This is one of the most effective means by which to obtain paclitaxel. However, over-reliance on epigenetic and environmental factors and the slow growth rate of Taxus plants are issues that are still a cause of concern. In , Holton and coworkers successfully synthesized paclitaxel [ 11 ].
However, paclitaxel has a complex molecular structure, and its synthesis is very complicated; the process entails a total of 25—40 steps. Moreover, the commercial production of paclitaxel is not yet feasible, as the reaction conditions are extremely difficult to control, large amounts of toxic products are produced, and the cost of production is extremely high.
In , the first use of chemical semi-synthesis to synthesize paclitaxel from deacetylbaccatin III DAB was reported [ 12 ]. Paclitaxel is produced through chemical semi-synthesis by converting analogs or precursors found in Taxus plants, such as deacetylbaccatin and baccatin III, into paclitaxel. This can be done through the asymmetric epoxidation pathway, asymmetric double hydroxylation reaction, chiral auxiliary strategy, Diels—Alder reaction, or enol imine condensation, among other methods [ 13 , 14 ].
Asymmetric hydroxylation is a chemical reaction in which an olefin is converted into a vicinal diol in the presence of ruthenium tetroxide with a chiral quinine ligand. This reaction typically requires a catalytic amount of citric acid with potassium ferricyanide or N-methylmorpholine as well as an N-oxide regeneration reaction. This method both reduces the level of toxic emissions produced during paclitaxel synthesis and lowers the price. The amounts of paclitaxel found in different parts of Taxus plants, organs, and tissues greatly differ; therefore, explants of Taxus have been cultured in a targeted manner.
In , T. After 2 years, T. Since then, many other Taxus species have been found to grow well, including T. Breeding with high-yield cell lines, using two-stage culture systems, optimizing carbohydrate sources, using pre-feeding strategies, and using fungal culture inducers e.
Taxus cell culture has many advantages. Cultures, unlike wild plants, are unaffected by weather, seasons, and environmental pollution. Culturing Taxus cells also allows for the continuous production of paclitaxel of identical purity, and the cultures are renewable, environmentally friendly, and source-independent. Culturing Taxus cells is a good way to obtain paclitaxel, especially in combination with metabolic and genetic engineering techniques that increase the yield.
However, there are several difficulties associated with culturing Taxus cells. Culturing can be hindered by slow cell growth, stress factor generation, induction difficulties, cell aggregation, increased cellular shear sensitivity, high costs, and unstable yields. Innately undifferentiated cambial meristematic cells CMCs circumvent many of the problems associated with traditional dedifferentiated cells DDCs. These cells may provide a cost-effective and environmentally friendly platform for the sustainable production of a variety of important natural plant products.
In , Stierle and Strobel isolated Taxomyces andreanae , an endophytic fungus, from T. In , Chen also isolated strains of endophytic fungi from the inner bark and branches of T. By thin-layer chromatography and high-performance liquid chromatography analysis of 52 strains of endophytic fungi, it was found that 19 strains can produce taxol and taxane [ 21 ].
There is some evidence that suggests that endophytic fungi can synthesize paclitaxel or paclitaxel analogs and that the microbial synthesis pathway of paclitaxel in endophytic fungi is significantly different from the biosynthesis pathway of paclitaxel in Taxus.
Due to its complexity, the microbial synthesis pathway remains unclear, and some steps in this pathway are different from the known synthetic pathway. Heining and coworkers found that it was not possible to demonstrate the independent synthesis of taxanes in any endophytic fungus, including the first published endophytic fungus, T.
Kusari and coworkers stated that further research on the production of paclitaxel using endophytic fungus biotechnology is needed [ 24 ]. Due to this, the use of endophytic fungi to produce paclitaxel remains a controversial issue.
The genetic properties of endophytic fungi can be altered by physical, chemical, or aerospace techniques, as well as by complex mutagenesis. Protoplast fusion is a technology by which plant cells with distant phylogenetic relationships are integrated, and this technique can be used to achieve long-range hybridization of cells and expand the recombination range of genetic material.
It is a powerful tool in the modification of genetic material, and, as such, it plays a significant role in microbial genetic breeding.
Due to their non-polar membranes, microbial cell protoplasts are more easily fused, allowing the whole cytoplasms and nuclei to fuse with each other while leaving the genetic material intact, allowing for the production of hybrids.
The combination of mutational and protoplast fusion techniques is effective in increasing the amount of paclitaxel produced by endophytic fungi [ 25 ]. The biotechnological screening of high-producing fungal strains is widely used to enhance the yield of filamentous fungi.
It is a valuable tool in the identification of useful genetic material and suitable transformation methods for fungi—particularly endophytic fungi. Advances in DNA recombination technology have resulted in updates to the original metabolic pathway scheme, and the successful expression of the microbial paclitaxel synthesis pathway genes was a breakthrough in improving yield of paclitaxel.
The identification and cloning of key enzyme genes in the microbial paclitaxel synthesis pathway, determination of suitable vectors, and genetic engineering techniques to study the expression of exogenous genes have all contributed to increasing the yield of paclitaxel produced by endophytic fungi. The biosynthetic pathway of paclitaxel includes at least 19 steps. In recent years, scientists have made significant progress in characterizing each step [ 16 ].
In the presence of taxadiene synthase TS , geranylgeranyl pyrophosphate GGPP is cyclized to form taxa-4 5 ,11 12 -diene. The biosynthetic pathway involves enzymes from several different classes that are located in several different cellular compartments, including the plastid, endoplasmic reticulum and cytosol. Modifications, such as acylation and ketonation of baccatin, are carried out. Then, the functional side chain groups are added, ending in the complete synthesis of paclitaxel [ 27 ].
The synthesis pathway is summarized in Fig. Part of the biosynthetic pathway of paclitaxel has been transferred to heterologous expression systems, such as Saccharomyces cerevisiae , Escherichia coli , and certain plants. Now, a multivariate modular approach in E. This approach divides the metabolic pathway of paclitaxel into two modules; in the first, IPP is formed from heterogeneous upstream MEP, and in the second, terpenoids are formed.
The highest recorded concentration of paclitaxel extracted from E. Many enzymes participate in the biosynthetic pathway. Genetic and metabolic engineering can be used to produce these enzymes and obtain higher yields of paclitaxel at the cellular and molecular levels. Due to its complexity, this pathway is not well understood, and further research is needed to fully characterize and describe it.
Recently, advances have been made in our understanding of the possible applications of classic drugs in tumor immunotherapy. Many studies have shown that paclitaxel directly kills tumor cells and regulates various immune cells, such as effector T cells, dendritic cells DCs , natural killer NK cells, regulatory T cells Tregs , and macrophages [ 30 ].
Other chemotherapeutics have similar immunomodulatory properties, such as belinostat [ 31 ], doxorubicin [ 32 ], bleomycin [ 33 ], and bortezomib [ 34 ]. Carboplatin and paclitaxel CP chemotherapy is used as a second-line chemotherapy regimen, and it is commonly used to treat melanoma. Carboplatin down-regulates the T-cell inhibitory molecule programmed death receptor-ligand 2 PD-L2 , which is expressed by DCs and melanoma cells to enhance T-cell activation [ 35 ].
In addition, paclitaxel reduces the number of Tregs, aids in the production of the cytokine interleukin IL , transforms growth factor-beta by Tregs, and stimulates DC-mediated antigen presentation.
A study has shown that the peptide-pulsed DC vaccine in combination with CP therapy DCCP is more likely to be effective than dacarbazine-containing regimens [ 36 ]. Low-level, non-toxic doses of paclitaxel prevent DC precursors from becoming functionally tolerant. Moreover, there is evidence which suggests that low-toxicity doses of paclitaxel inhibit DCs and maintain the response to DC and lipopolysaccharide stimulation [ 37 ].
Mouse myeloma experiments have shown that injection of paclitaxel induces tumor-specific cytotoxic T-lymphocyte responses and prolongs tumor immunity. This is characterized by a pre-existing systemic inflammatory state in which there is an increase in both selected chemokines and advanced B-cell differentiation, both of which are associated with poor prognosis [ 39 ]. Adoptive cellular immunotherapy using DCs and cytokine-induced killer [CIK] cells is a cancer treatment strategy in which tumor cells themselves or killer cells of allogeneic tumors are perfused.
CIK cells have many immune cell properties. For example, the non-major histocompatibility complex of NK cells and the strong antitumor activity of T lymphocytes grant these cells the advantages of rapid proliferation, high killing activity and broad spectrum of tumor killing, and few side effects on bone marrow hematopoiesis.
Paclitaxel inhibits cell mitosis and is a first-line chemotherapy drug. Paclitaxel chemotherapy can increase the rate of apoptosis in tumor cells, release tumor antigens, and enhance the phagocytosis of antigen-presenting cells APCs. APCs are activated to release more pro-inflammatory cytokines, thereby promoting the cross-presentation of APCs with tumor antigens. DCs are a class of heterogeneous cells that play an important regulatory role in cellular and humoral immunity.
It has been clinically confirmed that extensive amplification of DCs results in significant tumor-killing and virus-eliminating effects. Paclitaxel has been shown to inhibit the function of Tregs and reverse the immune escape of tumors. Therefore, paclitaxel combined with immunotherapy could increase the efficacy of treatment. Clinically, paclitaxel combined therapy has been used to treat breast cancer, NSCLC, ovarian cancer, and other malignant tumors.
Clinical studies using paclitaxel—carboplatin—bevacizumab in concert to treat lung cancer are in stage IIIB or stage IV [ 41 ]. One study aimed to evaluate the efficacy and toxicity of liposomal paclitaxel and carboplatin combined with radiotherapy for locally advanced lung squamous cell carcinoma LSCC [ 42 ]. In human cancers, tyrosine kinases of the epidermal growth factor receptor EGFR family are frequently mutated [ 43 ].
Paclitaxel is insoluble in water less than 0. Molecular-targeted therapy has become an attractive anticancer approach. Liposomal paclitaxel and carboplatin combined with radiotherapy have been shown to have significant antitumor effects on LSCC and controllable toxicity. These results indicate that liposomal paclitaxel-based chemoradiotherapy is a safe treatment for locally advanced LSCC, especially in allergic diseases. Mark and colleagues demonstrated that albumin-bound paclitaxel is a safe and effective therapeutic agent for NSCLC [ 50 , 51 ].
Julide and coworkers compared two taxanes in the second-line treatment of NSCLC and found that there was no significant difference in survival, treatment response, or side effects between the two [ 52 ]. However, this combination may result in a higher toxicity profile.
Therefore, the benefits and risks should be considered before making a treatment decision. Little is yet known about this, as immunotherapy is still in the research stage. Paclitaxel acts by interfering with normal microtubule breaks during cell division. Increases in the number of memory T cells may provide an opportunity for developing long-term immune memory, and providing protection for recurrence and metastasis after chemotherapy in patients with ovarian cancer.
Tumors actively recruit and induce Tregs to block innate and adaptive immune initiation, its effects, and the memory response. Paclitaxel and carboplatin have high immunogenicity and induce apoptosis in ovarian cancer cells.
The chemotherapy class taxanes includes the drug Taxotere docetaxel as well as Taxol. This photo contains content that some people may find graphic or disturbing. Tumor cells grow by a process called mitosis, the clinical name for cell division. Taxol is a mitotic inhibitor: It targets rapidly growing cancer cells by getting inside them and attaching to the scaffold-like structures of the cells called microtubules.
In this way, the drug prevents cancer cells from dividing. You will be monitored regularly while you are taking Taxol to assess your response to therapy. Periodic blood work to monitor your complete blood count CBC , as well as the function of other organs such as your kidneys and liver , will also be ordered by your healthcare provider.
Taxol is a clear, colorless fluid that's mixed with Cremophor EL polyoxyethylated castor oil and given by infusion —in other words, it's administered directly into a vein. It is thick and sticky, so a pump is necessary to properly infuse it.
As such, you'll have to go to a hospital or clinic to receive it. It can be given as high-dose chemo, once every two or three weeks, or in low doses once a week. In some cases, Taxol is given slowly over the course of 24 hours.
The amount of Taxol you are prescribed depends on many factors, including your height and weight, your general health, and the type of cancer or condition being treated. A healthcare provider must administer Taxol; if not administered properly, it can cause tissue damage. Medications such as Benadryl diphenhydramine are given before and during infusion of Taxol to reduce the risk of an allergic reaction.
Most people tolerate Taxol well, especially in low doses. It does have side effects, however, which include:. There are ways to prevent some of the problems these side effects can cause. Before you begin treatment with Taxol, your healthcare provider will probably have you take supplements of an amino acid called L-glutamine to reduce your risk of neuropathy.
It has also become increasingly common to receive injections of either Neupogen filgrastim or Neulasta pegfilgrastim to boost white blood cell counts. These must be given at least 24 hours after your chemotherapy infusion has been completed, but early enough to stimulate formation of white blood cells before they hit their lowest point called the nadir. Furthermore, to avoid risky interactions, you will be advised not to drink alcohol while you're being treated with Taxol, and to avoid medications that include aspirin.
Most side effects of chemotherapy resolve rapidly after treatment is completed, although some long-term side effects of chemotherapy may persist. In particular, peripheral neuropathy may sometimes be permanent, and fatigue may sometimes take years to fully improve.
If taken during pregnancy, Taxol can potentially harm a developing fetus. It should not be used by pregnant women; if you are not pregnant and are sexually active, you'll have to use birth control while you are on Taxol. Taxol can be passed through breast milk, so you will not be able to breastfeed. Taxol is associated with future infertility. Talk to your healthcare provider before beginning therapy if you plan to become pregnant.
Since chemotherapy drugs compromise the immune system, some vaccines live vaccines are not recommended while you are undergoing Taxol treatment. Killed vaccines such as the flu shot, but not the oral preparation are, however, often recommended. That said, vaccines may not work as well as usual when you are receiving chemotherapy. You will be susceptible to infections while on Taxol, which can often become very serious—even life-threatening.
This risk may be present even if you are also receiving Neulasta or Neupogen. Call your healthcare provider immediately if you develop a fever, chills, pain, or notice redness or swelling at the infusion site. Some people may have an allergic reaction to Taxol or to Cremophor EL, and therefore should avoid this drug.
As with any form of chemotherapy, Taxol can take a toll on your energy. The following symptoms require medical attention, but are not an emergency. Contact your health care provider within 24 hours of noticing any of the following:.
You will be checked regularly by your health care professional while you are taking Taxol, to monitor side effects and check your response to therapy. Periodic blood work to monitor your complete blood count CBC as well as the function of other organs such as your kidneys and liver will also be ordered by your doctor.
Cancerous tumors are characterized by cell division, which is no longer controlled as it is in normal tissue. Cancerous cells lose this ability.
Cancer cells no longer have the normal checks and balances in place that control and limit cell division. The process of cell division, whether normal or cancerous cells, is through the cell cycle. The cell cycle goes from the resting phase, through active growing phases, and then to mitosis division. The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division.
If the cells are unable to divide, they die. The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink. They also induce cell suicide self-death or apoptosis. Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific.
Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific. The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective.
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