title: Avoiding tumor resistance - different approaches for new chemotherapeutic agents and their mechanistic assessment
Creators: name: Gold, Madeleine
Publisher: name: University of Bayreuth
Year: 2021
Subjects: subject: antitumoral agents
subject: chemoresistance
subject: drug research
subject: metal complexes
subject: thieno[2,3-d]pyrimidone
subject: circulating tumor cells
subject: 500

description: With growing biochemical knowledge and the development of targeted therapies since the beginning of the 21st century, the individualization of therapy for every single patient and their tumor has taken center stage in cancer research. Despite all advancements in this field, in 90% of cases chemoresistance is responsible for the failure of antitumoral therapy. For this reason there is a considerable demand for new therapeutic agents, selectively addressing resistant tumor cells, but also for new biomarkers enabling an early detection of existing or imminent resistance. In the first section of this work, some preclinical studies of new potential drug candidates, which were designed to avoid chemoresistance in different ways, are described. Moreover, the assessment of their particular mechanisms of action on a molecular level was in the focus. Two new series of drugs aimed at the circumvention of p53-related chemoresistance. As p53 plays a key role in the induction of apoptosis, cells with p53 mutations are significantly less sensitive or even resistant against apoptosis-inducing stimuli, e.g. chemotherapeutic agents. In this work, new ruthenium(II) and gold(I) complexes inducing apoptosis in a p53-independent way were investigated. A benzochromene ruthenium(II) complex derived from lawsone (2-hydroxy-1,4-naphthoquinone), the pigment and active ingredient of the henna plant, avoids p53-dependency by induction of cellular senescence. Therapy-induced senescence represents one alternative to conventional cytotoxic chemotherapy and implicates even more advantages. As its aim is not to eliminate malignant cells, but to irreversible inhibit their proliferation, side effects for the patient could be reduced especially in the longtime treatment of specific cancer types. Also [1,3-diethyl-4,5-diarylimidazol-2-yliden](L) gold(I) complexes showed activity against tumor cells independent from their p53 mutational status. By confocal microscopy with 518A2 melanoma cells, organelle-specific cellular uptake of those complexes was observed. Whereas, mainly the nature of ligand L, responsible for the complex charge, size and lipophilicity, was decisive for the site of cellular accumulation. This concept of controlling the intracellular distribution of metallodrugs by choice of secondary ligands and the complex charge could be exploited in a rational design of drugs particularly active against resistant tumor cells. Topoisomerase I inhibitors are established antitumoral agents mainly applied within combination regimens. The high rate of chemoresistance development also represents a big issue for this kind of therapy. To date, the camptothecin family agents, like topotecan or irinotecan, are the only topoisomerase I-specific drugs with clinical approval. With camptothecin resistance often significantly depending on the molecular structure of the agent, the implementation of a novel, structural-independent class of topoisomerase I inhibitors may contribute to bypass this problem. In the scope of this work, three topoisomerase I inhibiting copper(II) complexes with Schiff base-like ligands were identified. In contrast to established copper complexes with topoisomerase I inhibiting activity, neither an interaction with DNA nor an impact on the intracellular concentration of reactive oxygen species was observed. The new copper(II) complexes with Schiff base-like ligands are potentially interesting drug candidates for further studies. Another possibility for the avoidance of tumor resistance are pleiotropic agents that address more than one cellular target at a time. Derived from the concept of polychemotherapy - to date the most successful approach to prevent the development of chemoresistance - these agents aim to reduce side effects, as well as pharmacokinetic discrepancies between individual combinational drugs. In this work, a series of multimodal thienopyrimidone derivatives were tested regarding their antitumoral properties. From a structural point of view, these substances combine the ß-tubulin binding 3,4,5-trimethoxyphenyl fragment with the biologically active thieno[2,3-d]pyrimidone pharmacophore. By means of different in vitro and in vivo assays, one derivative with improved activity and tolerability compared to the reported lead structures was identified within the series. In the second part of this work, a potential monitoring tool for the early detection of therapy response in patients with colorectal cancer was investigated via a clinical proof-of-principle study. Circulating tumor cells are an important link between the primary tumor and distant metastasis and are readily accessible from the blood of cancer patients. Moreover, they reflect changes of the tumor cells on a translational, transcriptional, or genetic level in real-time, enabling the early realization of upcoming resistances. Different studies have already demonstrated that the longitudinal monitoring of the number and properties of circulating tumor cells provide valuable information on therapy response and disease progression. In the case of non-metastatic colorectal cancer patients, the detection rate via established techniques is too low to further analyze potential correlations. This work demonstrates that the Maintrac® method is appropriate for the monitoring of circulating tumor cells during therapy in patients with colorectal cancer of all stages. Although this study´s results confirm reported trends, further studies with bigger patients´ collectives have to show, which conclusions for therapy decisions may be implicated from the profile of circulating tumor cells during therapy of colorectal cancer patients.