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In many cases, only advanced stage colorectal cancer is diagnosed. At this point, it has often already metastasised to the liver. In these cases, not only the patient’s primary tumor, but also metastases have to be treated. For the treatment of both liver metastases and primary tumors there are local procedures to be offered.
The objective of this project was to investigate new methods of local therapy of liver tu-mors/metastases, which can be used either as neoadjuvant, adjuvant or stand-alone treatment.
It was the aim of this study to investigate minimally invasive local tumor therapy using a low dose of drugs. The study on efficacy and tolerance of this method was conducted in 20 rab-bits with implanted VX2 liver tumors. The initial idea was to allow local percutaneous treat-ment of tumors with therapeutically active substances delivered by drug-coated balloon cath-eters. In this way, a large tissue surface area will be attained by the increased surface of the balloon through its expansion. In addition, the coating will be sustainably pressed into the tumor tissue. After that, the active substance should be slowly dissolved in the tissue or slowly washed away from its location.
The following cytostatics were selected: paclitaxel, arsenic trioxide, 5-fluorouracil, fantolon, bortezomib, doxorubicin and mitoxanthrone. In addition, the drugs were compared with appropriate drug-free controls.
The above mentioned substances were tested in vitro for their cytotoxicity against the VX2 tumor cells in culture. The cells were exposed to any substance at four different concentra-tions (2-32 μmol/l for paclitaxel, arsenic oxide, fantolon, 5-fluorouracil and mitoxanthrone, 10-25 μmol/l for doxorubicin, 0.1-0.4 μmol/l for bortezomib) for 24, 48 and 72 hours. As a con-trol, tumor cells were incubated without drugs.
The total remaining intramitochondrial dehydrogenase activity as a measure of the cellular vitality compared to the control was the lowest for doxorubicin with 12 3% (16 μmol/l after 72 h incubation) and the highest for arsenic trioxide with 52 4% (15 μmol/l after 48 h) when the lowest value was selected for each substance.
All tested substances were shown to be effective, and their selection for the investigation in the animal study was based on their physicochemical properties and mechanism of action, as well as on the experience with these substances in previous studies for other indications.
Not all test substances selected in this study were shown to be suitable for the coating of balloon catheters, thereby limiting this method of administration in the in vivo experiments. For that reason another mode of administration of these substances had to be chosen. Arse-nic trioxide and doxorubicin were injected directly into the tumor using a syringe (four animals per group). Four rabbits were used for each drug to be tested. The applied doses were be-tween 1.57 to 1.78 mg for paclitaxel, 11.5 to 22.0 mg for arsenic trioxide, 1.12 to 1.16 for fantolon and 5.94 to 20.78 for doxorubicin. In the course of the study the doses for doxorubi-cin and arsenic trioxide could be increased due to their good tolerability and low effect. Half of the animals in the control group were treated with an uncoated balloon catheter (two ani-mals), while the other half of the same group (two animals) received a physiological saline solution by injection to mimic mechanical manipulation of the tumor in treatment with the drugs.
The effectiveness of the treatment on tumor growth was controlled after 1-2 weeks by com-puter tomography during and shortly after injection of a contrast agent. In contrast-enhanced computed tomography the liver tumor is detected by its low blood supply, defined here as perfusion defect, when compared to the healthy liver tissue. A reduction in the size of the perfusion defect after therapy indicates a decrease in the tumor size, while an increase can be attributed to tumor growth or necrosis. Therefore, after dissection TCC staining of vital parts of the tissue with a perfusion defect was performed.
Overall, the effect of the investigated substances in vivo did not completely correspond to the results in cell culture experiments. In only two out of twenty animals a reduction of the tumor-related perfusion defect in the liver was observed: one animal in the group treated with fantolon (-36% of the value measured one week before) and one control animal treated with an uncoated balloon (-6% of the value measured one week before). In all other animals the assessment of the efficacy of the substances is only based on the increase of the perfusion defect. The lowest percentage growth in the perfusion defect was observed in animals treat-ed with paclitaxel (271 ± 186%), followed by animals of the control group (903 ± 925%). The largest increase in the perfusion defect was seen after treatment with arsenic trioxide (3580 ± 4871%), where the largest proportion of the poorly or not perfused liver tissue was necrotic.
None of the substances and formulations tested in this study showed the desired local cyto-toxic properties in vivo. However, it cannot be excluded that local administration of paclitaxel and arsenic trioxide inhibits tumor growth. This assumption is supported by the results of exvivo measurements of the tumor size and by pathological examination. Thus, further experi-ments regarding the dose, formulations and mode of administration should be conducted, especially for arsenic trioxide, in order to demonstrate reproducibility of the findings, gain insight certainty with respect to vitality of the damaged tissue defined as perfusion defect and to assess the potential benefits of these substances for local tumor therapy.