A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

378 CANCER CHEMOTHERAPY
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, t 1/2 20–40 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 t 1/2 9 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
• 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 anthracycline cardiomyopathy
and allow dose intensification are under investigation.
Pharmacokinetics
Doxorubicin is given intravenously. The plasma concentration–time
profile shows a triphasic decline. Doxorubicin does
not enter the central nervous system (CNS). Hepatic extraction
is high, with 40% appearing in the bile (as unchanged
drug and metabolites, e.g doxorubicinol, which has antitumour
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 topotecan are
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 replication
and RNA transcription. Camptothecins stabilize the DNA
topoisomerase I–DNA complex. Cell killing is most likely via
induction of apoptosis (programmed cell death).
Pharmacokinetics
Irinotecan is converted to a more potent cytotoxic metabolite
SN38, which is inactivated by hepatic glucuronidation (via
UGT1A1, see Chapters 5 and 14). Topotecan is hydrolysed by
the blood carboxylesterase and is excreted in the urine, requiring
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 anticholinergics
(for acute diarrhoea) and loperamide, or treatment
with octreotide. Other less severe side effects include
alopecia and fatigue.