Clinical Pharmacology and Therapeutics

DRUGS USED IN CANCER CHEMOTHERAPY 379
Table 48.9: Summary of the clinical pharmacology of the vinca alkaloids
Drug Route Side effects Pharmacokinetics Additional comments
Vincristine i.v. Vesicant if extravasated, Hepatic metabolism (CYP3A4).
reversible peripheral
t 1/2 85 h, non-linear kinetics
neuropathy, alopecia, SIADH
Vinblastine i.v. Less neurotoxic, but more Hepatic metabolism (CYP3A4) – active
myelo-suppressive than
metabolite, t 1/2 24 h
vincristine, SIADH
Vinorelbine i.v. injection Bone marrow suppression, Hepatic metabolism (CYP3A4), Refractory breast and
or infusion, SIADH t 1/2 30–40 h advanced lung cancer
weekly
SIADH, syndrome of inappropriate antidiuretic hormone.
DNA TOPOISOMERASE II INHIBITORS
A component of the cytotoxic action of anthracyclines (e.g.
doxorubicin, see above) is due to inhibition of DNA topoisomerase
II. Etoposide and teniposide, synthetic derivatives of
podophyllotoxin (which is extracted from the American mandrake
or May apple, and is topically effective against warts),
are also reversible inhibitors of topoisomerase II.
ETOPOSIDE
Uses
Etoposide is one of the most active drugs against small-cell
lung cancer and is used in combination therapy. It is also used
to treat lymphomas, testicular and trophoblastic tumours.
Mechanism of action
DNA topoisomerase II is a nuclear enzyme that binds to and
cleaves both strands of DNA. It is necessary for DNA replication
and RNA transcription. Etoposide stabilizes the topoisomerase
II–DNA complex, leading to apoptosis, as for camptothecins.
Adverse effects
These include the following:
• nausea and vomiting;
• alopecia;
• bone marrow suppression (dose-dependent and reversible).
Pharmacokinetics
Etoposide is given by intravenous injection or orally (50%
bioavailability). It undergoes hepatic metabolism (CYP3A) to
inactive metabolites and a small amount is eliminated in the
urine.
MICROTUBULAR INHIBITORS (VINCA ALKALOIDS
AND TAXANES)
VINCA ALKALOIDS
The Madagascar periwinkle plant was the source of vincristine
and vinblastine, the first agents in this class. Newer synthetic
analogues include vinorelbine. Despite their close structural
relationship, these drugs differ in their clinical spectrum of
activity and toxicity. Vincristine is used in breast cancer, lymphomas
and the initial treatment of acute lymphoblastic
leukaemia. Vinblastine is a component of the cytotoxic combinations
used to treat testicular cancer and Hodgkin’s disease.
Vinorelbine has activity against advanced breast cancer and
non-small-cell lung cancer, where it is often combined with
platinum compounds.
Mechanism of action
Vinca alkaloids bind to β-tubulin, a protein that forms the microtubules
which are essential for the formation of the mitotic spindle.
They prevent β-tubulin polymerizing with α-tubulin and
thus inhibit mitosis. Blockade of microtubular function involved
in neuronal growth and axonal transport probably accounts for
their neurotoxicity. Further important clinical pharmacology of
vinca alkaloids is summarized in Table 48.9.
Key points
Practical ‘do’s and don’ts’ of cytotoxic therapy
• Patients should have recovered fully from the toxic
effects of the previous cycles of cytotoxic therapy
before starting the next treatment cycle.
• Ensure that the dose and schedule of certain drugs is
adjusted for concurrent renal and hepatic impairment.
• Avoid the concomitant use of platelet-inhibiting drugs.
• Haematopoietic growth factors (for myelosuppression)
reduce the duration of the nadir neutropenia, but
should not be prescribed routinely.
TAXANES
PACLITAXEL AND DOCETAXEL
Uses
Paclitaxel (Figure 48.7) was derived from the bark of the Pacific
yew tree and is used as single agent or in combination therapy
for the treatment of a broad range of solid tumours, including carcinoma
of the lung, breast, ovary and cervix and head and neck
tumours, and for lymphomas. Paclitaxel is given intravenously.