Microtubule active taxanes inhibit polycystic kidney disease progression in cpk mice.
Homozygous cpk/cpk mice develop polycystic kidney disease and die of uremia between the fourth and fifth weeks of age. Cpk/cpk mice treated weekly with paclitaxel (Taxol) can live to over six months of age. This dramatic moderation of polycystic kidney disease progression has been postulated to be a result of paclitaxel's ability to stabilize microtubules. In this study, the ability of taxanes with differing abilities to promote spontaneous in vitro assembly of tubulin dimers into microtubules were tested for their ability to inhibit the progression of polycystic kidney disease in polycystic cpk/cpk mice. We found that taxanes that are active in promoting microtubule assembly, including paclitaxel, 10-deactyl-taxol and cephalomannine increased the survival of polycystic cpk/cpk mice significantly longer than control animals. In contrast, the microtubule inactive taxane baccatin-III has no effect on the progression of renal failure in cpk/cpk mice. We conclude that the ability to promote microtubule assembly may be necessary for paclitaxel and related taxanes to modulate the progression of polycystic kidney progression in cpk/cpk mice.
Woo
D D
DD
dwoo@med1.medsch.ucla.edu
Tabancay
A P
AP
Wang
C J
CJ
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D043823:Taxoids
D000470:Alkaloids; D043823:Taxoids; C073950:baccatin III; C056348:cephalomannine; C031494:10-deacetyltaxol; D017239:Paclitaxel