No abstract

Abstract. More than 60 years after their isolation and characterization, aminoglycoside (AG) antibiotics remain powerful agents in the treatment of severe gram-negative, enterococcal or mycobacterial infections. However, the clinical use of AGs is hampered by nephrotoxicity and ototoxicity, which often develop as a consequence of prolonged courses of therapy, or of administration of increased doses of these drugs. The discovery of non-ototoxic antibacterial agents, showing a wider spectrum of activity, has gradually decreased the use of AGs as first line antibiotics for many systemic infections. However, AGs are now undergoing an unexpected revival, being increasingly indicated for the treatment of severe emerging infections caused by organisms showing resistance to most first-line agents (e.g., multidrug-resistant tuberculosis, complicated nosocomially-acquired acute urinary tract infections). Increasing adoption of aminoglycosides poses again to scientists and physicians the problem of toxicity directed to the kidneys and to the inner ear. In particular, aminoglycoside-induced deafness can be profound and irreversible, especially in genetically predisposed patients. For this reason, an impressive amount of molecular strategies have been developed in the last decade to counteract the ototoxic effect of aminoglycosides. The present article overviews: i) the molecular mechanisms by which aminoglycosides exert their bactericidal activity, ii) the mechanisms whereby AGs exert their ototoxic activity in genetically-predisposed patients, iii) the drugs and compounds that have so far proven to prevent or modulate AG ototoxicity at the preclinical and/or clinical level, and iv) the dosage regimens that have so far been suggested to decrease the incidence of episodes of AG-induced ototoxicity. Aminoglycoside antibiotics: a revival?Aminoglycoside (AG) antibiotics have been extensively used for the prophylaxis and the treatment of a wide variety of systemic infections, for the outstanding features displayed by these antibacterial agents, i.e., the concentration-dependent bactericidal activity, the post-antibiotic effect, the favorable pharmacokinetic profile, and the strong synergism with other antibiotics such as vancomycin and ß-lactams (1). More than 60 years after their isolation and characterization, these drugs remain powerful tools for treatment of severe gram-negative, enterococcal or mycobacterial infections. AGs are usually administered in combination with ß-lactam antibiotics for a variety of systemic infections (e.g., bacterial endocarditis or various pseudomonal infections), but are also used as monotherapy for infections of the urinary tract. Streptomycin, the first AG isolated and adopted for human therapy (Fig. 1), MOLECULAR MEDICINE REPORTS 1: 3-13, 2008 3 Prevention and modulation of aminoglycoside ototoxicity (Review) GIANPAOLO

Abstract.Previous results from our research group have shown that the c.-1310 C¨G single nucleotide polymorphism in the promoter region of the XRCC6/Ku70 gene is significantly associated with breast cancer in a sample human patient population. In an attempt to attribute a functional meaning to this polymorphism, we performed a thorough analysis using a number of established in silico tools that strongly suggested that the c.-1310C¨G transversion would activate a cryptic splicing acceptor located upstream of the canonical promoter of Ku70, but downstream of a putative alternative promoter (PAP) of the same gene. Experimental investigation of alternative transcripts, as well as of the activity of the PAP detected in silico, did not support the initial hypothesis of a functional role of the c.-1310C¨G mutation in alternative splicing. Although a functional role of the SNP has yet to be determined, some evidence points to the linkage disequilibrium of the G variant of the polymorphism, with mutations located at critical sites within the promoter region of Ku70. IntroductionBreast cancer is a major public health issue worldwide. Globally, it is by far the most frequent cancer in women, with an estimated 1.15 million new cases in 2002 (23% of all cancers), and more than half of these cases occurring in the industrialized countries of Europe and North America (1). In Europe in 2006, breast cancer accounted for 28.9% of all cancer cases in women, and was the leading cause of cancerrelated death within the European Union (16.7%) (2).In several independent studies also conducted by our group, an enhanced in vitro chromosomal radiosensitivity was observed in a significant number of breast cancer patients (3-7). Since the most detrimental form of radiation-induced DNA damage is the double-strand break (DSB), it is plausible that DSB-initiated chromosomal instability drives breast carcinogenesis. Furthermore, the key breast cancer susceptibility genes, BRCA1 and BRCA2, ATM and TP53, play important roles in DSB repair and chromosome stability (8,9). These genetic factors are present in only 6-11% of the general breast cancer patient population, indicating that other mutations in low penetrant genes or subtle defects arising from low penetrant variations in highly penetrant genes may also create a predisposition to breast cancer (9-12). Recently, several population-based case-control studies have shown a link between single nucleotide polymorphisms (SNPs) in DSB repair genes and breast cancer risk (8,9,(12)(13)(14)(15)(16)(17). Moreover, the breast is a selected microenvironment, subjected to endogenous oxidative stress through hormone exposure. Estrogen in particular has attracted considerable attention, as it may act as a complete carcinogen (8). During the oxidative metabolism of estrogen, reactive oxygen species (ROS) and DNA adducts are formed, leading to the oxidation and depurination of the DNA (18). This type of damage can further result in clustered sites of DNA damage, including DSBs. DSBs are also induced in prolife...