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Mammalian DNA topoisomerases II are targets of anticancer anthracyclines that act by stabilizing enzyme-DNA complexes wherein DNA strands are cut and covalently linked to the protein. This molecular mechanism is the molecular basis of anthracycline anticancer activity as well as the toxic effects such as cardiomyopathy and induction of secondary cancers. Even though anthracyclines have been used in the clinic for more than 50 years for solid and blood cancers, the search of breakthrough analogs has substantially failed. The recent developments of personalized medicine, availability of individual genomic information, and immune therapy are expected to change significantly human cancer therapy. Here, we discuss the knowledge of anthracyclines as Topoisomerase II poisons, their molecular and cellular effects and toxicity along with current efforts to improve the therapeutic index. Then, we discuss the contribution of the immune system in the anticancer activity of anthracyclines, and the need to increase our knowledge of molecular mechanisms connecting the drug targets to the immune stimulatory pathways in cancer cells. We propose that the complete definition of the molecular interaction of anthracyclines with the immune system may open up more effective and safer ways to treat patients with these drugs.

We investigated the mechanism of how the papillomavirus E2 transcription factor can activate promoters through activator protein (AP)1 binding sites. Using an unbiased approach with an inducible cell line expressing the viral transcription factor E2 and transcriptome analysis, we found that E2 induces the expression of the two AP1 components c-Fos and FosB in a Brd4-dependent manner. In vitro RNA interference confirmed that c-Fos is one of the AP1 members driving the expression of viral oncogenes E6/E7. Mutation analysis and in vivo RNA interference identified an essential role for c-Fos/AP1 and also for the bromodomain protein Brd4 for papillomavirus-induced tumorigenesis. Lastly, chromatin immunoprecipitation analysis demonstrated that E2 binds together with Brd4 to a canonical E2 binding site (E2BS) in the promoter of c-Fos, thus activating c-Fos expression. Thus, we identified a novel way how E2 activates the viral oncogene promoter and show that E2 may act as a viral oncogene by direct activation of c-Fos involved in skin tumorigenesis.

In this study, simultaneous positron emission tomography (PET)/magnetic resonance (MR) imaging was employed to evaluate the feasibility of the PET tracers 2-deoxy-2- 18 F-fluoro-D-glucose ( 18 F-FDG), 11 C-choline, and 18 F-fluorothymidine ( 18 F-FLT) to detect papillomavirus-induced tumors in an established rabbit model system. The combined PET/MR allowed the analysis of tracer uptake of the tumors using the morphologic information acquired by MR. New Zealand White rabbits were infected with cottontail rabbit papillomavirus genomes and were imaged for up to 10 months with a simultaneous PET/MR system during the course of infection. The uptake characteristics of the PET tracers 11 C-choline and 18 F-FLT of tumors and reference tissues were examined relative to the clinical standard, 18 F-FDG. Tracer biodistribution of various organs was measured by gamma-counting after the last PET scan and compared to the in vivo PET/MR 18 F-FDG uptake. Increased tracer uptake was found 2 months postinfection in primary tumors with 18 F-FDG and 11 C-choline, whereas 18 F-FLT failed to detect the tumors at all measured time points. Our data show that the PET tracer 18 F-FDG is superior for imaging papillomavirus-induced tumors in rabbits compared to 11 C-choline and 18 F-FLT. However, 11 C-choline imaging, which has previously been applied to detect various tumor entities in patients, appears to be an alternative to 18 F-FDG.