A national centre of pharmaceutical drug research

Abstract

Anthracyclines belong to a class of cytostatic compounds that are commonly used to treat various types of cancers, including lymphoma, breast cancer and primary liver cancer. The aim of this thesis was to study how two anthracyclines, doxorubicin and idarubicin, induced cytotoxicity in tumor cells, as well as their off-target effect on the gastrointestinal system. In Paper I, we exposed four different cancer cell lines to various concentrations of doxorubicin in two different formulations, and measured the cell viability and how much doxorubicin was taken up by the cells. We found that the cell lines differed in their uptake and sensitivity, and that the most resistant cell line had an intracellular exposure of doxorubicin that was about 100 times lower when compared to the more sensitive cell lines. To study the off-target gastrointestinal toxicity, we dosed rats with doxorubicin and studied how chemotherapy-induced mucositis developed during seven days in Paper II. The main effect parameter was intestinal villus atrophy, which was most severe after three days. This was preceded by an increased cell death and decreased proliferation in the crypts, which occurred within the first day after doxorubicin exposure. To study how different cytostatic drugs affected chemotherapy-induced mucositis, and to what extent they caused diarrhea, rats were dosed with one of six different chemotherapies, including doxorubicin and idarubicin, in Paper III. All selected chemotherapies caused similar villus atrophy three days after dosing, but only a third, including idarubicin, caused clear diarrhea. In paper IV the objective was to treat or prevent idarubicin-induced mucositis and diarrhea, by using the anti-inflammatory drugs anakinra and/or dexamethasone. Anakinra alone stopped the diarrhea, while the combination of anakinra and dexamethasone prevented villus atrophy. These positive effects encourage further investigations into the use of anakinra and dexamethasone as supportive therapies for chemotherapy-induced mucositis and diarrhea.

The overall long-term impact of the different studies in this thesis is to increase the specific anti-tumoral effect of chemotherapies, while also alleviating the adverse effects. This would improve quality-of-life and treatment outcomes of cancer patients.