Combretastatin A-4 phosphate enhances CPT-11 activity independently of the administration sequence.
We evaluated the effect of different intervals and sequences of the vascular targeting agent combretastatin A-4 disodium phosphate (CA4DP) and CPT-11 administration on tumour growth delay and intratumoral uptake of CPT-11 using a syngeneic rhabdomyosarcoma tumour model. Irrespective of the administration sequence, the combination of CA4DP and CPT-11 significantly increases tumour growth delay in comparison with both drugs alone (P<0.001). Intratumoral CPT-11 concentration generally decreased (up to 5-fold) in the combination groups, while SN-38, the active metabolite of CPT-11, increased up to 9-fold. However, the increased amount of intratumoral SN-38 trapping after CA4DP injection did not correlate with the observed tumour growth delay. In conclusion, CA4DP significantly enhances the antitumour effect of CPT-11, which is not greatly influenced by the administration sequence, and which lacks a correlation with the intratumoral trapping of CPT-11 or SN-38. Mechanisms other than trapping are likely to be involved in the chemosensitising capacity of CA4DP.
Wildiers
H
H
Laboratory of Experimental Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. hans.wildiers@uz.kuleuven.ac.be
Ahmed
B
B
Guetens
G
G
De Boeck
G
G
de Bruijn
E A
EA
Landuyt
W
W
van Oosterom
A T
AT
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D004357:Drug Synergism; D006801:Humans; D000077146:Irinotecan; D009368:Neoplasm Transplantation; D051381:Rats; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D013267:Stilbenes; D000077146:Irinotecan; C058728:fosbretabulin; D002166:Camptothecin