engleski

Molecular alteration induced in drug resistant cells

The treatment with genotoxic agents, especially repeated, induced numerous alterations in cell genom, that are reflected in drug resistance. In our laboratory we have developed from human cervical and laryngeal carcinoma cells nine sublines resistant to cisplatin, doxorubicin, vincristine or carboplatin. Previously we determined cross-resistance pattern of these cells and examined some of the molecular mechanisms involved in drug resistance. In the present study we determined whether drug resistance is accompanied by the increased levels of cathepsin D (cath D), urokinase type plasminogen activator (uPA) and inhibitor of plasminogen activator inhibitor type (PAI-1). In the cytosol of resistant and parental cells the level of cath D was measured by solid phase two-site immunoradiometric assay, while uPA and PAI-1 concentrations were determined by use of ELISA. In all examined drug resistant cell lines the concentration of cathepsin D was increased (in two non significant). UPA levels were similar in parental and drug resistant cervical carcinoma cells, but significantly higher in all examined drug resistant laryngeal carcinoma sublines. PAI-1 concentrations were similar in parental and cisplatin resistant cervical carcinoma cells, but significantly higher in doxorubicin resistant cells. In laryngeal carcinoma cells, similar concentrations of PAI-1 were determined in parental and resistant cells, except for one carboplatin resistant and one cisplatin resistant cell line. The schedule of resistance development influenced the concentrations of cath D, uPA and PAI-1. Thus, our results suggest that cells treated with cytostatics became resistant to different drugs, and that this drug-resistance is connected with increased levels of proteases and/or its inhibitor.

drug resistance; cathepsin D; urokinase plasminogen activator; inhibitor of plasminogen activator type 1

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