A Textbook of Clinical Pharmacology and Therapeutics

DRUGSUSED INCANCERCHEMOTHERAPY 377

patients who are concurrently taking allopurinol. This is
important because allopurinolpretreatment 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

Doxorubicinanddaunorubicinare the most widely used
drugs in this group, but newer analogues (e.g. epirubicin,
idarubicin) have reduced hepatic and cardiac toxicity, and
idarubicinmay be administered orally.

DOXORUBICIN

Uses

Doxorubicinis 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 formu-
lations of doxorubicinare available.

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.

Table 48.7:Summary of clinical pharmacology properties of common antimetabolites

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