Clinical Pharmacology and Therapeutics

DRUGS USED IN CANCER CHEMOTHERAPY 373
doses are used to prepare patients with acute leukaemia or
aplastic anaemia for allogeneic bone marrow transplantation.
Cyclophosphamide is 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
Cyclophosphamide undergoes metabolic activation in the liver
via CYP2B6 and chronic use autoinduces the metabolic activation
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). Cyclophosphamide and 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 cyclophosphamide
and ifosfamide. Mesna is given by intravenous
injection or by mouth. Because mesna is excreted more rapidly
(t 1/2 is 30 minutes) than cyclophosphamide and ifosfamide, 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 cyclophosphamide or
ifosfamide. Urine is monitored for volume, proteinuria and
haematuria. The side effects of mesna include headache, somnolence
and rarely rashes.
Mechanism of action
Mesna protects 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 combination
therapy for Hodgkin’s disease and brain tumours.
Procarbazine is given daily by mouth. The other agent in this
class is dacarbazine.
Mechanism of action
Procarbazine is 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
Procarbazine is well absorbed. The plasma t 1/2 is approximately
ten minutes. Procarbazine and 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
Procarbazine blocks aldehyde dehydrogenase (for comparison
see disulfiram, Chapter 53) and consequently causes
flushing and tachycardia if ethanol is taken concomitantly. It
is also a weak monoamine oxidase inhibitor and may precipitate
a hypertensive crisis with tyramine-containing foods
(Chapter 20).
PLATINUM COMPOUNDS
CISPLATIN
Uses
Cisplatin is an inorganic platinum (II) co-ordination complex
in which two amine (NH 3 ) and two chlorine ligands occupy
cis positions (the trans compound is inactive). Cisplatin is
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 carboplatin and oxaliplatin. The comparative
pharmacology of carboplatin and oxaliplatin is summarized
in Table 48.6.
Mechanism of action
Platinum compound cytotoxicity results from selective inhibition
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;