Current Pharmaceutical Design - Volume 14, Issue 21, 2008

This special issue of Current Pharmaceutical Design is focussed on innovative therapeutical approaches for hematological malignancies based on molecular targeted therapies. Macor group [1] summarizes recent advances in human tumor xenograft models for moving toward more clinically relevant models, which are essential for characterizing potential therapeutic targets in cancer therapy, including hematological malignancies. Calin group [2] describes the potential involvement of microRNAs in the regulation of neoplastic hematopoiesis and provides background on the biogenesis and function of miRNAs, discussing the potential therapeutic applications of miRNA-based technology in hematological malignancies. Phipps' group [3] shows the link between the overexpression of a key modulator of inflammation, such as cyclooxygenase-2 (Cox-2), and the ability of some hematological malignancies to avoid immune responses by producing factors that enhance angiogenesis and the metastastatic potential. Thus, Cox-2 selective inhibitors, which are already used in clinical practice, have promising therapeutic also for the treatment of hematological malignancies. The reviews of van Blitterswijk [4] and Vaccarezza [5] groups outline the importance of key intracellular pathways, such as Akt and PKC in the development of hematological malignancies and the new therapeutic opportunities provided by synthetic anticancer alkylphospholipids (APLs), such as perifosine and enzastaurin, which act on cellular membranes rather than at the DNA level. Di Pietro [6] provides an overview on the use of fully humanized agonistic monoclonal antibodies targeting TRAIL-death receptors in clinical trials including hematological malignancies. Such approach is particularly promising, expecially if associated to anti-CD20 rituximab antibody, in B cell malignancies. Finally, starting from the observation that most hematological malignancies display a wild-type p53 status, Secchiero et al. [7] describes the potential use of small molecule inhibitors of the p53/MDM-2 interactions, able to activate or re-activate the p53 pathway in primary malignant cells. References [1] Macor P, Secco E, Zorzet S, Tripodo C, Celeghini C, Tedesco F. An Update on the Xenograft and Mouse Models Suitable for Investigating New Therapeutic Compounds for the Treatment of B-Cell Malignancies. Curr Pharm Des 2008; 14(21): 2023-2039. [2] Barbarotto E, Calin GA. Potential Therapeutic Applications of miRNA-Based Technology in Hematological Malignancies. Curr Pharm Des 2008; 14(21): 2040-2050. [3] Bernard MP, Bancos S, Sime PJ, Phipps RP. Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise. Curr Pharm Des 2008; 14(21): 2051-2060. [4] van Blitterswijk WJ, Verheij M. Anticancer Alkylphospholipids: Mechanisms of Action, Cellular Sensitivity and Resistance, and Clinical Prospects. Curr Pharm Des 2008; 14(21): 2061-2074. [5] Mischiati C, Melloni E, Corallini F, Milani D, Bergamini C, Vaccarezza M. Potential Role of PKC Inhibitors in the Treatment of Hematological Malignancies. Curr Pharm Des 2008; 14(21): 2075-2084. [6] Sancilio S, Grill V, Di Pietro R. A Combined Approach with Rituximab Plus Anti-TRAIL-R Agonistic Antibodies for the Treatment of Haematological Malignancies. Curr Pharm Des 2008; 14(21): 2085-2099. [7] Secchiero P, di Iasio MG, Gonelli A, Zauli G. The MDM2 Inhibitor Nutlins as an Innovative Therapeutic Tool for the Treatment of Hematological Malignancies. Curr Pharm Des 2008; 14(21): 2100-2110.

B-cell malignancies account for over the 90% of all lymphoid neoplasms. The clonal proliferations of B-cells show a high degree of variation in terms of clinical and presenting features, histopathology, immuophenotype, and genetics. Primary tumor samples are useful for examining the characteristics of a patient's own tumor, although both primary leukemic cells and cell lines provide an initial step for screening novel compounds for their activity in some hematological malignancies, they should be followed by models in intact animals. In this review, we try to summarize the animal models generated to study B-cell malignancies, in particular, B-cell lymphoma, B-cell CLL and MM that represent the major part of B-cell malignancies. Animals that spontaneously develop cancer are flawed to predict human disease. The development of human tumor xenograft models represented a big step towards more clinically relevant models. The major problems of these models are the requirement of immunocompromised animals and the inability of these models to recapitulate the complex relationship between the tumor and the microenvironment. A number of strategies have been also applied to develop genetically engineered models of malignancies, in which the tumor arises “naturally” in the host. The disadvantages of these models include the differences between rodent and human stroma and that they can not be used to characterise anti-tumor activity of many immunotherapeutic drugs. These models can be used to study the molecular processes critical for the development, proliferation and survival of hematological malignancies and to characterise potential therapeutic targets.

MicroRNAs (miRNAs) are an abundant class of approximately 22-nucleotide-noncoding RNAs, which play important regulatory roles in animal and plant development: they are involved in gene expression at the posttranscriptional level by degrading or blocking translation of messenger RNA (mRNA) targets. miRNAs can induce RNA cleavage and chromatin modifications, and are implicated in apoptotic pathways and regulation of cell growth and proliferation. It is becoming clear that miRNAs play important roles in the regulation of gene expression during development, and our knowledge of the expression levels or function of miRNAs in normal and neoplastic cells is increasing. Accumulating experimental evidence suggests that different miRNAs are deregulated in primary human tumors and that many human miRNAs are located at genomic regions linked to cancer. miRNAs may be important regulators of mammalian hematopoiesis. They are involved in a variety of hematological malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and primary effusion lymphoma. Here, we provide background on the biogenesis and function of miRNAs and discuss potential therapeutic applications of miRNA-based technology in hematological malignancies.

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase- 2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

Synthetic anticancer alkylphospholipids (APLs), such as edelfosine, miltefosine and perifosine, are a group of structurally related lipids that act on cellular membranes rather than the DNA. APLs have essentially one long hydrocarbon chain that allows easy partitioning into membrane lipid bilayers, but they resist catabolic degradation. APLs therefore accumulate in cell membranes and can interfere with normal lipid metabolism and lipid-dependent signal transduction. This action, often leading to apoptosis, is most effective in metabolically active, proliferating cells, such as cancer cells, but not in quiescent normal cells. This review describes the general mechanisms of APL cellular uptake and action. Most important for their biological effect are the inhibition of phosphatidylcholine synthesis, the inhibition of the MAPkinase/ ERK proliferative and phosphatidylinositol 3-kinase/ Akt survival pathways and the stimulation of the Stressactivated protein kinase/JNK pathway, which may lead to apoptosis in cancer cells. APLs are most promising in combination with conventional cancer therapies. For example, ALPs increase the cancer cell sensitivity to radiotherapy in vitro and in vivo. We highlight the clinical potential of perifosine, an orally available APL.

The serine/threonine protein kinase C (PKC) family, the main target of tumor-promoting phorbol esters, is functionally associated to cell cycle regulation, cell survival, malignant transformation, and tumor angiogenesis. Although PKC isozymes represent an attractive target for novel anticancer therapies, our knowledge of PKC in tumorigenesis is still only partial and each PKC isoform may contribute to tumorigenesis in a distinct way. Specifically, PKC isoforms have wide and different roles, which vary depending on expression levels and tissue distribution, cell type, intracellular localization, protein-protein and lipid-protein interactions. Although PKC activation has been linked to tumor cell growth, motility, invasion and metastasis, other reports have shown that some PKC isoforms can also have opposite effects. Therefore, it will be necessary to analyze the relative contribution of each PKC isozymes in the development and progression of different tumors in order to identify therapeutic opportunities, using either PKC inhibitors or PKC activators as molecular tools of investigation. This minireview is focussed on the role of PKC signaling and on the perspective of PKC inhibition in hematological malignancies.

Molecular targeted therapies have changed the landscape of cancer research. Agonistic monoclonal antibodies (MoAbs) targeting TRAIL-death receptors (TRAIL-Rs) have been developed and currently used in clinical trials. Binding of such antibodies to TRAIL-R1 and TRAIL-R2 results in death inducing signalling complex (DISC) formation and induction of apoptosis, which represents a natural mechanism of cell growth control and an ideal target for drug development. These novel fully humanized compounds have been associated with conventional chemotherapy in the treatment of advanced solid malignancies, including different types of lymphoma. Here we outline the rationale and potential of a new molecular-based strategy combining agonistic anti-TRAIL-death receptor monoclonal antibodies plus the pioneer of the new biological frontiers of cancer therapy: rituximab.

At variance to solid tumors, which show percentage of p53 deletions and/or mutations close to 50%, more than 80% of haematological malignancies express wild-type p53 at diagnosis. Therefore, activation of the p53 pathway by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy for the great majority of haematological malignancies. Recently, potent and selective small-molecule MDM2 inhibitors, the Nutlins, have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation might represent an alternative to the current cytotoxic chemotherapy. Interestingly, Nutlins not only are able to induce apoptotic cell death when added to primary leukemic cell cultures, but also show a synergistic effect when used in combination with the chemotherapeutic drugs commonly used for the treatment of haematological malignancies. Of interest, Nutlins also display non-cell autonomous biological activities, such as inhibition of vascular endothelial growth factor, stromal derived factor-1/CXCL12 and osteprotegerin expression and/or release by primary fibroblasts and endothelial cells. Moreover, Nutlins have a direct anti-angiogenic and anti-osteoclastic activity. Thus, Nutlins might have therapeutic effects by two distinct mechanisms: a direct cytotoxic effect on leukemic cells and an indirect non-cell autonomous effect on tumor stromal and vascular cells, and this latter effect might be therapeutically relevant also for treatment of haematological malignancies carrying p53 mutations.

The present review discusses the mechanism of late stent thrombosis and its distinction from restenosis and summarizes the advisory note issued by FDA on the proper usage of different treatments available for atherosclerosis. In light of the latest developments, a plethora of new stents have been and continue to be developed globally. Hence, there is a need to review the available methodology to control their quality and to understand the delivery of drugs to the lesion. This can be achieved by systematically reviewing the novelties in each type. The article evaluates upcoming drugs, biocompatible coatings, and new concepts. We have also provided the latest update on the three new promising drug eluting stents (DES) - Medtronic's Endeavor, Abbott's Xience, and Conor Medsystem's CoStar. In addition, the article also summarizes other DES in horizon.

Polycystic ovary syndrome (PCOS) is one of the most frequent diseases that affects women in their reproductive age. The heterogeneity of PCOS makes not only the diagnosis but also the choice of an adequate treatment difficult. The biguanide, N, N’ dimethyl-biguanide : Metformin is an antidiabetic drug that increases glucose utilization in insulinsensitive tissues and is useful in the reduction of both insulin resistance and circulating androgens as well as restoring ovulation. However, metformin is being clinically used without a complete understanding of the mechanism involved. The present review explores some of the actions and efficacy of metformin in the treatment of PCOS during different reproductive periods.