Potentiation of the antitumour effect of cyclophosphamide in mice by thalidomide.
OBJECTIVE
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.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Qi
Q
Ding
Philip
P
Kestell
Bruce C
BC
Baguley
Brian D
BD
Palmer
James W
JW
Paxton
George
G
Muller
Lai-Ming
LM
Ching
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental
D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide