Medical Pharmacology Chapter 33-34: Anticancer Drugs
Natural Products: Microtubule Antagonists
Taxanes:
Docetaxel (Docefrez, Taxotere)9
The initial approved use for docetaxel (1996) focused on metastatic breast cancer patients who had either progressed or relapsed following anthracycline-based protocols.
Later, docetaxel received approval for use, in combination with adriamycin and cyclophosphamide for stage II breast cancer treatment as well as for first-line management of both locally advanced or metastatic disease.
Docetaxel may also be used in:
Nonresectable, either locally advanced or metastatic non-small-cell lung cancer (NSCLC) either after failure or along with cisplatin.
Metastatic castration sensitive or resistant prostate cancer.
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First-line treatment of gastric adenocarcinoma.
Inoperable, locally advanced squamous cell head and neck cancer (combination with cisplatin and 5-fluorouracil)9
Cabazitaxel (Jetava)9
Carbazitaxel is a semisynthetic derivative of a natural taxoid.9
This agent stabilizes the beta-tubulin subunit which inhibits microtubule depolymerization as well as cell division.
As noted earlier for other taxanes, this agent induces cell cycle arrest at G2/M, thus limiting tumor growth.
Carbazitaxel shows antitumor effects against many tumor systems resistant to docetaxel.
Examples include:
Prostrate (2nd line treatment if docetaxel therapy fails)
Melanoma
Mammary
Kidney
Colon
Head and neck
Lung
Gastric.
Docetaxel resistance development is related to the multidrug resistance P-glycoprotein efflux pump for which docetaxel is a substrate.
By contrast, carbazitaxel is only a poor substrate for this efflux pump, thus explaining its usefulness in managing docetaxel-resistant cancers, such as refractory prostate cancer.
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Carbazitaxel exhibits additional differences relative to docetaxel including:9
Access to the brain despite the blood-brain barrier
Improved efficacy compared to docetaxel in tumors for which castration resistance develops due to loss of the retinoblastoma tumor suppressor (RB)
Better cytostatic/cytotoxic responses, compared to docetaxel, independent of androgen receptor status in castrate resistant prostate cancer
Differing molecular actions associated with the distinct gene-expression profile, compared to docetaxel.9