Paclitaxel-Resistant Human Ovarian Carcinoma Cell Lines
- Others
-
(1997) Giannakakou P, et al. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem. 272(27):17118-25.
- *Abstract
-
Acquired resistance to paclitaxel can be mediated by P-glycoprotein or by alterations involving tubulin. These are two paclitaxel-resistant sublines derived from 1A9 human ovarian carcinoma cells. Single-step paclitaxel selection with verapamil yielded two clones that are resistant to paclitaxel and collaterally sensitive to vinblastine. The resistant sublines are not paclitaxel-dependent, and resistance has remained stable. All cell lines accumulate [3H]paclitaxel equally, and no MDR-1 mRNA was detected by polymerase chain reaction following reverse transcription. Total tubulin content is similar, but the polymerized fraction increased in parental but not in resistant cells following the paclitaxel addition. Purified tubulin from parental cells demonstrated paclitaxel-driven increased polymerization, in contrast to resistant cell tubulin, which did not polymerize under identical conditions. In contrast, epothilone B, an agent to which the resistant cells retained sensitivity, increased assembly. Comparable expression of beta-tubulin isotypes was found in parental and resistant cells, with predominant expression of the M40 and beta2 isotypes. Sequence analysis demonstrated acquired mutations in the M40 isotype at nucleotide 810 (T --> G; Phe270 --> Val) in 1A9PTX10 cells and nucleotide 1092 (G --> A; Ala364 --> Thr) in 1A9PTX22 cells. These results identify residues beta270 and beta364 as important modulators of paclitaxel's interaction with tubulin.
These cell lines are owned by the National Cancer Institute/NIH, which has given Cornell permission to distribute them under the Simple Letter Agreement for non-profit research purposes. For a commercial license please contact the NCI Technology transfer office -- contact information is here
- *Licensing
- Brian J. Kellybjk44@cornell.edu212-746-6186
- Country/Region
- USA
