Update on taxane development: new analogs and new formulations

Abstract

The taxanes (paclitaxel and docetaxel) represent an important class of antineoplastic agents that interfere with microtubule function leading to altered mitosis and cellular death. Paclitaxel (Taxol®) was originally extracted from a yew tree (Taxus spp., Taxaceae) a small slow-growing evergreen, coniferous tree. Due to the initial scarcity of paclitaxel, docetaxel (Taxotere®) a semisynthetic analog of paclitaxel produced from the needles of European yew tree, Taxus baccata was developed. Docetaxel differs from paclitaxel in two positions in its chemical structure and this small alteration makes it more water soluble. Today, paclitaxel and docetaxel are widely prescribed antineoplastic agents for a broad range of malignancies including lung cancer, breast cancer, prostate cancer, Kaposi’s sarcoma, squamous cell carcinoma of the head and neck, gastric cancer, esophageal cancer, bladder cancer, and other carcinomas. Although very active clinically, paclitaxel and docetaxel have several clinical problems including poor drug solubility, serious dose-limiting toxicities such as myelosuppression, peripheral sensory neuropathy, allergic reactions, and eventual development of drug resistance. A number of these side effects have been associated with the solvents used for dilution of these antineoplastic agents: Cremophor EL for paclitaxel and polysorbate 80 for docetaxel. In addition, reports have linked these solvents to the alterations in paclitaxel and docetaxel pharmacokinetic profiles. In this review, we provide preclinical and clinical data on several novel taxanes formulations and analogs which are currently US Food and Drug Administration (FDA)-approved or in clinical development in various solid tumor malignancies. Of the new taxanes nab-paclitaxel and cabazitaxel have enjoyed clinical success and are FDA-approved; while many of the other compounds described in this review are unlikely to be further developed for clinical use in daily practice. Furthermore, the successful clinical emergence of novel nontaxane microtubule-targeting chemotherapy agents such as epothilones and eribulin is liable to further restrict the development of novel taxanes.

Comparison of elicitor-based effects on metabolic responses of Taxus × media hairy roots in perfluorodecalin-supported two-phase culture system

“…Taxane-type compounds are well-known drug agents used in anti-cancer therapies against tumors of ovaries, breast, prostate and lung cancers, Kaposi’s sarcoma, squamous cell carcinoma of head and neck, and many others (Yared and Tkaczuk 2012). Based on constantly rising market-demand for paclitaxel and other taxanes, various biotechnological platforms for their production have been developed (which was extensively discussed in Tabata 2004; Vongpaseuth and Roberts 2007; Frense 2007; Maheshwari et al 2008; Expósito et al 2009; Sabater-Jara et al 2010; Malik et al 2011; Onrubia et al 2013a; Cusido et al 2014).…”

Lignan accumulation in two-phase cultures of Taxus x media hairy roots

“…cell, tissue and organ culture systems have been developed for the production of paclitaxel and other taxanes, an important class of anticancer agents (Yared and Tkaczuk 2012), which was reviewed in detail by Zhong (2002), Tabata (2004Tabata ( , 2006, Maheshwari et al (2008), Expósito et al (2009), Sabater-Jara et al (2010, Malik et al (2011), Onrubia et al (2013). Using various biotechnological methods to enhance paclitaxel production the exceptional progress has been made and finally the process was commercialized (Frense 2007;Expósito et al 2009).…”

Naturally Derived Formulations and Prospects towards Cancer

“…Alkaloids are classified based on their primary metabolite purine alkaloids that are produced from adenine or guanine. Tropane alkaloids (TA) are produced from ornithine, Isoquinoline alakloids (IQA) are produced from tyrosine, Monoterpenoid indole alkaloids (MIA) derived from tryptophan [87]. They are used widely as anti-cancer agents, anti-malarials and analgesic and in the treatment of Parkinson's hypertension and central nervous system disorders [88].…”