A Textbook of Clinical Pharmacology and Therapeutics

378 CANCER CHEMOTHERAPY

• Chronic: cardiomyopathy, leading to death in up to 60% of
  those who develop signs of congestive cardiac failure. It is
  determined by the cumulative dose. Risk factors for
  cardiomyopathy include prior mediastinal irradiation, age
  over 70 years and pre-existing cardiovascular disease.
  Agents to protect against anthracyclinecardiomyopathy
  and allow dose intensification are under investigation.

Pharmacokinetics

Doxorubicinis given intravenously. The plasma concentra-
tion–time profile shows a triphasic decline. Doxorubicindoes
not enter the central nervous system (CNS). Hepatic extrac-
tion is high, with 40% appearing in the bile (as unchanged
drug and metabolites, e.g doxorubicinol, which has anti-
tumour activity). Renal excretion accounts for less than 15% of
a dose. Dose reduction is recommended in patients with liver
disease, particularly if accompanied by hyperbilirubinaemia.

TOPOISOMERASE INHIBITORS

DNA TOPOISOMERASE I INHIBITORS

CAMPTOTHECINS

Camptothecins are alkaloids derived from a Chinese tree
Camptotheca acuminata.Irinotecan(CPT-11) and topotecanare
available for clinical use.

Uses

The camptothecins are active against a broad range of tumours,

including carcinomas of the colon, lung and cervix. They are

given intravenously.

Mechanism of action

Camptothecins act during the S-phase of the cell cycle. DNA

topoisomerase I is necessary for unwinding DNA for replica-

tion and RNA transcription. Camptothecins stabilize the DNA

topoisomerase I–DNA complex. Cell killing is most likely via

induction of apoptosis (programmed cell death).

Pharmacokinetics

Irinotecanis converted to a more potent cytotoxic metabolite

SN38, which is inactivated by hepatic glucuronidation (via

UGT1A1, see Chapters 5 and 14). Topotecanis hydrolysed by

the blood carboxylesterase and is excreted in the urine, requir-

ing dose reduction in renal impairment.

Adverse effects

The principal adverse effects are myelosuppression, acute and

delayed diarrhoea (particularly irinotecan), which can be

dose limiting and require prophylactic therapy with anti-

cholinergics (for acute diarrhoea) and loperamide, or treat-

ment with octreotide. Other less severe side effects include

alopecia and fatigue.

Table 48.8:Clinical pharmacology of antitumour antibiotics

Drug Indications and route Side effects Pharmacokinetics Additional comments

of administration

Mitoxantrone Advanced breast cancer; Nausea and vomiting, Hepatic metabolism, Intercalates into DNA

leukaemia and lymphoma, stomatitis, low incidence extensively bound to and inhibits DNA

i.v. dosing of cardiotoxicity ( 3%) tissues, t1/220–40 h topoisomerase II

Mitomycin C Gastro-intestinal tumours, Vesicant cumulative Pharmacokinetics not It is a prodrug –

advanced breast cancer, toxicity, myelosuppression, affected by renal or transformed to an

head and neck tumours. interstitial alveolitis, hepatic function alkylating

Intravenous infusions haemolytic-uraemic intermediate; alkylates

syndrome guanine residues (10%

of its adducts form

inter-strand breaks);

synergistic with 5-FU

and radiotherapy

Bleomycin Lymphomas, testicular Fever, shivering, mouth 50–70% of a dose is It causes single- and

carcinoma and ulcers, skin erythema – excreted in the urine, double-strand breaks

squamous cell pigmentation, interstitial t1/29 h; prolonged in DNA. Arrests

in renal dysfunction cells in G 2 /M phase

tumours, i.v. dosing lung disease if dose Also metabolized by

>300 units peptidases; skin and

lung have high drug

concentrations as they

lack peptidases