The combined effects of high-energy shock waves and cytostatic drugs or cytokines on human bladder cancer cells

Abstract

Summary The effects of shock waves generated by an experimental Siemens lithotripter in combination with cytostatic drugs or cytokines on several bladder cancer cell lines were examined in vitro. Proliferation after treatment was determined with the 3-4,5-dimethylthiazol-2,5 diphenyl tetrazolium bromide assay. Dose enhancement ratios were calculated for each drug and each shock wave application mode in order to characterise the sensitising effect of shock wave pretreatment. The influence of the time between shock wave and drug treatment as well as the effects of different sequences of shock wave and drug treatment or concomitant treatment were assessed for selected combinations of cell lines and drugs. It was found that shock wave treatment could render certain cell lines more susceptible to subsequent cis-platinum, mitomycin C or actinomycin D incubation. Cell lines sensitive to tumour necrosis factor a or interferon a were further sensitised to these cytokines by shock wave pretreatment. The enhanced sensitivity to cis-platinum and actinomycin D decreased rapidly during the first hours after shock wave treatment. The antiproliferative effect was most pronounced after concomitant shock wave and drug treatment. The sensitisation to interferon a diminishes more slowly after shock wave exposure. From the results presented in this study it is concluded that transient shock wave-induced permeabilisation of cell membrane not only enhances drug efficiency, but also causes damage to cell organelles and alterations in cellular metabolism For more than a decade, high-energy shock waves (HESW) have been routinely used to disintegrate urinary calculi (Simon et al., 1989). Nowadays, even biliary and salivary stones can be fragmented by extracorporeal shock wave lithotripsy (Sackman & Paumgartner, 1992;Iro et al., 1992). Although the patient's stress is reduced as compared with open surgery, lithotripsy causes well-described side effects, in particular damage to the vascular system (haemorrhages, capillary thrombi, haematuresis), release of cytoplasmic enzymes and cellular alterations in the tissue adjacent to the treated loci (Lingeman et al., 1988; Brummer et al., 1990).The possibility of exposing a spatially limited region of the body to a potentially destructive form of mechanical energy led to the idea of employing HESW in tumour therapy (Russo et al., 1985). Appropriate in vitro and in vivo studies showed that shock waves cause only temporary growth delay. Nevertheless, considerable morphological changes at the cellular level could be observed, including effects on plasma membrane, mitochondria, cytoplasm and nucleus (Russo et al., 1987;Randazzo et al., 1988;Brauner et al., 1989;Kohri et al., 1990;Yu et al., 1991;Steinbach et al., 1992 Materials and methodsCell culture Three human transitional carcinoma cell lines were evaluated. RT4 (Rigby & Franks, 1970) and J82 (O'Toole et al., 1978) represent the phenotype of a differentiated GI papillary carcinoma and a highly malignant G3 carcinoma of the bladder respectivel...

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