Background: Taxol* is a natural product produced by the Pacific Yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. Taxol's biochemical mode of action has been well studied: it binds to microtubules, stabilizing them and preventing their depolymerization to tubulin subunits. At lower dosage levels, taxol also interferes with the normal dynamics of the tubulin-microtubule equilibrium. This biochemical effect causes taxol's ultimate physiological effect, cell cycle arrest; taxol is thought to block anaphase A of mitosis. Taxol also causes a number of intriguing secondary effects on interphase cells that are poorly understood. We believed that a bio-active fluorescent taxol derivative could be a useful tool in the study of these cellular mechanisms, especially in interphase cells. Results: We have synthesized and characterized a series of stable, fluorescently labeled derivatives of taxol that bind to microtubules and have cytotoxicities similar to that of taxol. Fluorescence microscopy experiments in interphase human foreskin fibroblast (HFF) cells indicate that one of these, a sulforhodamine taxoid, is particularly well suited for optical microscopy. The use of this taxoid in HFF cells revealed a previously undetected localization of taxoids to the nucleolus during interphase. Conclusion: The production of a new fluorescent derivative of taxol provides a useful tool, enabling cellular biologists to study taxol's mechanism of action. It is hoped that this material will prove particularly useful for the study of taxol's effects upon interphase cells.
|Number of pages||11|
|Journal||Chemistry and Biology|
|State||Published - Dec 1996|
Bibliographical noteFunding Information:
We thank Klaus Hahn and Dai Vo for their assistance with cytotoxicity measurements. R.K.G. thanks Anne-Marie Yvon and Jennifer Waters for heluful discussions and suggestions. The work was supported financially by the George Hewitt Foundation for Medical Research (RKG), NSF grant MCB 93-16540 (R.D.S.) and the NIH (K.C.N.). D. Huang and G. Siuzdak are thanked for NMR and mass spectroscopic assistance, respectively.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry