Summary.-The surviving fraction (SF) of Chinese hamster cells and HeLa cells after treatment with a range of Adriamycin concentrations and exposure times was determined. The cytostatic effect was proportional to the product of extracellular drug concentration (c) and exposure time (t) according to the equation: SF=e-ktc. By determining the intracellular drug concentration at various exposures, it could be shown that absorbed dose is not proportional to exposure dose.
Summary.-Chronically hypoxic cells were 5 times more resistant to Adriamycin (ADR) than exponentially growing oxic cells. On reoxygenation, resistance decreased slowly to reach the ADR sensitivity of oxic cells after 24 h. With increasing pH, ADR efficiency increased more in oxic than in chronically hypoxic cells. With increasing cell density, ADR efficiency decreased linearly.The differences in ADR efficiency under the various conditions were accompanied by differences in intracellular ADR uptake. Chronically hypoxic cells incorporated 1.6 times less than oxic cells; the incorporation rate at pH 6-5 was half that at pH 7-4; and at a cell density of 5 x 105/bottle the intracellular uptake was 6 times that at 5 x 106/bottle.The observed differences in uptake of ADR were not, however, sufficient to explain the differences in cytotoxicity.
2, and 3Physikalisch-Technische Abteilung der GSF, 8042 Neuherberg, FRG.Summary Clonogenic survival of HeLa, Chinese hamster and HaK cells after treatment with a range of cisplatin concentrations and exposure times was determined and cellular platinum concentrations were measured by PIXE. It was demonstrated that cisplatin cytotoxicity of the three cell lines varied considerably as a function of drug exposure dose. These differences are related to differential cellular drug uptake.
The effect of a combination of shock waves with cisplatin was examined in vivo with subcutaneously implanted amelanotic melanomas (A-Mel 3) in Syrian golden hamsters and cisplatin-sensitive or cisplatin-resistant fibrosarcoma (SSK2/0 and SSK2/R2) in C3H mice. In all 3 tumor models, 4 treatment modalities were compared: control, cisplatin treatment, shock waves and the combination of shock waves and cisplatin. Shock waves significantly delayed tumor growth in all 3 tumor models when compared to the respective control group. Cisplatin alone delayed the growth of A-Mel 3 and SSK2/0, whereas SSK2/R2 remained uninfluenced by the drug. In all 3 tumor models the combined treatment with shock waves and cisplatin additively and significantly delayed tumor growth. In A-Mel-3-bearing animals the combined treatment significantly increased survival time. The growth of SSK2/0 and SSK2/R2 tumors was delayed to a similar extent by the combined treatment modality as compared to shock-wave treatment alone. This indicates that the cisplatin resistance of SSK2/R2 tumors has been overcome by the simultaneous shock wave treatment. An increased intracellular cisplatin accumulation in the tumors due to shock wave exposure is suggested as the mechanism of interaction between shock waves and cisplatin.
Heat sensitization to cisplatin was studied in drug-sensitive Chinese hamster fibroblast (CH) and inherently drug-resistant hamster kidney (HaK) cells. Under normothermic conditions the slopes of the survival curves differed by a factor of 3.6, while the cellular uptake was higher in CH cells by a factor of 3. When heat and drug treatment were given simultaneously, both effects were increased in CH and HaK cells: thermal enhancement factors at 43 degrees C were 5.5 (CH) and 2.9 (HaK) for cytotoxic drug action and 3.9 and 2.2 for the increase in cellular drug content. Increase in cell sensitization was also obtained if the cells were heat pretreated (42.5-44 degrees C for various times) followed by drug exposure at 37 degrees C. It is concluded that thermal enhancement depends on the efficiency of cisplatin cytotoxicity, which in turn correlates with cellular drug uptake in both the sensitive and resistant cell line.
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