Inhibition of metalloproteinases derived from tumours: new insights in the treatment of human glioblastoma.

Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumour in adults. Invasive behaviour is the pathological hallmark of malignant gliomas; consequently, its inhibition has been suggested as a therapeutic strategy. Tumour cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) have been included in clinical trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-isopropyl sulfonamido-based hydroxamates (compounds 1 and 2) as MMP-2 inhibitors used at nanomolar concentration. A standard broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compounds 1 and 2 resulted in potent inhibition of cell invasiveness (P<0.0001) without affecting viability. In some clinical trials, the combined therapy of temozolomide (an alkylating agent used in glioma treatment) plus marimastat (a broad spectrum MMP inhibitor) has provided evidence of the importance of MMPs to tumor progression and invasiveness. On this basis, the effect on U87MG cells of a combined treatment with temozolomide, plus each of the two MMP inhibitors at nanomolar concentration, was investigated. The obtained data demonstrated the inhibition of cell invasiveness and viability after treatment. These results can help in developing clinical combined therapy using MMP inhibitors that, at low doses, increase the anticancer efficacy of chemotherapeutic drugs, probably without causing the side effects typical of broad-spectrum MMP inhibitors.

Heart and lungs in COPD. Close friends in real life--separate in daily medical practice?

Chronic obstructive pulmonary disease (COPD) is associated with a 2-3 times higher rate of cardiovascular disorders (CVD) which is independent of other risk factors. A low FEV1 is a specific predictor of mortality as a result of cardiac causes, even stronger than increased cholesterol: for each 10% reduction of FEV1, cardiovascular mortality increases by 28%. The main causes of death among COPD patients are of cardiovascular origin. COPD and CVD have two major risk factors in common - advanced age and tobacco smoking. The search for a pathogenetic link between the two conditions focuses mainly on systemic extension of pulmonary inflammation. Despite such a frequent association, pulmonologists and cardiologists in both the clinical and the research settings often underestimate the importance of a correct diagnosis and severity stratification of the two combined conditions. Spirometry, in particular, is largely underprescribed. Missed diagnosis and severity stratification, incomplete knowledge of adverse drug events and lack of resources lead to undertreatment of patients combining COPD and CVD, and in particular, the underuse of beta-blockers, inhaled bronchodilators and rehabilitation. Clinical studies focusing on this group of patients should be promoted in the future to test therapies and manage options. Furthermore, efforts must be made to improve the present standards of care, which falls short of recommended levels, starting from the often-neglected use of spirometry to confirm a diagnosis of COPD.