This document discusses taxol and its derivatives used in cancer therapy. It provides background on the isolation of taxol from yew trees and the development of docetaxel as a semi-synthetic analogue. It describes the mechanism of action of taxanes as microtubule stabilizers, inhibiting cell division. Side effects and clinical uses of paclitaxel and docetaxel are outlined. Factors complicating treatment include drug resistance, debilitating side effects, and high costs.
3. INTRODUCTION
• Isolated from the bark of the Western yew tree in 1971, Taxol/Paclitaxel became useful in
the treatment of cancer when it was discovered that it possessed the unique ability to
promote the formation of microtubules by binding to their B-tubulin subunit and
antagonizing their disassembly.
• However, the amount of paclitaxel in yew bark was small, and extracting it was a
complicated and expensive process. In addition, bark collection was restricted because
the Western yew is a limited resource located in forests that are home to the
endangered spotted owl.
• Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the
treatment of several types of cancer, including mammary, prostate, ovarian and non-
small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of
tumor.
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4. Mechanism of Action
• Taxanes stabilize microtubules by
enhancing their polymerization and
inhibiting depolymerization.
• Microtubule dynamics are crucial to
mitotic spindle formation and
function; therefore, cells exposed to
taxanes are unable to undergo
chromosomal separation during
mitosis, become arrested in the G2/M
phases of the cell cycle, and are
subsequently targeted for apoptosis.
Pacltaxel
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6. Side Effects of Taxol
Common side effects include:
• nausea and vomiting
• loss of appetite
• change in taste
• thinned or brittle hair
• Joint pains more than 3 days
• color changes in nails
• tingling in the hands or toes
More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at
the injection site, change in normal bowel habits for more than two days, fever, chills,
cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe
exhaustion, skin rash, facial flushing , female infertility by ovarian damage, etc.
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7. Paclitaxel/Taxol In Cancer Therapy
1. Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer
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12. Docetaxel
• Docetaxel is of the chemotherapy drug
class; taxane, and is a semi-synthetic analogue of
Paclitaxel (Taxol) Due to scarcity of paclitaxel,
extensive research was carried out leading to the
formulation of docetaxel – an esterified product of
10-deacetyl baccatin III, which is extracted from
the renewable and more readily available leaves of
the European yew tree.
• Docetaxel differs from paclitaxel at two positions in
its chemical structure. It has a hydroxyl functional
group on carbon 10, whereas paclitaxel has an
acetate ester, and a tert-butyl carbamate ester
exists on the phenyl propionate side chain instead
of the benzamide in paclitaxel. The carbon 10
functional group change causes docetaxel to be
more water-soluble than paclitaxel.
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Docetaxel
13. Contd..
• While it is paclitaxel’s structural analog, it is much more potent in terms of potential
patient toxicity.
• It acts to kill cancer cells in the same way as paclitaxel.
• Useful in the treatment of: mainly prostate cancer, but also breast, ovarian and lung
cancer.
• Must be co-administered with dexamethasone to prevent progressive, often disabling,
fluid retention in the peripheries, lungs and abdomen.
• Side effects are more severe but more short-lived than Taxol and include: leukopenia,
peripheral edema, neutropenia.
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14. Drug Interactions of Docetaxel
Drug interacting with docetaxel Adverse effects from interaction
Cisplatin Increased risk of delayed neuropathy
Cyclosporine, dalfopristin, erythromycin, itraconazole,
ketoconazole, quinupristin, terfenadine,
troleandomycin
Increased risk of docetaxel toxicity including some or
all of the following: anemia, leucopoenia,
thrombocytopenia, fever, diarrhoea
Doxorubicin hydrochloride Cholestatic jaundice and pseudomembranous colitis
Doxorubicin hydrochloride liposome Increased doxorubicin exposure
Vaccinations for Bacillus of Calmette and Guerin,
measles, mumps, poliovirus, rotavirus, rubella,
smallpox, typhoid, varicella, yellow fever
Increased risk of infection by live vaccine
Thalidomide Increased risk of venous thromboembolism
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15. Taxanes: Complicating Factors
• Resistance to taxanes is a complicating factor to successful treatment and is often
associated with increased expression of the mdr-1 gene and its product, the P-
glycoprotein.
• Other resistant cells have B-tubulin mutations which inhibit the binding of
taxanes to the correct place on the microtubules; this renders the drug
ineffective. In addition, some resistant cells also display increased aurora kinase,
an enzyme that promotes completion of mitosis. Some cells display a heightened
amount of survivin, an anti-apoptotic factor.
• Side effects can be debilitating.
• These drugs are very expensive and must be administered in large amounts at
once due to the fact that much of the drug is excreted in the urine or allocated to
the plasma. This large administration volume cannot be tolerated in many
patients.
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16. References
• Chowdhury, P., Nagesh, P. K. B., Khan, S., Hafeez, B. B., Chauhan, S. C., Jaggi, M., & Yallapu, M. M.
(2018). Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer. Acta
Pharmaceutica Sinica B, 8(4), 602–614. doi:10.1016/j.apsb.2017.10.004
• Chowdhury, P., Nagesh, P. K. B., Hatami, E., Wagh, S., Dan, N., Tripathi, M. K., … Yallapu, M. M. (2018).
Tannic acid-inspired paclitaxel nanoparticles for enhanced anticancer effects in breast cancer cells.
Journal of Colloid and Interface Science. doi:10.1016/j.jcis.2018.09.072
• Chung, H.-J., Kim, H.-J., & Hong, S.-T. (2019). Tumor-specific delivery of a paclitaxel-loading HSA-haemin
nanoparticle for cancer treatment. Nanomedicine: Nanotechnology, Biology and Medicine, 102089.
doi:10.1016/j.nano.2019.102089
• Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: evaluation
of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic
cancer. BMC Cancer 2008;8:82.
• Von Hoff DD, Thomas E, Arena FP, Chiorean EG, Infante JR, Moore M. Randomized phase III study of
weekly nab-paclitaxel plus gemcitabine vs. gemcitabine alone in patients with metastatic
adenocarcinoma of the pancreas (MPACT). J Clin Oncol; 30: 2012
• Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN. The taxoids: paclitaxel (Taxol) and docetaxel
(Taxotere). Cancer Treat Rev 1993;19:351–86.
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