DNA repair targeted therapy: The past or future of cancer treatment?

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy

In Vivo Targeting Replication Protein A for Cancer Therapy

Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA-DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers

Isoscaling in dissipative projectile breakup

Dynamical breakup of projectile-like fragments (PLF) following dissipative reactions of Ca-48 projectiles with Sn-112 and Sn-124 is shown to exhibit "isoscaling" regularities that can be understood in terms of phase space governed by ground state masses. Ambiguities in isoscaling parameters obscure information on nuclear symmetry energy at subnormal densities

Rozmnażanie miodownika melisowatego (Melittis melissophyllum L.) w kulturach in vitro

An efficient method for in vitro propagation of bastard balm by enhanced axillary shoot branching has been developed. The material to establish in vitro culture was shoot tips collected from three-year-old plants in May. The shoots obtained from initial explants were placed on MS/B5 medium containing 0.1, 0.5 or 1.0 mg/l BA with 0.01 mg/l NAA or without the auxin. The highest number of shoots per explant was obtained on the medium with 1.0 mg/l BA (3.9 shoots per explant). For the rooting of shoots ½ MS/B5 with IBA (0.25, 0.50 and 1.0 mg/l) medium was used. The medium without plant growth regulators served as a control. The best root regeneration was observed on the medium without IBA (87.1% of cuttings rooted). IBA used in the medium for shoot rooting affected the morphological traits of obtained microcuttings but not affected their weight. Irrespective of auxin concentration in this medium, obtained microcuttings acclimated in ex vitro conditions very well.Opracowano metodę szybkiego rozmnażania miodownika melisowatego w kulturach in vitro na drodze stymulacji tworzenia pędów bocznych. Materiałem do inicjacji kultury in vitro były wierzchołki pędów pobierane z roślin 3-letnich w maju i odkażane 0,2% roztworem sublimatu. Otrzymane z eksplantatów inicjalnych pędy wykładano na pożywkę MS/B5 zawierającą 0,1; 0,5 lub 1,0 mg/l BA z dodatkiem 0,01 mg/l NAA lub bez dodatku auksyny. Najwięcej pędów bocznych otrzymano na pożywce zawierającej 1,0 mg/l BA (3,9 pędów na eksplantat). Do ukorzeniania pędów zastosowano pożywkę ½ MS/B5 z dodatkiem IBA (0,25; 0,50 i 1,0 mg/l). Kontrolę stanowiła pożywka bez regulatorów wzrostu. Najwięcej ukorzenionych mikrosadzonek obserwowano na pożywce bez dodatku IBA (87,1%). IBA zastosowane w pożywce do ukorzeniania pędów wpłynęło na cechy morfologiczne uzyskanych mikrosadzonek, ale nie wpłynęło na ich masę. Niezależnie od stężenia IBA w tej pożywce mikrosadzonki dobrze adaptowały się do warunków ex vitro