TAXOL-RESISTANT EPITHELIAL OVARIAN-TUMORS ARE ASSOCIATED WITH ALTEREDEXPRESSION OF SPECIFIC BETA-TUBULIN ISOTYPES

The treatment of advanced ovarian cancer with taxol is hindered by the development of drug resistance. The cellular target for taxol is the microtubule that is stabilized by the drug, Taxol preferentially binds to the beta subunit of tubulin of which there are six distinct isotyp es in mammalian cells, We have used highly specific oligonucleotides a nd polymerase chain reaction to analyze expression of all six beta-tub ulin genes, Human lung cancer cells (A549) were selected in 12 and 24 nM taxol resulting in cell lines that were 9- and 17-fold resistant, r espectively, These cells displayed an altered ratio of classes I, II, III, and IVa beta-tubulin isotypes, Ovarian tumors, seven untreated pr imary and four taxol-resistant tumor-bearing ascites, displayed signif icant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), a nd IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appear s to be related to the resistance phenotype, as the basal levels of th e class III and IVa isotypes in the untreated tumors were extremely lo w. This is the first report of altered expression of specific beta-tub ulin genes in taxol-resistant ovarian tumors and we propose that the l atter may play a role in clinical resistance to taxol.