Electropermeabilization in Experimental Tumour Treatment: Dosimetry and Tissue Effects

Sammanfattning: Short, electric high-voltage pulses can be used to transiently increase the permeability of cell membranes without significant loss of cell viability. During this period of time, extracellular and normally non-permeant, molecules are accessed the cytoplasm and the cell nucleus. This technique is called electroporation or electropermeabilization (EP). EP has been employed in vivo to internalise anticancer agents (bleomycin and cisplatin) into solid tumours. A large number of animal studies and several independent clinical trials have proven this technique to be efficient in many cases. It has recently been reported that EP also can be used to achieve high transfection efficiency of genes and proteins into tissues (e.g. muscle, liver and tumours) in vivo. This thesis investigates techniques to determine the efficiency of in vivo electropermeabilization and to investigate and optimise parameters governing the treatment outcome. In Paper II, radiolabelled bleomycin (111In-BLMC) was internalised by EP into s.c. rat brain tumours and traced continuously with a gamma camera. In Paper III gamma camera measurements of radiolabelled DTPA was used to study the influence of various pulse parameters on the drug uptake in muscle tissue after EP. Paper IV describes a technique for instant measurements of the EP efficiency by impedance spectrometry. The conductivity change in skeletal muscle before and after EP was measured and correlated to concomitant 99mTc-DTPA measurements. The thesis also includes two studies of tumour treatment using EP. Paper V describes the antitumour effect of combined radiation and EP treatment, as well as observed detrimental effect on tumour vasculature after repeated EP treatment. In Paper VI, an adenocarcinoma implanted in rat liver was treated with bleomycin, internalised into the tumour by EP. A 92% cure rate with a pronounced anti-metastasising effect was observed for EP-bleomycin treated animals, which suggests a stimulation of the immune defence. Macrophages and CD8 positive lymphocytes were found in viable tumour of EP+bleomycin treated animals.