A Textbook of Clinical Pharmacology and Therapeutics

DRUGSUSED INCANCERCHEMOTHERAPY 379

DNA TOPOISOMERASE II INHIBITORS

A component of the cytotoxic action of anthracyclines (e.g.
doxorubicin, see above) is due to inhibition of DNA topoiso-
merase II. Etoposideandteniposide,synthetic derivatives of
podophyllotoxin (which is extracted from the American man-
drake or May apple, and is topically effective against warts),
are also reversible inhibitors of topoisomerase II.

ETOPOSIDE

Uses

Etoposideis 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. Etoposidestabilizes 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

Etoposideis 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
andvinblastine, 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. Vincristineis used in breast cancer, lymph-

omas and the initial treatment of acute lymphoblastic

leukaemia.Vinblastineis a component of the cytotoxic combin-

ations used to treat testicular cancer and Hodgkin’s disease.

Vinorelbinehas 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 micro-

tubules which are essential for the formation of the mitotic spin-

dle. 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.

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 t1/285 h, non-linear kinetics

neuropathy, alopecia, SIADH

Vinblastine i.v. Less neurotoxic, but more Hepatic metabolism (CYP3A4) – active

myelo-suppressive than metabolite, t1/224 h

vincristine, SIADH

Vinorelbine i.v. injection Bone marrow suppression, Hepatic metabolism (CYP3A4), Refractory breast and

or infusion, SIADH t1/230–40 h advanced lung cancer

weekly

SIADH, syndrome of inappropriate antidiuretic hormone.

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 car-

cinoma of the lung, breast, ovary and cervix and head and neck

tumours, and for lymphomas. Paclitaxelis given intravenously.