Curr. Med. Chem. - Anti-Cancer Agents, 2003, 3, 133-138 133 1568-0118/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd. Second Generation Taxanes: from the Natural Framework to the Challenge of Drug Resistance Cristiano Ferlini 1 , Iwao Ojima 3 , Mariagrazia Distefano 1 , Daniela Gallo 1 , Antonella Riva 2 , Paolo Morazzoni 2 , Ezio Bombardelli 2 , Salvatore Mancuso 1 , and Giovanni Scambia 1, * 1 Laboratory of Antineoplastic Pharmacology, Dept. Obstetrics and Gynaecology, Università Cattolica Sacro Cuore, Rome, Italy, 2 Indena S.p.A., Milan, Italy and 3 Department of Chemistry at SUNY Stony Brook, Stony Brook, NY, USA Abstract: Taxanes represent the most important class of antitumor agents introduced in cancer therapy in the last decade. The first member of the family was paclitaxel, firstly isolated from Taxus Brevifolia and found active as antitumor agent at the end of 60's. In the mid of 90's, a semi-synthetic taxane derived from 10-deacetylbaccatin III was introduced and thereafter named as docetaxel. Taxanes act by inhibiting microtubule dynamics, thereby inducing the arrest in M phase and the consequent activation of the apoptotic program. Since target of taxanes is not directly the genome, they are effective alone or in combination with DNA-damaging drugs in tumors not responding to conventional chemotherapeutics, such as advanced breast and non small cell lung cancer. In this review we will cover the aspects of clinical applications of the currently used taxanes as well as the clinical problems related to their use. Taking into consideration such problems, new taxanes have been developed in order to extend the spectrum of taxane-sensitive tumors and several of them are currently undergoing clinical trials. Among these agents, a newly developed taxane (BAY 59- 8862) appears particularly interesting for the fact that it shows excellent oral bioavailability and activity in tumors with inherent resistance to paclitaxel. HISTORY AND PREHISTORY OF TAXANES Taxanes are natural compounds isolated from American (Taxus brevifolia), Canadian ( Taxus canadiensis), Chinese (Taxus mairei, T. yunnaensis, T. chinensis), Himalayan (Taxus wallichiana) and European (Taxus baccata) yews. The beginning taxane use in folk remedies is lost in the mists of time. However, the toxic properties of the foliage, seeds and bright red fruits (called arils) obtained from Taxus species were known from prehistory and the tree was considered holy for the ancient Celtic, Greek and Roman cultures. The religious significance attributed to Taxus may have occurred because this tree is symbolic of eternal life due to its evergreenness, exceptional longevity and the wood’s resistance to decay. Greeks consecrated yew to Hecate, the guardian of the Underworld, while Celtics planted Taxus baccata in their holiest shrines [1]. These practices were preserved after the conversion to Christianity, perhaps to further legitimise the new religion. Still now, it is possible to find the old European yews near the old churches in England and Ireland. Despite the relevance that yews had in the European tradition, the modern re-discovery of taxanes occurred in US during the 60’s. A natural product screening conducted by the U.S. National Cancer Institute (NCI) in conjunction with the U.S. Department of Agriculture identified extracts of the bark of Taxus Brevifolia that were highly cytotoxic and possessed antitumour activity against a panel of rodent tumors in mice and rats. Wani, and cooworkers isolated the *Address correspondence to this author at the Department of Obstetrics and Gynaecology, Università Cattolica Sacro Cuore, 00168, Rome- Italy; Tel./Fax: 06-35508736; E-mail: giovanni.scambia@libero.it active compound they called ‘Taxol’ from the bark of Taxus brevifolia and found it highly active against a panel of rodent tumors in mice [2]. The chemical name was subsequently changed to “paclitaxel” when Bristol-Myers registered TAXOL  as a brand name worldwide. Interest in this compound waned for nearly a decade until Susan Horwitz and her coworkers discovered that paclitaxel acts as a spindle poison and blocks cell cycle at M phase by inhibiting tubulin depolymerisation [3]. After such findings, the NCI began conducting phase I clinical trials in 1983 and, later, phase II clinical trials against several cancers [4-6]. To further develop this drug (still called taxol), the NCI offered exclusive rights to taxol available to the highest bidder upon consideration of public benefit. This offer was allowed through a recently enacted law in the U.S. Congress (the Hatch-Waxman Act), which provided an avenue by which discoveries in the public domain could become exclusive within the U.S. and commercially valuable if the public would benefit. Four U.S. pharmaceutical companies submitted Cooperative Research and Development Applications (CRADAs) and Bristol-Myers was awarded exclusive rights to market taxol for five years from the New Drug Application (NDA) approval date. After the excellent results obtained in advanced ovary carcinoma at Johns Hopkins Oncology Center, the Federal Drug Administration (FDA) in the U.S. approved the use of TAXOL  in 1992 for the treatment of advanced ovary cancer. The challenge of improving the natural framework of paclitaxel started even before that paclitaxel had finished clinical trials. In the second half of 80’s, researchers at the Rhone Poulenc laboratories developed ‘Taxotére’ (its chemical name is ‘docetaxel’) from the naturally occurring diterpene 10-deacetylbaccatin III, obtained from Taxus