A 95-fold epothilone B (EpoB) -resistant, but not dependent, A549 human lung carcinoma cell line, A549.EpoB40 (EpoB40), has a Gln to Glu mutation at residue 292 that is situated near the M-loop of BI-tubulin. Further selection of this cell line with higher concentrations of EpoB produced A549.EpoB480 (EpoB480), which is f900-fold resistant to EpoB. This cell line, like EpoB40, exhibits cross-resistance to Taxol and extreme sensitivity to vinblastine, but in contrast to EpoB40 it is unusually dependent on EpoB, requiring a minimum of 125 nmol/L EpoB to maintain normal growth. Sequence analysis of the Btubulin and KA1-tubulin genes in EpoB480 showed that, in addition to the B292 mutation, B60 was mutated from Val to Phe and A195 was mutated from Leu to Met. Mass spectrometry indicated that both the Val 60 Phe and Leu 195 Met mutations in BI-and KA1-tubulin, respectively, were expressed at the protein level. Molecular modeling indicated that B60 is located at the end of the H1-S2 loop that has been implicated as a principal partner of the M-loop for contacts between protofilaments. A mutation at B60 could inhibit the lateral contacts between protofilaments, thereby destabilizing microtubules. A195 is located at the external surface of the microtubule that has been proposed as the domain that interacts with a variety of endogenous proteins, such as stathmin and microtubule-associated protein 4. A mutation at A195 could modulate the interactions between tubulin and regulatory proteins. We propose that the BVal 60 Phe mutation plays a critical role in the drug-dependent phenotype of EpoB480 cells. [Mol Cancer Ther 2005; 4(6):987 -95]
Paclitaxel (Taxol) and docetaxel (Taxotère) are currently two of the most important anticancer drugs in cancer chemotherapy. However, clinical treatment with these taxane agents often encounters undesirable side effects and multidrug resistance (MDR) caused by overexpression of P-glycoprotein (Pgp). Photoaffinity labeling of Pgp using photoreactive radiolabeled paclitaxel analogs along with molecular modeling has revealed a unique binding region for paclitaxel on the C-terminal half of Pgp. Highly efficient taxane-based MDR reversal agents (TRAs) have been developed. Extensive structure-activity relationship (SAR) studies have led to the development of new generation taxanes that possess 2-3 orders of magnitude higher potencies against human cancer cell lines expressing the MDR phenotype. One of these taxanes, SB-T-1 10131 (IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines as well as human tumor xenografts in mice. This taxane is orally active with excellent bioavailability, and is currently undergoing phase II human clinical trials. Novel taxane-antibody immunoconjugates have shown very promising results for tumor-specific delivery and release of an extremely cytotoxic taxane, wherein epidermal growth factor receptor is used as the specific antigen on the tumor surface of human squamous cancer xenograft in SCID mice.
Summary P-glycoprotein (P-GP)-based multidrug resistance (MDR) and
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