Medical Pharmacology Chapter 33-34: Anticancer Drugs
Natural Products: Microtubule Antagonists
Taxanes represent a group of microtubule-stabilizing agents.9
The initial agent, paclitaxel was found to exhibit anticancer activity in carcinoma cell lines nearly 50 years ago (1971).
Certain other compounds, related to paclitaxel, were derived from Taxus baccata, such as docetaxel.9
Taxane microtubule binding causes mitotic arrest at the G2/M transition resulting in cell death.9
The G2 phase, a second subphase of interphase directly precedes mitosis.
The G2 phase (or Gap 2 phase) follows normal completion of S phase when cellular DNA is replicated.
Prophase onset begins with G2 phase ending.
Prophase is the first phase of mitosis characterized by cellular chromatin condensation into chromosomes.12
The G2/M DNA damage checkpoint prevents mitosis initiation until damage DNA is repaired following replication.
Cells entering mitosis carrying a defective G2/M status will proceed to apoptosis (cell death) following cell division.13
Taxanes may induce cancer cell death by other mechanisms.8
For example, in breast cancer intratumoral paclitaxel levels appear to induce mitotic arrest.
However, at clinical doses paclitaxel promotes abnormal chromosomal segregation which results in daughter cells having abnormal chromosomal numbers thus inducing cell death.
Other anticancer effects associated with taxanes include activation of apoptotic pathways.8
Paclitaxel because of limited aqueous solubility is administered in a solution consisting of 50% ethanol and 50% polyethoxylated castor oil.
Paclitaxel clearance proceeds main by metabolism of utilizing the hepatic microsomal metabolizing system (cytochrome P450 system) relying mainly the cytochrome P450 isoform CYP2C8 and to a lesser degree CYP3A4.1
The inactivating step catalyzed by CYP2C8 results in formation of the mainly inactive metabolite 6-hydroxypaclitaxel.
CYP3A4 catalysis results in the minor metabolite 3'-phenyl-p-hydroxypaclitaxel and dihydroxylated compounds.
Following metabolism by these hepatic cytochrome P450 oxidases clearance proceeds by biliary excretion.8
About 70% of a paclitaxel dose is found in the feces within about five days (parent compound or metabolites).
Clearance of paclitaxel and paclitaxel metabolites by the kidney is very limited.
With respect to pharmacokinetics, extended paclitaxel infusion is characterized by declining plasma concentrations exhibiting a biphasic character.
The initial rapid decline is attributed to drug distribution to peripheral compartments followed by a comparatively slow elimination phase.
Paclitaxel elimination appears best characterized by a three compartment model. 8
Paclitaxel was initially approved for treating ovarian cancer following first-line or subsequent chemotherapy.9
Later, paclitaxel was approved for:
Advanced breast cancer (after anthracycline-based protocols)
Advanced ovarian cancer in a protocol including a platinum-based agent
Second-line AIDS-related Kaposi's sarcoma
Frst-line non-small cell lung cancer treatment (in combination with cisplatin)
In "off-label" settings, paclitaxel is frequently used for treating cancer of:
Head and neck cancer and
Neutropenia: The major toxicity associated with paclitaxel administration is neutropenia observed a week to ten days following administration.8
For a paclitaxel dosing schedule of every three weeks, the neutropenic reaction resolves between week 2 and week 3.
An important factor that appears to correlate with neutropenic severity is the length of time that plasma paclitaxel levels remain above biologically "relevant" levels (0.05-0.1 Ámol/L).
Therefore, neutropenic reactions appear more severe when protocols call for extended, protracted IV infusions.
Myelotoxic chemotherapy administered prior to paclitaxel tends to exacerbate neutropenia severity.
Hypersensitivity: At present, major hypersensitivity reactions to paclitaxel has been reduced to about 1%-3% (by contrast to early trials in which the incidence of significant hypersensitivity responses was about 30%).
Significant hypersensitivity reactions are characterized by symptoms including:
Chest, back, and abdominal pain
These reactions tend to occur soon (within about the first 10 minutes) following initial paclitaxel treatment with complete resolution following treatment discontinuation.
The reduced incidence of hypersensitivity (1%-3%) depends on pretreatment with dexamethasone and antihistamine adminstration.
Minor hypersensitivity reactions (flushing and rash) is an incidence of about 40%. In the context of taxane rechallenge, skin testing along with rapid drug desensitization may be appropriate.8
Bradyarrhythmias have been associated with paclitaxel infusion.
This paclitaxel-induced arrhythmia was noted in about 30% of patients in one clinical trial .
Bradyarrhythmis is generally not considered an indication for discontinuation of paclitaxel, unless hemodynamic effects are noted.
The taxanes in general alter cardiac automaticity and impulse propagation, both of which may be considered as proarrhythmic.8
However, extended treatment with paclitaxel has not been associated with "progressive" cardiac dysfunction. In those patients who may be adversely affected by bradyarrhythmias cardiac monitoring during paclitaxel treatment is likely appropriate.
Patients with A-V conduction abnormalities or ventricular dysfunction may be least likely to tolerate bradyarrhythmia.
Combination of paclitaxel and certain other agents used in cancer treatment may cause a higher likelihood of cardiotoxicity.8
Doxorubicin administered along with paclitaxel is more likely to produce congestive cardiotoxicity compared to doxorubicin alone.
Trastuzumab which is known itself to be cardiotoxic but when given in combination with paclitaxel elevation in likelihood of congestive heart failure (CHF) has been noted.8
Paclitaxel like other taxanes are associated with adverse dermatological effects.8
Paclitaxel and related agents may induce scalp alopecia (reversible) along with facial and body hair loss.
A small percentage of patients experience permanent alopecia.8
Rash and photosensitivity is also been reported. In about 10% of taxane-treated individuals, desquamation and erythema of hands and sometimes feet may occur.
This "hand-foot"syndrome may require steroid cream or oral corticosteroids for management.
High paclitaxel doses or long infusion (96 hour) may induce mucositis.
Paclitaxel is not characterized as a potent vesicant by contrast to vinca alkaloids.8