Design and synthesis of new pyranoxanthenones bearing a nitro group or an aminosubstituted side chain on the pyran ring. Evaluation of their growth inhibitory activity in breast cancer cells

Some new 2,6-disubstituted pyrano- and 1,2-dihydropyrano[2,3-c]xanthen-7-ones have been synthesized and their antiproliferative activity has been evaluated against MDA-MB-231 breast cancer cells. The antiproliferative activity evaluation of the compounds provided evidence that a dimethylamino substituted side chain and the presence of 1,2 double bond play a key role in cell growth inhibition. Among the tested derivatives the 6-dimethylaminoethylamino-2-nitropyranoxanthenone analogue possessed a significant inhibitory effect in a wide range of concentrations.     

In vitro and in vivo antiresorptive effects of bisphosphonates in metastatic bone disease

Bone metastases commonly occur in the course of malignant tumor disease. For many years, attempts have been made to identify factors for the management of cancer-induced skeletal complications. Nowadays, synthetic antiresorptive agents are considered to be indispensable for the treatment of cancer-related skeletal events, such as bone metastasis. The most common of these drugs are the bisphosphonates, which represent one of the most significant advances over the last 10 years in the field of supportive care and cancer. They are used for the treatment of cancer-induced hypercalcemia, for the prevention and treatment of postmenopausal osteoporosis, for patients with bone metastases secondary to breast cancer and multiple myeloma. A third-generation bisphosphonate, zolendronate, has been shown to minimize the destructive consequences of bone metastases and to exert a profound effect on tumor-induced osteolysis and tumor growth in bone. Zoledronate is already used for the treatment of hypercalcemia of malignancy, multiple myeloma-related osteolytic events and for patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy. The structure-function activity of the three generations of bisphosphonates developed to date, the in vitro models used for studying their effects on osteoclasts and osteoblasts, as well as the results of clinical trials obtained by the third generation bisphosphonate, zoledronic acid, are presented.     

Small Tyrosine Kinase Inhibitors as Key Molecules in the Expression of Metalloproteinases by Solid Tumors

Critical steps for cancer cell growth, migration, invasion, and metastasis are the interactions of extracellular matrix (ECM) molecules with cells, the disconnection of intercellular adhesion, and the degradation of ECM. The latter is mediated mainly by metalloproteinases (MMPs), the expression and activation of which is related to various tyrosine kinase receptors (RTKs). The aberrant RTK activity is associated with the development and progress of various human cancers. Tyrosine kinase inhibitors (TKIs) are small molecules which compete with ATP for binding to the kinase domain of the RTKs and have been used for the treatment of solid tumors. In this review, the recent advances of the effects of TKIs on MMPs expressed by solid tumors are presented.     

High prevalence of elevated liver enzymes in blood donors: associations with male gender and central adiposity

OBJECTIVE: Nonalcoholic fatty liver disease is an increasingly recognized condition, but its exact prevalence is unknown. In this prospective, multicenter study, we evaluated the prevalence of elevated alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl-transpeptidase levels as indirect markers of nonalcoholic fatty liver disease in volunteer blood donors as well as their associations with epidemiological and anthropometrical characteristics. METHODS: Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl-transpeptidase levels were determined in blood donors from four transfusion centers during the morning sessions of a 3-month period. Cases with positive hepatitis B surface antigen, anti-hepatitis C virus, anti-HIV or elevated liver enzymes and alcohol abuse were excluded. RESULTS: Abnormal liver enzymes were found in 17.6% of 3063 participants (alanine aminotransferase: 14.5%, aspartate aminotransferase: 4.6%, gamma-glutamyl-transpeptidase: 4.7%). Individuals with abnormal compared with those with normal liver enzymes or alanine aminotransferase values were more frequently men and had higher weight, body mass index, waist, hip and neck circumference (P<0.001 for all comparisons). The prevalence of abnormal liver enzymes was also associated with the transfusion center ranging between 8.8 and 22.1% (P<0.001) and alcohol consumption (P=0.001). In multivariate analysis, presence of elevated enzymes was independently associated with male sex, higher weight or body mass index, higher waist circumference and transfusion center. CONCLUSIONS: More than 15% of Greek blood donors exhibit elevated liver enzymes, most likely as a result of unrecognized nonalcoholic fatty liver disease. The prevalence of nonalcoholic fatty liver disease is mainly associated with male sex, obesity and waist circumference, but it may range significantly among different population groups.     

Design, synthesis, and evaluation of the antiproliferative activity of a series of novel fused xanthenone aminoderivatives in human breast cancer cells

Derivatives of two novel, structurally related heterocyclic ring systems, xantheno[3,4-d]imidazole and chromeno[4,3,2-c,d]imidazo[4,5-f]indazole, bearing aminoalkyl side chains, have been synthesized, and their antiproliferative activity has been studied against the aggressive human breast MDA-MB-231 cell line. The pyrazole-fused analogue 27a possesses a pronounced antiproliferative effect on the tested cell line, evident at 1 muM, and achieves an IC50 of 6.5 microM.     

Estradiol–estrogen receptor: A key interplay of the expression of syndecan‐2 and metalloproteinase‐9 in breast cancer cells

Estrogens are related with the growth and development of target tissues and play a critical role in breast cancer progression. The effects of estrogens are mediated by the estrogen receptors ERα and ERβ, which are members of the nuclear steroid receptor superfamily. To date, it is not known how these hormones elicit many of their effects on extracellular matrix molecules and how these effects can be connected with ER expression. For this purpose, the effect of estradiol on ER expression as well as on proteoglycan and metalloproteinase expression was studied. The effect of E2 on extracellular matrix molecule expression has been studied using ERα suppression in breast cancer cells. Our studies using ERα‐positive MCF‐7 cells show that estradiol affects the expression of syndecan‐2, but not of syndecan‐4, through ERα. Furthermore, the ability of estradiol to affect MMP‐9 and TIMP‐1 expression is connected with ERα status. Together, these data demonstrate the significant role of ERα on mediating the effect of estradiol on extracellular matrix molecules.     

Cost-utility of ranibizumab versus aflibercept for treating Greek patients with visual impairment due to diabetic macular edema

Background

To conduct a cost-utility analysis of ranibizumab versus aflibercept for the treatment of patients with visual impairment due to diabetic macular edema (DME) in the Greek setting.

Methods

A Markov model was adapted to compare the use of ranibizumab 0.5 mg (pro re nata-PRN and treat and extend-T&E) to aflibercept 2 mg (every 8 weeks after five initial doses) in DME. Patients transitioned at a 3-month cycle among nine specified health states (including death) over a lifetime horizon. Transition probabilities, utilities, as well as DME-related mortality were extracted from relevant clinical trials, a network meta-analysis and other published studies. The analysis was conducted from payer perspective and as such only costs reimbursed by the payer were considered (year 2014). The incremental cost per quality-adjusted life year (QALY) gained and the net monetary benefit was the main outcome measures.

Results

Τhe use of PRN and T&E ranibizumab regimens were shown to be cost saving comparing to aflibercept (by €2824 and €22, respectively), and more beneficial in terms of QALYs gained (+0.05) and time without visual impairment (0.031 and 0.034 years), thereby dominating aflibercept. Moreover, ranibizumab used as PRN or T&E resulted in a net monetary benefit of €3984 and €1278, respectively.

Conclusions

Both PRN and T&E ranibizumab regimens were more beneficial and less costly compared to aflibercept for the management of DME. Hence, ranibizumab seems to be a dominant option for the treatment of visual impairment due to DME in the Greek setting.

     

Small tyrosine kinase inhibitors as key molecules in the expression of metalloproteinases by solid tumors

Critical steps for cancer cell growth, migration, invasion, and metastasis are the interactions of extracellular matrix (ECM) molecules with cells, the disconnection of intercellular adhesion, and the degradation of ECM. The latter is mediated mainly by metalloproteinases (MMPs), the expression and activation of which is related to various tyrosine kinase receptors (RTKs). The aberrant RTK activity is associated with the development and progress of various human cancers. Tyrosine kinase inhibitors (TKIs) are small molecules which compete with ATP for binding to the kinase domain of the RTKs and have been used for the treatment of solid tumors. In this review, the recent advances of the effects of TKIs on MMPs expressed by solid tumors are presented.