Vasculature-targeted tumor necrosis factor-alpha increases the therapeutic index of doxorubicin against prostate cancer

BACKGROUND: Poor penetration and uneven distribution of doxorubicin in tumors limits the efficacy of this drug in patients with prostate cancer (PC). Aim of the study was to investigate whether pre-treatment with NGR-TNF, a tumor necrosis factor-alpha derivative able to target tumor vessels and alter vessel permeability, increases the penetration and the efficacy of doxorubicin in pre-clinical models of PC. METHODS: Wild type C57BL/6 mice bearing androgen-independent TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develop PC and metastasis, were treated with repeated cycles of doxorubicin, administered either alone or following NGR-TNF. Tumor growth and drug uptake by cancer cells was evaluated. RESULTS: Doxorubicin as a single agent blocked the growth of TRAMP-C1 cells in vitro but not in vivo. Pre-treatment of mice bearing subcutaneous TRAMP-C1 tumors with NGR-TNF favored doxorubicin penetration into the tumor mass, and in both TRAMP-C1 and TRAMP models significantly delayed tumor growth without increasing drug-related toxicity. CONCLUSIONS: Pre-treatment with NGR-TNF significantly expanded the therapeutic index of doxorubicin in mouse models of hormone-dependent and -independent PC.     

A molecular analysis of prokaryotic and viral DNA sequences in prostate tissue from patients with prostate cancer indicates the presence of multiple and diverse microorganisms

BACKGROUND: Inflammation, both acute and chronic, is a common feature of prostate histology. While inflammation has been proposed to play an important role in both benign and malignant growth of the prostate, the stimuli for this inflammation remain poorly characterized. Infectious pathogens are potential stimuli for prostatic inflammation. METHODS: Universal eubacterial PCR was used to test 170 prostate tissue core samples from 30 cancer patients for 16S rDNA gene sequences. Positive PCR products (n=64, 37%) were cloned and sequenced. For comparison, tissue samples from 30 patients were cultured using standard clinical microbiological techniques. DNA samples from 200 additional patients were tested by organism-specific PCR for the presence of Chlamydia trachomatis, Propionibacterium acnes, Trichomonas vaginalis, BK virus, Epstein-Barr virus, human cytomegalovirus, human papillomavirus, and xenotropic murine leukemia-related virus. RESULTS: 16S sequencing results indicated the presence of 83 distinct microorganisms. Microbiological culture isolated markedly fewer species. In general, organism-specific PCR failed to detect multiple organisms previously reported as common in the prostate. There was no significant association between the presence of particular species of bacteria and histologic evidence of acute or chronic inflammation. CONCLUSIONS: Most prostates from men undergoing prostatectomy (87%) contain bacterial DNA from one or more species. However, the majority of individual tissue core samples were negative, suggesting regional heterogeneity in the presence of bacteria and a lack of a generalized or ubiquitous prostatic flora. Culture results suggest either the "unculturable" nature of species present in the prostate or that 16S rDNA sequences were derived from non-viable bacteria.     

A practical approach to diagnosis and treatment of symptomatic thromboembolic events in children with acute lymphoblastic leukemia: recommendations of the "Coagulation Defects" AIEOP Working Group

Intensified treatments with multi-drug regimens are responsible for the continuously increasing survival of children with acute lymphoblastic leukaemia. However, together with the widespread use of central venous lines, they are also considered the main risk factors for the growing number of thromboembolic complications in this population. The rate of thrombosis that was observed in 17 prospective studies was 5.2%. Due to the high survival rate, it is relevant to apply strategies to the long term survivors who overcome the disease but who experience thromboembolic complications. Specific treatment includes anticoagulants, especially unfractionated heparin and low molecular weight heparins, and thrombolytic drugs in few cases. Guidelines for the treatment of thrombosis in childhood only became available recently, but they do not include specific clinical subsets such as children with acute lymphoblastic leukaemia. The problems involved in scheduling thrombosis treatment in children with malignancy have recently been discussed, however the paper does not provide practical diagnostic schemes or treatment schedules. Some important questions regarding optimal prevention and treatment are still unanswered. Moreover, antithrombotic therapy in these patients is quite challenging owing to the higher risk of bleeding. We believe it would be possible to propose reasoned appropriate recommendations for treating thrombosis in children with acute lymphoblastic leukaemia, looking forward for the effects of recent patents. This paper is an attempt to provide a practical guide to the diagnosis and treatment of thrombotic events in children with acute lymphoblastic leukaemia, and it is aimed at physicians who have no specific knowledge of the diagnosis and management of thrombosis and haemostasis alterations in children.     

Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line

Isatin is a versatile compound with a diversity of effects. We designed to investigate the inhibitory effect of isatin derivatives on lipopolysaccharide/interferon-gamma-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, production of prostaglandin E(2) (PGE(2)), nitric oxide (NO), tumor necrosis factor (TNF-alpha), and their capacity to scavenge NO. Isatins inhibit TNF-alpha production and iNOS and COX-2 protein expression resulting on reduced levels of NO and PGE(2). Our results indicate isatin and it derivatives as inhibitors of iNOS and COX-2 enzymes, which might be used as anti-inflammatory and antitumoral agents.     

Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase

Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.