Taxol-resistant epithelial ovarian tumors are associated with altered expression 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 isotypes in mammalian cells. We have used highly specific oligonucleotides and polymerase chain reaction to analyze expression of all six beta-tubulin 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, respectively. These cells displayed an altered ratio of classes I, II, III, and IVa beta-tubulin isotypes. Ovarian tumors, seven untreated primary and four taxol- resistant tumor-bearing ascites, displayed significant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), and IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appears to be related to the resistance phenotype, as the basal levels of the class III and IVa isotypes in the untreated tumors were extremely low. This is the first report of altered expression of specific beta-tubulin genes in taxol-resistant ovarian tumors and we propose that the latter may play a role in clinical resistance to taxol.
Kavallaris
M
M
Department of Molecular Pharmacology, Division of Gynecological Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461, USA.
Kuo
D Y
DY
Burkhart
C A
CA
Regl
D L
DL
Norris
M D
MD
Haber
M
M
Horwitz
S B
SB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D014404:Tubulin / Q000032:analysis* / Q000235:genetics; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D017239:Paclitaxel