Current Drug Targets - Volume 3, Issue 5, 2002

Secreted aspartic proteinases (Saps) are important virulence factors in different types of candidiasis caused by Candida albicans (C. albicans). The various isoenzymes are expected to fulfil different tasks during mucosal or disseminated infections. It could be shown that the introduction of the proteinase inhibitors like saquinavir and indinavir in the therapy of human immunodeficiency virus (HIV) infected patients has an effect on Sap activity in vitro as well as in vivo. Therefore, drugs like the HIV proteinase inhibitors could play an essential role in the treatment of candidiasis in the future, especially if further adapted to this target.

Binding sites for the ETS domain family of transcription factors are found in the promoters of the matrix metalloproteinase (MMP) family of matrix degrading enzymes. Evidence is accumulating that both these groups of molecules are important in the process of angiogenesis in addition to matrix degradation. Furthermore, they are both expressed in tumor tissue as well as in the normal surrounding stroma. These factors along with various sites at which they may be regulated collectively makes them attractive targets to consider for therapeutic intervention in the processes of invasion and metastasis.

Hepatocellular carcinoma (HCC) is a one of the most prevalent cancers worldwide, especially in the Asia Pacific region. At present, the five-year survival of individuals with HCC is low, mainly due to the late presentation of the disease, and limited therapeutic options. The major risk factors for HCC in the Asia Pacific region include hepatitis B and C viral infection. Removing or reducing these risk factors, such as by immunizing against the hepatitis B virus, may reduce the incidence of hepatitis B-associated HCC in the distant future. However, immunization does not decrease the risk of HCC in individuals who are currently infected with HBV worldwide highlighting the continued importance of examining strategies for the treatment of HCC. Current treatment strategies include surgical resection, liver transplantation, chemotherapy, transcatheter arterial chemoembolism and percutaneous injection. Except for surgical resection and liver transplantation, which represent the most viable treatment options, most of the other present treatments are mainly for palliation. Hence novel treatment modalities continue to be investigated and several of these are currently in clinical trials. One of the more promising novel approaches for HCC treatment is gene therapy. Potential promising gene therapeutic approaches for the treatment of HCC include augmentation of tumor suppressor genes, inhibition of abnormally over-expressed oncogenes as well as specifically inducing death of cancer cells either via “suicide” gene therapy, conditional replicative adenovirus strategy, immunomodulation or inhibiting tumor angiogenesis. Nonetheless, successful implementation of these gene therapeutic approaches is dependent on overcoming current practical and technical hurdles underscoring the need for a better understanding of the basic aspects of gene therapy.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are greatly contributed to the treatment of hypercholesterolemia, and constitute an important part of comprehensive strategies for the treatment of cardiovascular disease in the 21st century. Particularly, a strategy for preventing acute coronary syndrome (ACS), the most important complication of hyperlipidemia, is urgently needed. Recent research has revealed a new mechanism of prevention of coronary heart disease by statins: they not only lowered cholesterol level as previously reported, but also contribute directly to plaque stabilization. Among many statins recently marketed, some act directly onto the blood vessel wall to stabilize plaques already formed (so-called vascular statins), while statins are originally classified as chemical or non-chemical. At the same time, reports on pleiotropic activities of statins, including improvement of osteoporosis, have accumulated to suggest an extended role of statins, not merely as a hypolipidemic agent but also possibly an antiarteriosclerotic / anti-aging drug. This article reviews the direct action of statins on the blood vessel wall, with reference to classification of statins based on difference in action on the blood vessel wall (hepatic statins vs. vascular statins).

Biomedical science is currently undergoing an epoch-marking transition from its classical phase to the post-genome era. The outstanding success of world-wide genome sequencing efforts, evidenced by the recent publication of the draft of the human genome, together with the completion of several genomes of eukaryotic model organisms and the availability of microbial genome sequences, is opening up data sources of unprecedented scale for drug discovery. Furthermore, the elucidation of genome expression states through transcriptomic and proteomic techniques is playing a crucial role in the characterisation of disease at the molecular level. At the same time, our still very limited knowledge of the biological functions of genes and proteins at different levels of cellular organisation is preventing full exploitation of the available data. This review will discuss current computational techniques for function prediction based on the sequence-structure-function paradigm. Newly emerging approaches aimed at gaining an expanded understanding of function through integration of data from various sources and modelling of complex cellular systems will also be highlighted.

Since there is some evidence for spontaneous immunity against renal cell carcinoma, vaccination strategies are often used in patients with this tumor type, both in the adjuvant and the metastatic setting. Therefore, therapeutic strategies aim at augmenting anti-tumor immunity, but tumor-specific antigens suitable for vaccination purposes in renal cell carcinoma still remain to be identified.Early approaches used whole tumor cells or cell lysates with or without non-specific adjuvants like BCG. Studies investigating tumor cell vaccines have demonstrated immunological responses following vaccination, like positive cutaneous delayed hypersensitivity reactions indicating biological acitivity of tumor cell vaccines, and clinical responses have been observed as well. However, no clinical benefit has been demonstrated in randomized phase III trials.In recent years, efforts to develop more potent vaccines resulted in more sophisticated methods of tumor vaccination: The insertion of “neo-antigens” to enhance immunogenicity, the insertion of T-cell co-stimulatory molecules to enhance antitumor T-cell activation and the local production of cytokines to enhance T-cell function or the migration of antigenpresenting cells. Tumor cells have been genetically modified to express and produce cytokines, which in turn enhance the immunogenicity of the vaccine. The important role of dendritic cells has been recognized and tumor antigen-pulsed dendritic cells have been proposed. Hybrid cell vaccines are another promising approach. Safety and some effectiveness of these vaccines were demonstrated in phase I and II trials. However, randomized phase III trials are mandatory to confirm the usefulness of vaccination strategies.This review will describe the principals of tumor vaccination and, in a second part, focus on clinical studies of tumor vaccination in patients with renal cell carcinoma.