AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo.
AQ4N (1,4-bis([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxy- anthracene-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reduction, forms a stable DNA affinic cytotoxic compound AQ4. The in vivo anti-tumour efficacy of AQ4N was investigated in B6D2F1 mice bearing the T50/80 mammary carcinoma. The effect of the drug was evaluated in combination with hypobaric hypoxia and with radiation (single and multiple fractions). Systemic toxicity was assessed by weight loss post treatment. This was low for AQ4N and was less than that obtained with the bioreductive drugs, RSU 1069 (1-[3-aziridinyl-2-hydroxypropyl]-2-nitroimidazole) and SR 4233 (Tirapazamine, 3-amino-1,2,4-benzotriazine-1,4-dioxide). The anti-tumour effect of AQ4N was potentiated in vivo by combination with hypobaric hypoxia with a dose enhancement ratio of 5.1. This is consistent with the proposal that AQ4N was reduced in vivo to AQ4, resulting in enhanced anti-tumour toxicity. When AQ4N (200 mg kg-1) was combined with single dose radiation (12 Gy) the drug was shown to have an additive interaction with radiation. This was obtained even if the drug was administered from 4 days before to 6 h after radiation treatment. Equivalent anti-tumour activity was also shown when both AQ4N (200 mg kg-1) and radiation (5 x 3 Gy) were administered in fractionated schedules. In conclusion, AQ4N shows significant potential as a bioreductive drug for combination with fractionated radiotherapy.
McKeown
S R
SR
School of Biomedical Sciences, University of Ulster at Jordanstown, UK.
Hejmadi
M V
MV
McIntyre
I A
IA
McAleer
J J
JJ
Patterson
L H
LH
D000818:Animals; D000880:Anthraquinones / Q000627:therapeutic use* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D015687:Cell Hypoxia; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D051379:Mice
D000880:Anthraquinones; D000970:Antineoplastic Agents; C094428:AQ4N