What Is a Taxane?

Taxanes are a series of derivatives that are antitumor active ingredients isolated from plants and are structurally modified to synthesize the compounds of the active ingredients that have been obtained. Taxane drugs mainly include paclitaxel, docetaxel, and derivatives with a taxane skeleton structure.

Taxanes are a series of derivatives that are antitumor active ingredients isolated from plants and are structurally modified to synthesize the compounds of the active ingredients that have been obtained. Taxane drugs mainly include paclitaxel, docetaxel, and derivatives with a taxane skeleton structure.

Taxanes are a series of derivatives that are antitumor active ingredients isolated from plants and are structurally modified to synthesize the compounds of the active ingredients that have been obtained. Taxane drugs mainly include paclitaxel, docetaxel, and derivatives with a taxane skeleton structure. The natural product paclitaxel is an effective anticancer component extracted from the plant bark Taxus brevifolia Nutt. The docetaxel is semi-synthesized from the precursors extracted from the needles of Taxus brevifolia T. baccata L. Product.

1. Taxanes 1. Research History

In 1963, the National Cancer Institute (NCI) screened the bark extract of Taxus brevifolia (a species of American yew) for its active cytotoxicity; in 1967, Dr. Wall An antitumor active ingredient, paclitaxel (Taxol), was isolated from the extract, and the chemical structure of paclitaxel was confirmed in 1971. Experimental studies have shown that paclitaxel has significant anti-breast cancer and melanoma activity. In 1977, NCI conducted extensive preclinical research on paclitaxel. In 1979, Horwitz reported that paclitaxel's unique mechanism of action is to promote the irreversible aggregation and synthesis of tubulin in microtubules, hinder the normal dynamic regeneration of microtubule bundles, and prevent cells from forming normal mitotic spindles during mitosis, thereby inhibiting Cell division and proliferation.

2. Taxanes 2. Status and Problems

In 1981, paclitaxel underwent a phase I clinical trial, entered phase II clinical trials in 1985, and was approved by the US FDA for the treatment of drug-dependent ovarian cancer in 1992. In 1994, the scope of clinical application was expanded to treat breast cancer. In 1996, the FDA approved its semi-synthetic derivative docetaxel (Taxotere) for the treatment of breast cancer. Since then, the clinical use and application of paclitaxel have gradually expanded, with sales of US $ 400 million in 1994 and US $ 1.6 billion in 2000, and are widely used in lung cancer, head and neck cancer, prostate cancer, cervical cancer, and AIDS. Related Kaposi's sarcomas and other treatments. Paclitaxel is by far the most successful anticancer drug. In the past two decades, no other natural product has attracted so much attention and so many participating disciplines.

The development of paclitaxel is plagued by two main problems: First, the natural source is limited; the medicinal plant Taxus has a narrow global distribution and extremely slow growth, and paclitaxel mainly exists in the bark. There are many difficulties in such links. Therefore, it is very easy to cause disorderly logging driven by huge benefits, leading to environmental damage and species extinction. The second is that paclitaxel has very low water solubility. As an anti-tumor drug, its clinical effectiveness has promoted its extensive research, but its extremely low water solubility (0.25 g / mL) is also a great obstacle to the clinical application of paclitaxel. Clinically used paclitaxel is dissolved in ethanol containing Cremophor EL, a polyethoxylated castor oil. This excipient brings a series of side effects to clinical patients. Although the above two factors have affected and limited the widespread clinical application of paclitaxel to some extent, they have also encouraged pharmacists to explore effective ways to improve the lack of paclitaxel, or to find, discover and study new resistance based on this Cancer drugs have greatly promoted the research and development of taxane derivatives in phytochemistry and medicinal chemistry.

3. FDA Taxanes 3. FDA-approved taxanes

3.1 Taxol

Taxol (paclitaxel) was developed by Bristol-Myers Squibb and approved for marketing in 1992. It is the first taxane antitumor drug approved for marketing. Its main indications include non-small cell lung cancer, breast cancer and ovarian cancer. Due to the very poor water solubility of paclitaxel (the solubility is only 0.25 g / ml), a 1: 1 mixture of polyoxyethylene castor oil and absolute ethanol was used as a co-solvent in the preparation. The mass concentration of paclitaxel was 6 mg / ml, which was available before use. Normal saline or 5% glucose injection was diluted to the final administered volume. The co-solvent used can cause a variety of adverse reactions, more specifically including allergic reactions and neurotoxicity. In addition, the small particles of polyoxyethylene castor oil formed in the blood circulation can encapsulate the paclitaxel molecules, preventing the drug from working.

3.2 Taxotere

Tysodi (Docetaxel Injection), produced by Sanofi-Aventis, was approved for marketing in 1996. It is a semi-synthetic taxane antitumor drug. It is prepared by dissolving the drug in surfactant Tween-80 (40g / L). It is diluted with 13% ethanol aqueous solution to 10g / L before clinical use, and further diluted with 5% glucose solution during administration. Make the final drug mass concentration 0.3-0.9mg / L. Because Tween-80 is hemolytic and highly viscous, a significant allergic reaction may still occur after injection.

1.3 Abraxane

Abraxane injection suspension is produced by American Abolis Scientific Corporation and approved for marketing in 2005. Because it does not add polyoxyethylene castor oil and Tween-80, it effectively avoids allergic reactions caused by surfactants; Abraxane is Paclitaxel albumin nanoparticles have been approved for metastatic breast cancer. The drug uses a nanoparticle albumin coating technology with a targeting effect, which combines biocompatible proteins with drugs to form amorphous nano-sized drug-containing microparticles. Nanoparticles play a role of "transporter" in it, which can be used as a carrier to transport drugs with hydrophobic properties like paclitaxel in the body, and use the attractiveness of tumors to form albumin to target.

Taxane outlook

With the development of natural product chemical component isolation and identification technology, by expanding the scope of plant variety screening, it is possible to find new plant effective components, solve the problem of lack of paclitaxel resources, and hope to find new anti-tumor drugs from it, through semi-synthesis And chemical structure modification and transformation methods can improve the water solubility of paclitaxel, improve biological activity, increase anti-tumor selectivity, and reduce toxic and side effects. It is believed that with the deepening and development of taxane compounds, more efficient and low-toxic new taxane drugs will be marketed and entered into clinical applications.