The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N.
AQ4N is a bioreductive drug that can significantly enhance the anti-tumour effect of radiation and cyclophosphamide. The aim of this study was to examine the ability of AQ4N to potentiate the anti-tumour effect of cisplatin and to compare it to the chemopotentiation effect of tirapazamine. In the T50/80 murine tumour model, AQ4N (50-100 mg/kg) was administered 30 min, 2.5 or 6 h prior to cisplatin (4 mg/kg or 8 mg/kg); this produced an anti-tumour effect that was approximately 1.5 to 2 times greater than that achieved by a single 4 or 8 mg/kg dose of cisplatin. Tirapazamine (25 mg/kg) administered 2.5 h prior to cisplatin (4 mg/kg) resulted in a small increase in anti-tumour efficacy. AQ4N was also successful in enhancing the anti-tumour effect of cisplatin in the SCCVII and RIF-1 murine tumour models. This resulted in an increased cell kill of greater than 3 logs in both models; this was a greater cell kill than that observed for tirapazamine with cisplatin. Combination of cisplatin with AQ4N or tirapazamine resulted in no additional bone marrow toxicity compared to cisplatin administered alone. In conclusion, AQ4N has the potential to improve the clinical efficacy of cisplatin.
Gallagher
R
R
Radiation Science Research Group, School of Biomedical Sciences, University of Ulster at Jordanstown, Newtownabbey, Co. Antrim, Northern Ireland BT37 0QB.
Hughes
C M
CM
Murray
M M
MM
Friery
O P
OP
Patterson
L H
LH
Hirst
D G
DG
McKeown
S R
SR
D000818:Animals; D000880:Anthraquinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011355:Prodrugs; D014227:Triazines; D000077704:Tirapazamine; C094428:AQ4N; D002945:Cisplatin