Potentiation of the antitumour effect of cyclophosphamide in mice by thalidomide.

Abstract:

PURPOSE:Thalidomide has recently shown significant promise in the treatment of some types of cancer, and trials in combination with conventional chemotherapy are being undertaken. We wished to determine whether thalidomide potentiated the effect of cyclophosphamide, a commonly used cytotoxic drug, in a murine tumour model. METHODS:C57Bl/6 mice implanted with subcutaneous Colon 38 tumours were treated with cyclophosphamide alone or together with thalidomide as a single intraperitoneal injection and tumour growth was measured. Concentrations of cyclophosphamide, 4-hydroxycyclophosphamide, 4-ketocyclophosphamide and 2-dechloroethylcyclophosphamide were determined in plasma, liver and tumour tissue using coupled high-performance liquid chromatography-mass spectrometry at different times after treatment. RESULTS:Cyclophosphamide alone (220 mg/kg) induced growth delays of 11-13 days with no cures, whereas cyclophosphamide together with thalidomide (100 mg/kg) cured mice of their tumours. Thalidomide at lower doses (1-20 mg/kg) also potentiated the antitumour effect. Coadministration of thalidomide (100 mg/kg) dramatically decreased the clearance of cyclophosphamide and its metabolites from plasma and tissue, with corresponding increases in the area under the concentration-time curves. The magnitude of the effect was dependent on the dose of thalidomide over the range 1-20 mg/kg with no further effect at a dose of 100 mg/kg. CONCLUSIONS:Coadministration of thalidomide and cyclophosphamide gave markedly greater activity against Colon 38 tumour compared with either drug alone. Investigation of the reason for this effect revealed thalidomide to possess the novel property of dramatically decreasing the clearance of cyclophosphamide and its metabolites.

authors

Ding Q,Kestell P,Baguley BC,Palmer BD,Paxton JW,Muller G,Ching LM

doi

10.1007/s00280-002-0482-y

keywords:

subject

Has Abstract

pub_date

2002-09-01 00:00:00

pages

186-92

issue

3

eissn

0344-5704

issn

1432-0843

journal_volume

50

pub_type

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