The clinical development of new mitotic inhibitors that stabilize the microtubule.
Microtubule-stabilizing agents are increasingly studied for cancer treatment based largely on the prior success of paclitaxel and docetaxel. In this review, we focus on the clinical development of epothilones and discodermolide, and we discuss salient preclinical and clinical highlights of these two novel natural products. These agents are distinguished by their biochemical features making them poor P-glycoprotein substrates and capable of inducing cytotoxicity in cell lines or in vivo tumor models harboring mutations in tubulin. There is now considerable data regarding the efficacy of the epothilones in human beings and discodermolide holds such promise, as well.
Mani
Sridhar
S
Departments of Medicine and Oncology, Albert Einstein College of Medicine, Montefiore and Jacobi Medical Center, Bronx, NY, USA. smani64@aol.com
Macapinlac
Manuel
M
Goel
Sanjay
S
Verdier-Pinard
Dominik
D
Fojo
Tito
T
Rothenberg
Mace
M
Colevas
Dimitrios
D
D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods / Q000639:trends; D034261:Epothilones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology*; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D015337:Multicenter Studies as Topic; D011753:Pyrones
D000473:Alkanes; D002219:Carbamates; D034261:Epothilones; D007783:Lactones; D008869:Microtubule-Associated Proteins; D011753:Pyrones; C071229:discodermolide