A Textbook of Clinical Pharmacology and Therapeutics

Table 48.7: Summary of clinical pharmacology properties of common antimetabolites
patients who are concurrently taking allopurinol. This is
important because allopurinol pretreatment is used to reduce
the risk of acute uric acid nephropathy due to rapid tumour
lysis syndrome in patients with leukaemia.
ANTIBIOTICS
Several antibiotics (e.g. anthracyclines, anthracenediones –
mitoxantrone) are clinically useful antineoplastic agents (see
Table 48.8).
ANTHRACYCLINES
Doxorubicin and daunorubicin are the most widely used
drugs in this group, but newer analogues (e.g. epirubicin,
idarubicin) have reduced hepatic and cardiac toxicity, and
idarubicin may be administered orally.
DOXORUBICIN
Uses
Doxorubicin is a red antibiotic produced by Streptomyces
peucetius. It is the most widely used drug of the anthracycline
group, with proven activity in acute leukaemia, lymphomas,
sarcomas and a wide range of carcinomas. Liposomal formulations
of doxorubicin are available.
DRUGS USED IN CANCER CHEMOTHERAPY 377
Drug Use Mechanism Side effects Additional comments
Cytosine arabinoside Acute leukaemia (AML) Inhibits pyrimidine Nausea and vomiting, Short half-life,
(cytarabine) synthesis and in its bone marrow suppression, continuous infusions or
triphosphate form mucositis, cerebellar daily doses intravenously
inhibits DNA syndrome or subcutaneously, dose
polymerase reduced in renal
dysfunction
Fludarabine Chronic lymphocytic Inhibits purine Myelosuppression, pulmonary Daily i.v. dosing, reduce
leukaemia (CLL) synthesis toxicity, CNS toxicity dose in renal failure
2-Chlorodeoxy CLL and acute Converted to Severe neutropenia i.v. infusion
2-chlorodeoxy leukaemia (ANLL) triphosphate and
adenosine inhibits purine
(cladribine) synthesis
Gemcitabine Pancreatic and lung cancer Cytidine analogue – Haematopoietic suppression, i.v. infusion, inactivated
triphosphate form mucositis, rashes by cytidine deaminase,
incorporated into DNA, active throughout the
blocks DNA synthesis cell cycle, dose reduced in
renal dysfunction
Hydroxyurea CML and myelo- Inhibits ribonucleotide Neutropenia, nausea, Oral dosing, short
proliferative disorders reductase, affecting skin reactions half-life, rapidly
DNA and RNA synthesis reversible toxicity
Mechanism of action
Cytotoxic actions of anthracyclines lead to apoptosis, and
include:
• intercalation between adjacent base pairs in DNA, leading
to fragmentation of DNA and inhibition of DNA repair,
enhanced by DNA topoisomerase II inhibition;
• membrane binding alters membrane function and
contributes to cardiotoxicity;
• free-radical formation also causes cardiotoxicity.
Adverse effects
These include the following:
• cardiotoxicity – acute and chronic (see below);
• bone marrow suppression with neutropenia and
thrombocytopenia;
• alopecia – may be mitigated by scalp cooling;
• nausea and vomiting;
• ‘radiation recall’ – anthracyclines exacerbate or reactivate
radiation dermatitis or pneumonitis;
• extravasation causes severe tissue necrosis.
Anthracycline cardiotoxicity
• Acute: this occurs shortly after administration, with the
development of various dysrhythmias that are occasionally
life-threatening (e.g. ventricular tachycardia, heart block).
These acute effects do not predict chronic toxicity.