The laboratory of experimental radiology was initially established as “tumor test labor”. Its primary goal was to test the sensitivity of tumor samples towards cisplatin. In the past 3-4 years under the guidance of Dr. Nico Ruprecht, the focus has changed and lies now on the investigation of the interaction of metal drugs with cells.
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Among the many metal-containing drugs used in medicine, cisplatin and gadolinium-based contrast agents (GBCA) are probably the two most commonly used. Both the cancer drug cisplatin and the MRI contrast agent have been in use for over 30 years. Nevertheless, there are still unsolved problems. With cisplatin one is the development of resistance, with GBCA the deposition of gadolinium (Gd) in the organism, that can lead to a broad range of adverse events. In both cases, the key to the solution lies in understanding the interaction / effect of the drug at the cellular level.
Since the late 1980s, GBCA are used for enhanced magnetic resonance imaging (MRI) examinations. During this period, several million doses have been applied worldwide and have been tolerated very well by most patients. Next to the wellknown adverse event “nephrogenic systemic fibrosis” in patients with renal insufficiency due to Gadolinium depositions in various tissues and organs, it recently became evident that gadolinium deposits in the organism may be detectable even in patients with intact renal function. Gadolinium was located in cerebral areas (e.g. nucleus dentatus, globus pallidus) by several groups around the globe.
One of the key questions, namely, the interaction of GBCA on a cellular level, so far has only been studied occasionally ex vivo and with inconsistent results. These fundamental controversies demonstrate that the accumulation of gadolinium deposits in tissue and interaction with cells is not fully understood, albeit of paramount interest.
Of special interest in this context are the cells that have the first contact with GBCA, namely, blood cells, and cells of the blood brain barrier.
Our laboratory showed that single cell ICP-MS (SC-ICP-MS) allows quantification of metallodrugs in both single cells and even in cell organelles such as nuclei. Based on this successful application of SC-ICP-MS, the uptake of Gd-DOTA in erythrocytes and WBCs was measured by SC-ICP-MS in ex vivo experiments. Erythrocytes showed no uptake as measured by SC-ICP-MS, whereas WBCs showed a clear and rather similar uptake of gadoterate (unpublished). One of the relevant question to be answered is whether the ex vivo results are valid in vivo too. For this a clinical study was performed, recently (DLF-Nr: 5209 | BASEC-Nr: 2022-00872; Cellular GBCA Uptake). The outcome showed that patient’s WBCs became loaded with Gd in vivo, too. Moreover, the results suggested that two populations with different susceptibility exist amongst the patient’s collective. This preliminary finding, however, needs confirmation by a more extensive study with a larger patient population, which is currently being planned.
Lung cancer is the most frequently diagnosed cancer in men and the leading cause of cancer death. Eightyfive percent of all cases and thus the most abundant form of lung cancer is non-small cell lung cancer NSCLC. In spite of newly developed anticancer agents platinum-based chemotherapy governs the first-line treatment. Inherent or acquired platinum resistance is a major limitation to improve long-term outcomes in cancer therapy. Recent discoveries were describing multiple novel resistance mechanisms. These mechanisms with an effect on the development of cisplatin resistance with clinical implications include decreased drug import, increased drug export, increased drug inactivation by detoxification enzymes, increased DNA damage repair, and inactivated cell death signaling, just to name the major possible mechanisms.
Starting with lung adenocarcinoma cells (A24) we recently established cell lines with lasting, highlevel cisplatin resistance. These cells might serve as a powerful model to study the molecular mechanism of the development of resistance to cisplatin and potential re-sensitization mechanisms. In addition, future molecular characterization of these cell lines might also lead to discovery of biomarkers for cisplatin resistance and/or resistance development in NSCLC.
SNF: Unraveling the secrets of Gadolinium based contrast agents trafficking across the blood-brain barrier after enhanced MRI examination (Heverhagen / Engelhardt; 700’000 CHF, 2023)
Bern Center for Precision Medicine (BCPM): Understanding Drug Resistance by Tuning Met-al-based Anticancer Therapeutics (Broekmann / Furrer / Ruprecht / von Tengg-Kobligk; 123’000 CHF, 2022)