A Textbook of Clinical Pharmacology and Therapeutics

DRUGSUSED INCANCERCHEMOTHERAPY 373

doses are used to prepare patients with acute leukaemia or
aplastic anaemia for allogeneic bone marrow transplantation.
Cyclophosphamideis highly effective in treating various
lymphomas, leukaemias and myeloma, but also has some use
in other solid tumours. It is an effective immunosuppressant
(Chapter 50).

Adverse effects

Adverse effects are listed in Table 48.5.

Pharmacokinetics

Cyclophosphamideundergoes metabolic activation in the liver
via CYP2B6 and chronic use autoinduces the metabolic acti-
vation to cytotoxic alkylating metabolites, the most potent of
which is the short-lived phosphoramide mustard. Absorption
from the gastro-intestinal tract is excellent (essentially 100%
bioavailabilty). Cyclophosphamideand its metabolites are
excreted in the urine. Renal excretion of one of its metabolites,
acrolein, causes the haemorrhagic cystitis that accompanies
high-dose therapy.

MESNA (UROPROTECTION AGENT)

Use

Mesna(2-mercaptoethane sulphonate) is solely used to protect
the urinary tract against the urotoxic metabolites of cyclophos-
phamideand ifosfamide.Mesnais given by intravenous
injection or by mouth. Because mesnais excreted more rapidly
(t1/2is 30 minutes) than cyclophosphamideandifosfamide, it
is important that it is given at the initiation of treatment, and
that the dosing interval is no more than four hours. The mesna
dose and schedule vary with the dose of cyclophosphamideor
ifosfamide. Urine is monitored for volume, proteinuria and
haematuria. The side effects of mesnainclude headache, som-
nolence and rarely rashes.

Mechanism of action

Mesnaprotects the uro-epithelium by reacting with acrolein
in the renal tubule to form a stable, non-toxic thioether.

OTHER ALKYLATING AGENTS

PROCARBAZINE

Uses

Procarbazine, a hydrazine, is a component of combina-
tion therapy for Hodgkin’s disease and brain tumours.
Procarbazineis given daily by mouth. The other agent in this
class is dacarbazine.

Mechanism of action

Procarbazineis activated in the liver by CYP450 enzymes to
reactive azoxy compounds that alkylate DNA. In addition, it
methylates DNA and inhibits DNA and protein synthesis.

Adverse effects

These include the following:

• dose-related haematopoietic suppression, leukopenia and
  thrombocytopenia at 10–14 days after treatment;


• nausea and vomiting.

Pharmacokinetics

Procarbazineis well absorbed. The plasma t1/2is approxi-

mately ten minutes. Procarbazineand its metabolites penetrate

the blood–brain barrier. It is converted to active metabolites in

the liver (see above); these are excreted by the kidneys.

Drug interactions

Procarbazineblocks aldehyde dehydrogenase (for compari-

son see disulfiram, Chapter 53) and consequently causes

flushing and tachycardia if ethanolis taken concomitantly. It

is also a weak monoamine oxidase inhibitor and may precipi-

tate a hypertensive crisis with tyramine-containing foods

(Chapter 20).

PLATINUM COMPOUNDS

CISPLATIN

Uses

Cisplatinis an inorganic platinum (II) co-ordination complex

in which two amine (NH 3 ) and two chlorine ligands occupy

cispositions (the transcompound is inactive). Cisplatinis

markedly effective for testicular malignancies and several

other solid tumours, including carcinoma of the ovary, lung,

head and neck, and bladder may also respond well. Cisplatin

is given intravenously in combination with other cytotoxic

agents. Because of the efficacy of platinum compounds and

the toxicity of cisplatin, there has been a search for less toxic

analogues, yielding carboplatinandoxaliplatin. The compara-

tive pharmacology of carboplatinandoxaliplatinis summar-

ized in Table 48.6.

Mechanism of action

Platinum compound cytotoxicity results from selective inhib-

ition of tumour DNA synthesis by the formation of intra- and

inter-strand cross-links at guanine residues in the nucleic acid

backbone. This unwinds and shortens the DNA helix.

Adverse effects

These include the following:

• severe nausea and vomiting;


• nephrotoxicity (especially cisplatin) which is dose-related
  and dose-limiting. Prehydration and fluid diuresis reduce
  the immediate effects, but cumulative and permanent
  damage still occurs;


• hypomagnesaemia and hypokalaemia;


• ototoxicity develops in up to 30% of patients: audiometry
  should be carried out before, during and after treatment;