by the appearance of yet another PDE4 inhibitor - this time from Novartis. Our editorial panel has selected this molecule for special attention based on its improved efficacy and specificity. Novartis also features in our "Focus on Cardiovascular" section following the emergence of key data from the company's Basel center showing that MCP-1 could represent a central target for preventing the inflammatory progression of ischemic stroke. Alzheimer's disease represents a second highly prominent area of CNS disease. We have recently produced a number of dossiers that overview molecules able to prevent the accumulation of disease causing beta amyloid. Continuing on this theme our editorial panel has now selected a publication describing a series of pentapeptide amides that are able to prevent fibrillation of beta amyloid once it has been secreted.

Over the past few months our "Focus on metabolic disease" section has been highlighting the field of insulin resistance. Leptin has long been considered to play a role in this underlying feature of a number of conditions including diabetes and obesity. Leptin reduces both food intake and insulin resistance and it is therefore paradoxical that leptin levels are increased in obese patients. This suggests that leptin resistance may occur in these conditions and in this respect a recent publication suggesting that IL-1ra may play a role in this phenomenon is important both from a standpoint of etiology and target identification.

We hope that this edition of TherapeuticAdvances is as useful to you as it is to much of our audience. Please remember that you can learn a little bit more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit.

************************************** is a company founded by industrial researchers for the drug development sector. Our panel of pharmaceutical scientists produces TherapeuticAdvances, a twice-monthly bulletin of cutting edge scientific research with therapeutic potential. Selected research is fully analyzed in DiscoveryDossiers. These dossiers can be produced for institutions as due diligence reports or to boost technology transfer/partnering activity. Alternatively, dossiers can be purchased as overviews to support target identification or development efforts.

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