EGFR-targeting antitumor therapy: Neuregulins or antibodies?

Malignancies such as lung, breast and pancreatic carcinomas are associated with increased expression of the epidermal growth factor receptor, EGFR, and its role in the pathogenesis and progression of tumors has made this receptor a prime target in the development of antitumor therapies. In therapies targeting EGFR, the development of resistance owing to mutations and single nucleotide polymorphisms, and the expression of the receptor ligands themselves are very serious issues. In this work, both the ligand neuregulin and a bispecific antibody fragment to EGFR are conjugated separately or together to the same drug-delivery system to find the most promising candidate. Camptothecin is used as a model chemotherapeutic drug and superparamagnetic iron oxide nanoparticles as a delivery system. Results show that the lowest LD50 is achieved by formulations conjugated to both the antibody and the ligand, demonstrating a synergy. Additionally, the ligand location in the nucleus favors the antitumor activity of Camptothecin. The high loading capacity and efficiency convert these systems into a good alternative for administering Camptothecin, a drug whose use is otherwise severely limited by its chemical instability and poor solubility. Our choice of targeting agents allows treating tumors that express ErbB2 (Her2+ tumors) as well as Her2- tumors expressing EGFR.

Activator-independent transcription of Snf1-dependent genes in mutants lacking histone tails.

Transcriptional regulation of Snf1-dependent genes occurs in part by histone-acetylation-dependent binding of the transcription factor Adr1. Analysis of previously published microarray data indicated unscheduled transcription of a large number of Snf1- and Adr1-dependent genes when either the histone H3 or H4 tail was deleted. Quantitative real-time PCR confirmed that the tails were important to preserve stringent transcriptional repression of Snf1-dependent genes when glucose was present. The absence of the tails allowed Adr1 and RNA Polymerase II to bind promoters in normally inhibitory conditions. The promoters escaped glucose repression to a limited extent and the weak constitutive ADH2 transcription induced by deletion of the histone tails was transcription factor- and Snf1-independent. These effects were apparently due to a permissive chromatin structure that allowed transcription in the absence of repression mediated by the histone tails. Deleting REG1, and thus activating Snf1 in the H3 tail mutant enhanced transcription in repressing conditions, indicating that Snf1 and the H3 tail influence transcription independently. Deleting REG1 in the histone H4 tail mutant appeared to be lethal, even in the absence of Snf1, suggesting that Reg1 and the H4 tail have redundant functions that are important for cell viability.

Genome-wide amplifications caused by chromosomal rearrangements play a major role in the adaptive evolution of natural yeast.

The relative importance of gross chromosomal rearrangements to adaptive evolution has not been precisely defined. The Saccharomyces cerevisiae flor yeast strains offer significant advantages for the study of molecular evolution since they have recently evolved to a high degree of specialization in a very restrictive environment. Using DNA microarray technology, we have compared the genomes of two prominent variants of S. cerevisiae flor yeast strains. The strains differ from one another in the DNA copy number of 116 genomic regions that comprise 38% of the genome. In most cases, these regions are amplicons flanked by repeated sequences or other recombination hotspots previously described as regions where double-strand breaks occur. The presence of genes that confer specific characteristics to the flor yeast within the amplicons supports the role of chromosomal rearrangements as a major mechanism of adaptive evolution in S. cerevisiae. We propose that nonallelic interactions are enhanced by ethanol- and acetaldehyde-induced double-strand breaks in the chromosomal DNA, which are repaired by pathways that yield gross chromosomal rearrangements. This mechanism of chromosomal evolution could also account for the sexual isolation shown among the flor yeast.