Abstract
BackgroundBleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug. The aim of the study was to evaluate whether a physical drug delivery system – electroporation can increase radiosensitising effect of bleomycin in vitro and in vivo.MethodsLPB sarcoma cells and tumors were treated either with bleomycin, electroporation or ionizing radiation, and combination of these treatments. In vitro, response to different treatments was determined by colony forming assay, while in vivo, treatment effectiveness was determined by local tumor control (TCD50). Time dependence of partial oxygen pressure in LPB tumors after application of electric pulses was measured by electron paramagnetic oxyimetry.ResultsElectroporation of cells in vitro increased radiosensitising effect of bleomycin for 1.5 times, in vivo radiation response of tumors was enhanced by 1.9 fold compared to response of tumors that were irradiated only. Neither treatment of tumors with bleomycin nor application of electric pulses only, affected radiation response of tumors. Application of electric pulses to the tumors induced profound but transient reduction of tumor oxygenation. Although tumor oxygenation after electroporation partially restored at the time of irradiation, it was still reduced at the level of radiobiologically relevant hypoxia.ConclusionOur study shows that application of electric pulses to cells and tumors increases radiosensitising effect of bleomycin. Furthermore, our results demonstrate that the radiobiologically relevant hypoxia induced by electroporation of tumors did not counteract the pronounced radiosensitising effect of electrochemotherapy with bleomycin.
Highlights
Bleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug
Its effectiveness in local tumor control was demonstrated in numerous animal tumor models and in several clinical studies in cancer patients with different tumors, malignant melanoma, sarcomas and carcinomas [13,14,15]
Radiosensitisation of LPB cells in vitro In order to determine the radiosensitising effect of BLM, LPB cells exposed to BLM alone or ECT were irradiated with graded X-ray doses up to 8 Gy (Figure 2)
Summary
Bleomycin is poorly permeant but potent cytotoxic and radiosensitizing drug. The aim of the study was to evaluate whether a physical drug delivery system – electroporation can increase radiosensitising effect of bleomycin in vitro and in vivo. It has been shown that electroporation, a physical method of drug delivery into the cells and tissues, induces transient permeabilization of the cell membrane, enabling facilitated transport of BLM and other cytotoxic drugs like cisplatin into the cells, resulting in their increased cytotoxicity [10,11,12]. This combined treatment of chemotherapeutic drugs with hampered transport through the cell membrane and electroporation in vivo was termed electrochemotherapy (ECT). It was demonstrated that application of electric pulses to the tumor as well as normal tissues reduces blood flow and oxygenation [16,17,18,19]
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