Effects of orally active taxanes on P-glycoprotein modulation and colon and breast carcinoma drug resistance
Effects of orally active taxanes on P-glycoprotein modulation and colon and breast carcinoma drug resistance
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DOI：
10.1093/jnci/93.16.1234
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发表时间：
2001-08-15
影响因子：
10.3
通讯作者：
Bernacki, RJ
中科院分区：
文献类型：
--
作者：
Vredenburg, MR;Ojima, I;Bernacki, RJ
Background. The taxane paclitaxel (Taxol) is often of limited efficacy in chemotherapeutic regimens because some cancer cells express high levels of the efflux pump, P-glycoprotein (Pgp), which removes the drug from the cells. The orally active paclitaxel analog IDN-5109 has been reported to overcome Pgp-mediated drug resistance. We tested whether IDN-5109 acts by modulating Pgp activity. Methods: Human MDA435/LCC6(mdr1) and MDA435/LCC6 breast carcinoma cells, which express and do not express Pgp, respectively, were incubated with [H-3]IDN-5109 and paclitaxel to determine intracellular drug accumulation. Flow cytometry was used to analyze intracellular retention of two Pgp substrates, rhodamine 123 (Rh-123) and doxorubicin, in both breast carcinoma cell lines and in human colon carcinoma cells (SW-620, DLD1, and HCT-15, whose Pgp levels vary) treated with different taxanes. The effects of [H-3]IDN-5109 and paclitaxel on tumor growth in vivo were studied with the use of tumors established through xenografts of Pgp-expressing SW-620 and DLD1 cells in severe combined immunodeficiency mice. All statistical tests were two-sided. Results: Pgp-expressing cells treated with IDN-5109 or with the taxane-based drug resistance reversal agent tRA96023, which blocks Pgp activity, retained 8.1- and 9.4-fold more Rh-123 (P =.0001), respectively, and 1.7- and 1.9-fold more doxorubicin (P =.001), respectively, than cells treated with paclitaxel. Non-Pgp-expressing cells treated similarly demonstrated no increased retention of either substrate. MDA435/ LCC6(mdr1) cells retained 5.3-fold more [H-3]IDN-5109 than [H-3]paclitaxel after 2 hours (P =.01). IDN-5109 showed statistically significantly higher tumor growth inhibition than paclitaxel. against the SW-620 xenograft (P =.003). Conclusions: IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.
