Editorial [Hot Topic:Targeted Therapeutics - From Chemical Structures to Diagnostic and Therapeutic Agents(Executive Editor: Christine Armbruster)]

The first targeted therapeutic is presented by penicillin that was discovered by Alexander Fleming in 1928. The first radioactive-tracer experiments were performed as early as in 1913 by Fritz Haber, Ernest Rutherford and George Charles de Hevesy. The term “Magic bullet” was released by Paul Ehrlich and refers to the concept of selectively targeting a distinct bacterium without affecting other organisms. HIV infection which was first described in 1981 led to tremendous advances in drug design resulting in an effective therapeutic agent five years after first description of the disease and two years after identification of the infectious agent, the Human Immunodeficiency Virus (HIV). Essential prerequisite of drug design is the opportunity to perform high-resolution structural analysis by means of structural biochemical procedures as protein crystallography, nuclear magnetic resonance, and computational biochemistry. Based on recent advances in discovering enzymes through genome mining and metagenomics biocatalysis is emerging as transformational technology for drug discovery and production as will be presented by Ningqing Ran et al. in this issue of “Current Pharmaceutical Design”. Why do we need targeted drugs in diagnosis and treatment of infectious diseases and cancer? The answer seems to be simple: To enhance efficacy and to reduce harm of healthy tissue. Are these aims achievable? In part: In case of HIV infection targeted drugs as reverse transcriptase inhibitors (RTIs) - the first-generation treatments of HIV-1 disease- had only limited efficacy based on the interference of these drugs with human cell metabolism. The HIV-1 protease emerged as promising target and led to the development of protease inhibitors (PIs) that are still one of the most effective antiretroviral drugs. However, drug resistance and side effects are major concerns. Recently approved compounds that attack another target, the chemokine receptor CCR5 and the HIV-1 integrase demonstrated to have a more favorable safety profile. In order to overcome the development of drug resistance agents that are synergistic in action, that lack cross-resistance and overlapping toxicity are combined representing the multi-drug regimens that are commonly used in the treatment of HIV infection [1]. As in HIV infection significant progress has been made in the understanding of molecular mechanisms being involved in cancer development and progression leading to similar steps aiming at personalized therapy of cancer patients. Again some concerns with respect to successful therapy are left: Firstly, the molecular mechanisms leading to proliferation of malignant cells and to tumor angiogenesis are complex. Secondly, cancer cells overcome different growth factor signaling pathways by using escape mechanisms for their growth and survival advantage. Thirdly, drug resistance occurs based on mutational changes within the target e.g. the tyrosine kinase as has been discussed recently by Quintas-Gardama and Cortes [2]. Consequences are on the one hand the design of compounds against these mutants and on the other hand the combination of agents of the same or different drug classes as multi-kinase inhibitors (e.g. sorafenib), regimens consisting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor (VEGF) inhibitors as well as combining targeted drugs with conventional chemotherapeutic agents (e.g. erlotinib, gemcitabine and cisplatin; TALENT trial) [3]. Another approach is packaging drugs into nanoparticles resulting in improved bio-availability, bio-compatibility and safety profiles. Targeting particles can signal the presence of the disease site, block a function there, and release a drug to it as will be presented by Paul Debbage in this issue of the journal. Targeting is desirable because many barriers in human's body hinder free access of the drug to its targets as it is common knowledge for the blood brain barrier that lowers the efficacy of therapies. According to the “AIDS epidemic update” published in December 2007 33.2 million people are living with HIV worldwide, 2.5 million have been newly infected in 2007, and 2.1 million people died from AIDS in 2007 [4]. From the very beginning of the AIDS epidemic treatment has dominated and prevention strategies have been marginalized. But, treatment and prevention are inextricable connected in HIV infection as well as in cancer. Prevention in general needs to embrace political, social, as well as economical determinants. In comparison, 1,444,920 new cancer cases were projected in 2007 in the U.S., colorectal and lung cancer representing the most frequent solid tumors in both women and men. However, the U.S. cancer statistics give some hope since the incidence rates of the most frequent solid tumors began to decline since 1992. In contrast a report studying 18 different cancer types in 39 European countries demonstrated an increase from 2.4 million cancer cases in 2004 to 3.2 million in 2006 [5]. The one side of the coin are global statistics the other side is that successful prevention and treatment of solid tumors require the acceptance that these are not single diseases existing as a variety of phenotypes with different response rates especially to targeted drugs. Present chemotherapy regimens reached an efficacy plateau thus leading to the development of targeted therapeutics. An important lesson learned is that kinases are druggable targets for anti-cancer therapy leading to about 90 encoded tyrosine kinases that are major players in human cancers. Basically clinical benefit for patients with cancer requires either improvement of overall survival and of quality of life. Surrogate endpoints in clinical trials should ideally be validated as a predictor of these parameters. Very recently the discussion was raised if these surrogate endpoints are appropriate in case of patients with metastatic renal cell carcinoma. Furthermore ethical considerations arose with respect to crossover in case of disease progression [6, 7]. Additionally to surrogate endpoints appropriate inclusion criteria as well as patient and tumor characteristics that might serve as predictors for treatment efficacy or failure have to be defined.