Medical Pharmacology Chapter 33-34: Anticancer Drugs
Natural Products: Microtubule Antagonists
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.
First-line treatment of gastric adenocarcinoma.
Inoperable, locally advanced squamous cell head and neck cancer (combination with cisplatin and 5-fluorouracil)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.
Prostrate (2nd line treatment if docetaxel therapy fails)
Head and neck
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.
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