EXPRESSION OF RESISTANCE FACTORS (P-GLYCOPROTEIN, GLUTATHIONE-S-TRANSFERASE-PI, AND TOPOISOMERASE-II) AND THEIR INTERRELATIONSHIP TO PROTOONCOGENE PRODUCTS IN RENAL-CELL CARCINOMAS

Background. This study investigates whether or not an interrelationshi p exists between the expression of resistance-related proteins (P-glyc oprotein, glutathione S-transferase, topoisomerase II) and proto-oncog ene products (c-fos, c-myc, c-K-ras, epidermal growth factor receptor [EGF-R], and c-neu proteins.) Methods. Thirty-eight human renal cell c arcinomas of previously untreated patients were analyzed for expressio n of P-glycoprotein (P-170), glutathione S-transferase-pi (GST-pi), to poisomerase II (Topo II) and proto-oncogene proteins by means of immun ohistochemistry. Because of significant heterogeneity in most tumor bi opsies, all analyses were done on tumor-derived primary cell culture l ines on the third or fourth passage. Results. An interrelationship bet ween increased expression of P-170 and GST-pi and down-regulation of T opo II was found. Expression of the c-fos protein was seen in 66% of t he tumors; expression of the c-myc protein, in 50%; of the c-K-ras pro tein, in 16%; of the EGF-R protein, in 61%; and of the c-neu protein, in 54% of the tumors. A significant correlation between the resistance factors and the c-fos, EGF-R, and c neu-proteins was observed (GST/c- fos, P = 0.012; Topo II/c-fos, P = 0.024; P-170/EGF-R, P < 0.001; GST/ EGF-R, P = 0.018; Topo II/EGF-R, P 0.027; P-170/c-neu, P 0.005; GST/c- neu, P = 0.018; Topo II/EGF-R, P = 0.027; P-170/c-neu, P = 0.005; GST/ c-neu, P = 0.008; Topo II/c-neu, P = 0.05). In contrast, interrelation ships between resistance proteins and c-myc and c-K-ras proteins were not found. A significant interrelationship between the investigated re sistance-related proteins or proto-oncogene proteins and the stage or grading of the tumors was not observed. Conclusions. The results demon strate that in renal cell carcinomas a significant relationship exists between resistance-related proteins, such as P-170, GST-pi, or Topo I I, and proto-oncogenes, such as c-fos, c-erbB1, and c-neu.