Mini Reviews in Medicinal Chemistry - Volume 11, Issue 6, 2011

The last years have witnessed important development in the understanding and treatment of oncohematological affections. Until recently, for example, “classic” chemotherapy and hematopoietic stem-cell transplantation were the only therapeutic options in acute leukemia. Today, the target therapy provides a new approach for the treatment of these malignances, in which biological drugs are used to affect only cancer cells, without effects on surrounding cells, decreasing the side effects. Today monoclonal antibodies are widely used for the treatment of oncohematological diseases. In this issue, their use and application are discussed. Laurenti and coworkers demonstrated that monoclonal antibodies such as rituximab and alemtuzumab have changed the therapy of chronic lymphocytic leukemia (CCL). Nowadays there are several new promising monoclonal antibodies under investigation against CD20, CD23, CD37 and CD40 molecules. Application of newer monoclonal antibodies represents an area of ongoing clinical research in CLL. Deaglio and coworkers described the behaviour of CD38, which is an independent negative prognostic factor in CLL patients and has been the starting point for investigations into the functional role of the molecule in the neoplastic context. As reported by Risitano and coworkers there are many diseases due to the absence of the complement regulators as CD55 and CD59. Also in this case the use of monoclonal antibodies is possible: in fact, authors demonstrated that residual hemolysis may be due to persistent activation of the early phases of the complement cascade, leading to progressive C3-deposition on PNH (paroxysmal nocturnel emoglobinuria) erythrocytes and possible subsequent extravascular hemolysis through the reticuloendothelial system. Here the authors critically review the available clinical results of eculizumab treatment for PNH patients, pointing out the recent insights into the pathophysiology of the disease. Moreover, they provide a theoretical rationale for the development of novel strategies of complement inhibition which could further improve in future on the already substantial efficacy of eculizumab. Furthermore, Risitano and coworkers reported the use of monoclonal antibodies also for the treatment of acquired bone marrow failure syndromes. Authors review the recent data on the anti-CD52 monoclonal antibody alemtuzumab as a novel immunosuppression agent for marrow failures: this drug represents an excellent alternative to ATG for all immune-mediated marrow failure syndromes. Even if the dose and the schedule may still require further refining, the available data support the need of large prospective trials comparing alemtuzumab to current standard immunosuppression regimens. On the other hand, Serio and coworkers have explorated whether predisposition to bone marrow failure syndromes, such aplastic anemia, paroxysmal nocturnal hemoglobinuria and myelosysplastic syndromes, is found in killer cell immunoglobulin-like receptor and human leukocyte antigen ligand gene variations or cytokine polymorphisms. The use of monoclonal antibodies has also been evaluated by D'Arena and coworkers: in fact, the authors reported that regulatory T-cells (Tregs) play a central role in maintaining peripheral tolerance to self-antigens and in regulating the immune response to non-self-antigens. Clinical strategies are developing targeting Tregs with the aim to reduce or abrogate the antitumor suppression. One of the major challenges is to identify a unique marker of Tregs that can be used to more specifically target these cells with selective monoclonal antibodies. Combination therapies with conventional drugs and vaccination strategies are under investigation by the authors. Another promising strategy in the treatment of leukemias is the use of natural substances. Diet components may also modify the risk of cancer through the influence on multiple processes, including DNA repair, cell proliferation and apoptosis. In this issue, Miroddi and coworkers reported that garlic (Allium sativum L.), considered either food or herbal medicine, possesses antimutagenic and antiproliferative properties that can be used in anticancer interventions: they analyzed literature data on the effects of garlic and garlic compounds which can serve as basic information to design clinical approach in oncohematology. De Martino and coworkers reviewed the natural compounds as new models for the development of drugs against various pharmacological targets, including cancer, and, above all, leukaemia. On the basis of the activity of natural molecules, harmine and 1-methoxy-canthin-6-one, Peduto and coworkers designed and synthesized a series of novel 1,4-disubstituted and 1,4,9- trisubstituted β-carbolines and tetracyclic derivatives. Cytotoxic activities of these compounds in vitro were investigated in a human tumor cell line panel. Almost all compounds demonstrated interesting cytotoxic activities in particular against prostate cancer cells PC-3 with IC50 value in the low micromolar range, suggesting further studies with models of prostate cancer. The clinical relevance of targeting histone deacetylases in hematological malignancies was discussed by Petrella and coworkers: to date, several clinical trials of HDACi in hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma and myeloid malignancies. Finally, papers presented in this issue show the efficacy of an interdisciplinary collaboration among different researchers in the field of hematology, pharmacology, pharamcognosy and medical chemistry. I would like to acknowledge Ms. Sabiha Aftab for undertaking the important tasks of correspondence and publication management.

The use of non-conventional medicines, especially herbal medicine, is common in patients with cancers including haematologic malignancies. Diet components may also modify the risk of cancer through the influence on multiple processes, including DNA repair, cell proliferation and apoptosis. Garlic (Allium sativum), considered either food or herbal medicine, possesses antimutagenic and antiproliferative properties that can be used in anticancer interventions. We analyzed literature data on effects of garlic and garlic compounds which can serve as basic information to design clinical approach in oncohematology. Garlic contains water soluble and oil-soluble sulfur compounds. The latter are responsible for anticancer effects exerted through multiple mechanisms such as: inhibition of metabolic carcinogenic activation, arrest of cell cycle, antioxidant and pro-apoptotic action. Evidence about the effects of main sulfur compounds diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), ajoene and S-allylmercaptocysteine (SAMC) in oncohematology was described. Our research highlights that data on garlic in oncohematology are essentially represented by pre-clinical studies. Although these studies must be considered as preliminary, they provided insight into biological activities of garlic compounds and support a rationale for the use of substances such as DAS, DADS, DATS and ajoene as promising anticancer agents in oncohematology.

To date, Graft-versus-host disease (GVHD) represents one of the most important complications of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is one of the major determinants of transplant-related mortality and it also may be an additional cause that affects patients late outcome. Despite of the development of new and advanced Human Leukocyte Antigens (HLA) matching techniques, this complication occurs in approximately 50-80% of patients who underwent allogeneic hematopoietic stem cell transplantation, and it is responsible for one-third of deaths after transplantation. Moreover, GVHD occurrence, if moderate, may strongly contribute to the eradication of residual malignant cells which survived after myeloablative conditioning regimen, allowing the patients to have a reduced risk of relapse so that the presence of this complication may have a determinant role for the allogeneic transplantation outcome through the so-called graft-versus-tumor (GVT) effect.

Regulatory T-cells (Tregs) comprise a group of either thymically derived or peripherally induced suppressor CD4+ cells involved in the control of effector T-cells against both self- and foreign-antigens. They are found increased in tumor tissues and are thought to be involved in pathogenesis of cancer by providing tumors with a mechanism to evade immune detection and destruction. Despite the fact that mechanisms of Tregs regulation are still in progress, efforts are made aiming to develop approaches to deplete or inhibit tumor-associated Tregs function. This could lead to restore antitumor immunity and emerging strategies for therapeutic vaccination, and immunotherapeutic targeting of Tregs with specific drugs are underway.

On the basis of harmine and 1-methoxy-canthin-6-one chemical structures, a series of novel 1,4-disubstituted and 1,4,9-trisubstituted β-carbolines and tetracyclic derivatives were designed and synthesized. Cytotoxic activities of these compounds in vitro were investigated in a human tumor cell line panel. Almost all compounds demonstrated interesting cytotoxic activities in particular against prostate cancer cells PC-3 with IC50 in the low micromolar range. Compound X was found to be the most potent one with IC50 value of 8.0 μM; this suggests further studies with models of prostate cancer.

Human leukemia results from multiple mutations that lead to abnormalities in the expressions and functions of genes that maintain the delicate balance between proliferation, differentiation and apoptosis. Continued research on the molecular aspects of leukemia cells has resulted in the developments of several potentially useful therapeutic agents. Discovery of new cellular and/or molecular pathways enabling innate or acquired resistance of cancers to current chemotherapeutics to be overcome is therefore of crucial importance if one wants to efficiently combat those cancers associated with dismal prognoses. In this concern, natural compounds are regarded as new chemical entities for the development of drugs against various pharmacological targets, including cancer, and, above all, leukemia.

Human CD38 is a cell surface molecule endowed with multiple functions. As an enzyme, it catalyzes the production of Ca2+ active metabolites, predominantly cADPR and ADPR. As a receptor, it regulates the activation of an intracellular signaling pathway, generally linked to lymphocyte activation and proliferation in physiological conditions. The finding that CD38 behaves as an independent negative prognostic factor in CLL patients was the starting point for investigations into the functional role of the molecule in the neoplastic context. Data accumulating in over a decade concur to define a model where CD38 is a central element of a large supramolecular complex that includes surface signaling receptors, chemokine receptors, adhesion molecules and matrix metalloproteases. Expression of CD38 within this supramolecular complex makes signal transduction as well as chemotaxis and homing more efficient, suggesting that the molecule is an integrator of proliferative and migratory signals. These data indicate that CD38 is not only a reliable disease marker but also a functional molecule in the CLL context. The next decade will likely tell whether it can also be a useful therapeutic target.

Over the last few years, several new agents have been under evaluation in preclinical studies and clinical trials, showing promise in treating chronic lymphocytic leukemia (CLL). Among these agents, monoclonal antibodies (mAbs) such as rituximab and alemtuzumab have changed the natural course of the disease. Nowadays there are several new promising monoclonal antibodies under investigation against the CD20, CD23, CD37 and CD40 molecules. Application of newer monoclonal antibodies represents an area of ongoing clinical research in CLL.

Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been found in several human cancers leading to the development of HDAC inhibitors (HDACi) as anti-tumors drugs. In fact, over the last years, a number of HDACi have been evaluated in clinical trials; these drugs have the common ability to hyperacetylate both histone and non-histone targets, resulting in a variety of effects on both cancer cells and immune responses. Clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a better clinical efficacy of these drugs in hematological malignancies. In this review, will be highlighted the mechanisms of action underlying the clinical responses obtained with these drugs and the doubts regarding the use of HDACi in cancer therapy.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disorder characterized by complementmediated hemolytic anemia, thrombophilia and bone marrow failure. The clinical hallmark of PNH is evident chronic hemolysis due to the absence of the complement regulators CD55 and CD59 on PNH erythrocytes. Intravascular hemolysis drives the major clinical features of PNH, including anemia, hemoglobinuria, fatigue and other hemolysisrelated disabling symptoms, such as painful abdominal crises, dysphagia and erectile dysfunction. A peculiar thromboembolic risk has been associated with the hemolysis in PNH, but its pathophysiologic cause remains unclear. The treatment of PNH has remained supportive until a few years ago, when the first complement inhibitor, designated eculizumab, became available. Chronic treatment with eculizumab results in sustained control of intravascular hemolysis, leading to hemoglobin stabilization and transfusion independence in half of the patients. However, residual anemia may persist in a substantial fraction of patients. Recent observations by different groups, including our own, have demonstrated that residual hemolysis may be due to persistent activation of the early phases of the complement cascade, leading to progressive C3-deposition on PNH erythrocytes and possible subsequent extravascular hemolysis through the reticuloendothelial system. Here we critically review the available clinical results of eculizumab treatment for PNH patients, pointing out the recent insights into the pathophysiology of the disease. We discuss the role of the different components of the complement cascade leading to hemolysis, in both the absence and presence of the terminal effector pathway inhibition by eculizumab. Finally, we provide a theoretical rationale for the development of novel strategies of complement inhibition which could in the future further improve on the already substantial efficacy of eculizumab.

Acquired bone marrow failure syndromes (BMFS) are a heterogeneous group of hematological disorders characterized by impaired bone marrow function and subsequent cytopenia of one or more blood cell lineages [1,2]. The well-accepted pathogenic mechanism of the typical bone marrow failure - aplastic anemia (AA) - is a T cell mediated immune attack targeting the hematopoietic tissue [3]. This pathogenic mechanism is at least partially shared by other bone marrow failure syndromes, such as lineage-restricted aplasias and some myelodysplastic syndromes. Thus, for these disorders immunosuppression (IS) is the pivotal etiologic treatment. While the standard IS regimen include the heterologous anti-thymocyte globulin [4], here we review the recent data on the anti-CD52 monoclonal antibody alemtuzumab as a novel IS agent for marrow failures. Alemtuzumab led to objective responses in aplastic anemia patients in 3 recent prospective studies, with overall response rates ranging between 37% and 72%. Adverse events were irrelevant, ruling out even the concerns about the risk of infectious complications. Alemtuzumab was effective even for the treatment of lineage-restricted marrow failure, with very acceptable toxicity and excellent response rates (as high as 80%). More recently, even patients suffering from myelodysplastic syndromes showed a remarkable hematological response to alemtuzumab-based IS treatment. Thus, alemtuzumab is a novel IS agent representing an excellent alternative to ATG for all immune-mediated marrow failure syndromes. Even if the dose and the schedule may still require further refining, the available data support the need of large prospective trials comparing alemtuzumab to current standard IS regimens.

Aim: To explore whether predisposition to bone marrow failure syndromes (BMF), such aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and myelosysplastic syndromes (MDS), is found in killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) ligand (KIR-L) gene variations or cytokine polymorphisms. Patients: We studied a cohort of 77 patients with AA, 129 with MDS and 285 healthy controls for the frequencies of KIRL and KIR genotypes and 22 selected single nucleotide polymorphisms (SNPs) located within 10 cytokine (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL12, IFN-γ, TNF-α, TGF-β) and 3 cytokine receptor (IL-1R, IL-1RA, IL-4Rα) genes. Results: In AA we found a decreased frequency of inhibitory KIR-2DL3 genes. In MDS, no difference in the frequency of KIR genotype was identified; however, a decreased frequency of 2DL3 was found in hypocellular MDS. Analysis of the KIR genotype in correlation with the corresponding KIR-L profile, revealed a decreased frequency of stimulatory 2DS1/C2 mismatch both in AA and MDS. In AA and MDS cohorts, compared to controls, we found a higher frequency of TT codon 10 variant and of GG codon 25 variant of TGF-β gene, consistent with a high secretory phenotype. This relationship was even more pronounced in PNH and hypocellular MDS. We confirm that the hypersecretory genotype T/T at position -874 of INF-γ gene was overrepresented only in AA and correlates with presence of a PNH clone. Instead in MDS patients, the frequency of G/A polymorphism at position -308 on the TNF-α gene promoter, which correlates with higher TNF-α production, was found significantly higher. Moreover, hypocellular MDS was characterized by a higher prevalence of IL-10 GCC/GCC haplotype, which is functionally associated with a low secretor phenotype. Conclusion: Our findings suggest that alterations in KIR/KIR-L matching, such as increased 3DL2 and decreased 2DS1 mismatch, and in the polymorphisms of TGFβ1, IFN-γ, TNF-α and IL-10 may account for the propensity to immunemediated killing of hematopoietic stem cells and/or ineffective hematopoiesis characteristic of AA and MDS. Further studies are needed to elucidate whether these immunogenetic traits may be involved in increased risk of developing immune-mediated BMF.