Minderman Hans, Brooks Tracy A, O'Loughlin Kieran L, Ojima Iwao, Bernacki Ralph J, Baer Maria R
Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
Cancer Chemother Pharmacol. 2004 May;53(5):363-9. doi: 10.1007/s00280-003-0745-2. Epub 2004 Jan 27.
The taxanes paclitaxel and docetaxel are substrates for P-glycoprotein (Pgp), an ATP-binding cassette (ABC) transport protein associated with multidrug resistance (MDR). In contrast, the synthetic taxane ortataxel (BAY 59-8862, IDN-5109) is effective against Pgp-expressing cells by virtue of modulation of Pgp-mediated transport. The synthetic taxane tRA96023 also modulates Pgp and is noncytotoxic due to removal of the tubulin-binding side chain at the C-13 position of the taxane backbone. We studied the effects of ortataxel and tRA96023 on the other MDR-associated ABC transport proteins, multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP, MXR, ABCG2).
Modulation of mitoxantrone, daunorubicin and doxorubicin retention and cytotoxicity by ortataxel and tRA96023 was studied in established cell lines overexpressing Pgp, MRP-1 and wild type (BCRP(R482)) and mutant (BCRP(R482T)) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively.
Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRP(R482), in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRP(R482) and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRP(R482T).
The synthetic taxane derivatives ortataxel and tRA96023 are broad-spectrum ABC protein modulators. Further studies will seek to identify a noncytotoxic synthetic taxane that modulates Pgp, MRP-1 and BCRP.
紫杉烷类药物紫杉醇和多西他赛是P-糖蛋白（Pgp）的底物，P-糖蛋白是一种与多药耐药性（MDR）相关的ATP结合盒（ABC）转运蛋白。相比之下，合成紫杉烷奥他赛（BAY 59-8862，IDN-5109）通过调节Pgp介导的转运，对表达Pgp的细胞有效。合成紫杉烷tRA96023也可调节Pgp，并且由于紫杉烷骨架C-13位的微管蛋白结合侧链被去除而无细胞毒性。我们研究了奥他赛和tRA96023对其他与MDR相关的ABC转运蛋白，即多药耐药相关蛋白（MRP-1）和乳腺癌耐药蛋白（BCRP，MXR，ABCG2）的影响。
在过表达Pgp、MRP-1以及野生型（BCRP(R482)）和突变型（BCRP(R482T)）BCRP的细胞系中，研究奥他赛和tRA96023对米托蒽醌、柔红霉素和阿霉素潴留及细胞毒性的调节作用，并分别与已确定的Pgp、MRP-1和BCRP特异性调节剂PSC-833、丙磺舒和夫米地尔C的调节作用进行比较。
除Pgp外，奥他赛还能有效调节过表达MRP-1和BCRP(R482)的细胞系中的药物潴留和细胞毒性。tRA96023可调节过表达BCRP(R482)和Pgp的细胞系中的药物潴留和细胞毒性，但不能调节过表达MRP-1的细胞系中的药物潴留和细胞毒性。奥他赛和tRA96023均不能调节BCRP(R482T)。
合成紫杉烷衍生物奥他赛和tRA96023是广谱ABC蛋白调节剂。进一步的研究将致力于寻找一种调节Pgp、MRP-1和BCRP的无细胞毒性的合成紫杉烷。
