Fluorescent taxoids.
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.


CONCLUSIONS
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. Although in common usage for the last 20 years, Taxol is now a registered trademark of Bristol-Myers Squibb. The copyright of Bristol-Myers Squibb is recognized when Taxol or taxol is used in this article.
Guy
R
R
Department of Chemistry, The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Scott
Z
Z
Sloboda
R
R
Nicolaou
K
K
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000633:toxicity; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D012995:Solubility; D013053:Spectrophotometry; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D014404:Tubulin; D017239:Paclitaxel