1,721,010 research outputs found
Ruthenium complexes can target determinants of tumour malignancy
No full textMetastases are more decisive for tumour prognosis than primary lesions, because of their multiple
locations, low accessibility to surgery and/or radiotherapy, and generally poor responsiveness to
chemotherapy. The metastasis should therefore be the primary target for drug therapy. Among
ruthenium complexes, NAMI-A is a leading compound that shows selective effects for solid tumour
metastases related to a mechanism of action involving the inhibition of the processes of tumour
invasiveness. NAMI-A opens an avenue to new perspectives in cancer chemotherapy. This includes novel
compounds directed at targets selectively expressed by tumour metastases, thus reducing the typical
side effects of the current metal-based drugs that are active via their unselective DNA interaction
Evaluation of NAMI-A Cytotoxic Effects toward Leukemia Cell Lines: A Slippery Ground Giving Misleading Messages
No full textThe expansion of metal-based complexes in the last 20 years has been very intense and many metals have been involved. Among the many compounds studied, the ruthenium-based complex NAMI-A embodies the unique paradigm of the ability to selectively inhibiting and preventing the development and the growth of distant metastases originating from solid tumors in all the tumor models on which it has been tested. An activity that can be detected only in vivo since the compound is virtually free of measurable direct cell cytotoxicity in vitro. Recently, a published paper reported on a significant in vitro cytotoxicity against some leukemic cells. The present study was undertaken to reproduce those experiments to further support this novel antileukemic activity that would have put NAMI-A on a new trajectory for development. Our results do not confirm the efficacy of NAMI-A in vitro against the human HL-60 promyelocytic leukemia cell line either using test cultures identical to those reported in the study of reference or in even more stressed conditions, supporting the lack of in vitro direct cell cytotoxicity of NAMI-A. The present study also helps to elucidate that many factors can influence the outcome of in vitro tests of cytotoxicity and suggests caution to speculate on possible therapeutic properties based on the results of simple and reductive in vitro tests of cytotoxicity
Linking the future of anticancer metal complexes to the therapy of tumour metastases
No full textCancer chemotherapy is almost always applied to patients with one or more diagnosed metastases and is expected to impact these lesions, thus providing significant benefits for the patient. The outcome of metastasis is determined by the interplay between the specific subpopulation of metastatic cells and host homeostatic factors in specific microenvironments. In clinical practice, metal-based drugs are represented by platinum compounds, which are constituents of a wide variety of chemotherapeutic regimens, that and are only rarely active against tumour metastases unless they are combined with drugs that target specific pathways characterizing the malignancy of the tested tumour. On experimental grounds, a number of complexes based on ruthenium and other metals have been frequently studied in vitro using models and experimental conditions mimicking one or more steps of the metastatic process, such as invasion and migration. The ruthenium-based drug NAMI-A, is the only one to have been subject to clinical testing for the treatment of metastatic tumours. The capacity of NAMI-A to modulate the relationships established between metastatic cells and their microenvironment suggests that metal-based drugs shall be viewed as an opportunity for the treatment of tumour metastases
Metal-based antitumour drugs in the post-genomic era: what comes next?
No full textIn our Dalton Transactions Perspective article entitled, 'Metal-based antitumour drugs in the post genomic era', (Dalton Trans., 2006, 1929-1933) we discussed metal-based drugs in light of past decades of research. We concluded that the post-genomic era would dictate a change in the direction of the field with knowledge of the genome increasingly allowing protein targets to be identified and not simply assuming that DNA is the only relevant target of metal-based drugs. Since our article was published new insights into the mode of action of metal-based drugs have emerged making some older findings increasingly relevant to current drug design. In this article we discuss these developments in terms of what we believe should be the future direction for the field
Ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs
No full textRuthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials. Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells. These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues. Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA. Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials. The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy
Pharmacological Modulation of Host Immunity with Hen Egg White Lysozyme (HEWL)-A Review
Full text link: In the 100 years since its discovery, lysozyme has become an important molecule, both as model for studies in different fields and as a candidate for the therapy of various pathological conditions. Of the dozens of known lysozymes, in this review we focus on one in particular, lysozyme extracted from hen egg white (HEWL), and its interaction with the immune system when it is administered orally. Experimental data show that there is an axis that directs immune system activation from GALT (gut-associated lymphoid tissue) and the intestinal lymphocyte clusters. Although a contribution of peptidoglycans from digestion of the bacterial cell wall in the intestinal lumen cannot be excluded, immune stimulation is not dependent on the enzymatic activity of HEWL. The immune responses suggest that HEWL is able to recover from immunodepression caused by tumor growth or immunosuppressants, and that it also improves the success of chemotherapy. The positive results obtained in a small Phase 2 study in patients, the ease of oral administration of this protein, and the absence of adverse effects suggest that HEWL may play an important role in all diseases where the immune system is weakened or where its enhancement plays a critical role in the resolution of the pathology
Chemical and Molecular Approach to Tumor Metastases
Full text linkTumours are not merely masses of abnormally proliferating cancer cells. Today, we have a clearer view of cancer complexity in which the participation of cancer and host cells leads to a tremendous heterogeneity of neoplastic diseases concerning the genetics, epigenetics, proteomics and biochemistry of the tumour [1]. Such intra-tumour heterogeneity provides the basis for inter-metastatic heterogeneity among different metastatic lesions of the same patient, each originating from a founder cell, or small group of cells, with a very different mutation kit, and likely originating from different and distinct primary tumour areas. This situation has important implications regarding chemotherapeutic sensitivity and responses. In addition, the offspring of the founder cell(s) can generate heterogeneity among the cells of an individual metastasis, affecting the response to systemic therapies and providing the seeds for drug resistance
Lysozyme stimulates lymphocyte response to ConA and IL-2 and potentiates 5-fluorouracil action on advanced carcinomas
No full textDNA-adduct formation-guided design: thoughts about the future of metal based anticancer drugs
No full textThe development of metal-based anticancer drugs is mainly governed by the experience accumulated with cisplatin and its analogues. The synthesis is focused on adding appropriate leaving and non-leaving groups to a transition metal in order to get more favorable DNA binding properties, and the biological activity is tested in vitro, always in a second step, looking for the cell line that is killed at the lowest drug concentration. This strategy seems unproductive today for the area of new drug development where the knowledge on cancer genomics is suggesting the use of targets selectively expressed, or overexpressed by cancer cells. These targets almost always are proteins, constituting membrane receptors or components of crucial biochemical pathways. Some data indicate that the antitumor activity of cisplatin might also be due to the interaction with protein targets. This critical review examines the possibilities for metal-based drugs to challenge tumors with innovative strategies, based on genomic approaches, capitalizing on the chemical experiences with metals in medicine and focusing on the nature of the ligands which are added to a metal depending on the selected tumor cells and on their molecular targets
New anionic and neutral complexes of ruthenium (II) with nitrogen oxide
No full textA class of anionic and neutral complexes of ruthenium (II) containing nitrogen oxide (NO) and optionally a nitrogen ligand is described; a process for their preparation is also described. The preparation process includes the use of starting complexes of ruthenium (III) which are reacted with suitable reagents so as to obtain complexes containing NNO coordinated to ruthenium (II). Additional substitution reactions allow the introduction of new groups that coordinate to the ruthenium atom, among which some nitrogen ligands
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