BackgroundThe TP53 Arg72Pro polymorphism encodes two p53 variants with different biochemical properties. Here we investigated the impact of this polymorphism on the expression of key p53 target genes in a panel of human breast carcinomas, breast cancer risk, and age at onset.Methodology/Principal FindingsThe Arg72Pro polymorphism was genotyped in 270 breast cancer patients and 221 control subjects. In addition, the Arg72Pro genotype of 116 breast tumors was determined, and correlated with intratumoral mRNA expression of TP53 and its key target genes MDM2, p21, BAX, and PERP, as quantified by qRT-PCR. We found a significantly increased breast cancer risk associated with the Pro-allele (per-allele odds ratio, 1.46; 95% confidence interval, 1.08–1.99), and a significantly later mean age at breast cancer onset for Pro/Pro patients (63.2±18 years) compared to Arg/Arg patients (58.2±15 years). The frequency of somatic TP53 inactivation was 25.4% in Arg/Arg, 20.9% in Arg/Pro, and 16.7% in Pro/Pro patients, which may reflect a higher selective pressure to mutate the Arg-allele. The median mRNA levels of p21 and BAX in the tumors of Pro-allele carriers were significantly reduced to 55.7% and 76.9% compared to Arg/Arg patients, whereas p53, MDM2 and PERP expression were hardly altered.Conclusions/SignificanceThe p5372Arg variant appears to be a more potent in vivo transcription factor and tumor suppressor in human breast cancer than the p5372Pro variant. The Arg72Pro genotype has no significant effects in patients with TP53 mutated tumors, in which p53 is non-functional.

Pyrrolidine dithiocarbamate (PDTC) was examined for its potential in the intranasal treatment of human rhinovirus infections. Prior to clinical testing, a comprehensive non-clinical programme was performed to evaluate the general toxicity of PDTC. The animal experiments included investigations in rodents with study durations ranging from single dose to repeated dosing over a period of 28 days. The routes of administration were intranasal, inhalative, oral and intravenous for single-dose toxicity and pharmacokinetic studies, and intranasal for repeated dose studies. Blood and tissue samples were obtained from PDTC-treated rats to analyse pharmacokinetics and tissue distribution. Accumulation of selected metals due to PDTC treatment was examined in liver, brain, nerves and fat tissues.Pyrrolidine dithiocarbamate (PDTC) applied intranasally (up to 121 mg ⁄ kg) or via single inhalation (1.64% PDTC applied for 4 hr) or repeated intranasal dosing up to 28 days (up to 102 mg ⁄ kg ⁄ day) did not result in major systemic toxicities or local intolerance. Pharmacokinetic evaluations indicate a very rapid absorption of PDTC after intranasal application. A high single intravenous or oral dose of PDTC induced neurotoxicity. The neurotoxic effects are in accordance with the toxicity profile described for dithiocarbamates (DTCs) with effects on the autonomous and nervous system. The intravenous LD 50 was defined at 282 mg ⁄ kg in mice and at 306 mg ⁄ kg in rats. The oral LD 50 was calculated at above 1500 mg ⁄ kg for mice and rats. The results from in vitro and in vivo genotoxicity studies do not elucidate a genotoxic potential for PDTC.Concluding from the toxicology data set, PDTC qualifies as a valuable drug candidate for intranasal or inhalative administration.Pyrrolidine dithiocarbamate, a very effective NF-jB inhibitor [1], known to inhibit inflammatory processes [2], is suggested as a key factor in the treatment of human rhinovirus (HRV) infections. Unpublished in vitro data strongly support this hypothesis. Thus, the aim of this project was to describe the toxicity profile of PDTC allowing for clinical use of the potential HRV drug candidate. Pyrrolidine dithiocarbamate is a compound of the class of DTCs. Dithiocarbamates and their disulphides have been used in medicine, industry and agriculture for more than 20 years. The compounds class reported biological effects include ability to influence oxidative stress, apoptosis, enzyme inhibition or modulation of transcription as well as inhibition of inflammatory processes via NF-jB inhibition [1,[3][4][5][6][7][8].Two DTCs, diethyldithiocarbamate and its disulphide disulphiram (Antabuse) are marketed drugs: Diethyldithiocarbamate is used in the treatment of nickel intoxication, Antabuse is marketed for alcohol aversion therapy. The potential clinical use of closely related compounds is currently being explored for various indications including the treatment of ocular inflammations [9,10], infection caused by rhinovirus [11] and coxsackievirus [12], methicillin-resi...

Carrageenan has been widely used as food additive for decades and therefore, an extended oral data set is available in the public domain. Less data are available for other routes of administration, especially intranasal administration. The current publication describes the non-clinical safety and toxicity of native (non-degraded) iota-carrageenan when applied intranasally or via inhalation. Intranasally applied iota-carrageenan is a topically applied, locally acting compound with no need of systemic bioavailability for the drug’s action. Animal experiments included repeated dose local tolerance and toxicity studies with intranasally applied 0.12% iota-carrageenan for 7 or 28 days in New Zealand White rabbits and nebulized 0.12% iota-carrageenan administered to F344 rats for 7 days. Permeation studies revealed no penetration of iota-carrageenan across nasal mucosa, demonstrating that iota-carrageenan does not reach the blood stream. Consistent with this, no relevant toxic or secondary pharmacological effects due to systemic exposure were observed in the rabbit or rat repeated dose toxicity studies. Data do not provide any evidence for local intolerance or toxicity, when carrageenan is applied intranasally or by inhalation. No signs for immunogenicity or immunotoxicity have been observed in the in vivo studies. This is substantiated by in vitro assays showing no stimulation of a panel of pro-inflammatory cytokines by iota-carrageenan. In conclusion, 0.12% iota-carrageenan is safe for clinical use via intranasal application.

The last decades were characterized by enormous technological advances resulting in a better understanding of disease pathologies and improvement of treatment strategies. The development of targeted drugs, whose beginning can be traced back to Paul Ehrlich's theory of the 'magic bullet' approximately 100 years ago, is today widely appraised as a promising strategy to combat benign, as well as malignant, diseases. Over 40 years after US President Nixon declared the 'war on cancer', treatment outcome, especially of solid tumors in the advanced stages of disease, still lies far behind expectations. In this perspective article, the authors discuss the recent development of targeted cancer drugs and identify major hurdles. The authors further highlight future strategies that might improve and accelerate the drug-development process.

In order to understand the consequences of radiation a thorough understanding of the radiobiological mechanisms of the molecular up to the clinical level is of importance. Radiobiology therefore combines the basic principles of physics as well as biology and medicine and is concerned with the action of radiation from the subcellular level up to the living organism. Topics of interest and relevance are covered in much more broadness as is possible in the short following article in the literature to which the interested reader is referred to. Classical books in this field were written by Steel et al. (1989) as well as by Hall (1994). Topics usually covered by radiobiological reviews are the classification of different types of radiation, cell cycle dependency of radiation effects, types of radiation damage and cell death, dose response curves, measurement of radiation damage, the oxygen effect, relative biological effectiveness, the influence of dose rate, and several other important research areas. This short overview will concentrate on a subset of radiobiological topics of high importance and relative novelty.