Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine.
The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50-150 mg kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect equivalent to a single 200 mg kg 1 dose of cyclophosphamide. Tirapazamine (25 mg kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect equivalent to a single 150 mg kg(-1) dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50-200 mg kg(-1)); AQ4N (50-200 mg kg(-1)) produced a more effective combination than tirapazamine (12.5-50 mg kg(-1)). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg(-1)) 6 h prior to cyclophosphamide (100 mg k(-1)) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg(-1)).
Friery
O P
OP
Radiation Science Research Group, School of Biomedical Sciences, University of Ulster at Jordanstown, Antrim, Northern Ireland, UK.
Gallagher
R
R
Murray
M M
MM
Hughes
C M
CM
Galligan
E S
ES
McIntyre
I A
IA
Patterson
L H
LH
Hirst
D G
DG
McKeown
S R
SR
D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D011355:Prodrugs / Q000627:therapeutic use; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000627:therapeutic use*
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011355:Prodrugs; D014227:Triazines; D000077704:Tirapazamine; C094428:AQ4N; D003520:Cyclophosphamide