Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation

The use of bioreductive drugs as an adjunct to radiotherapy in the treatment of cancer is presently being tested in several clinical trials worldwide. We have developed a novel bioreductive compound AQ4N (1,4-bis-¿[2-(dimethylamino-N-oxide)ethyl]amino¿ 5,8-dihydroxy-anthracene-9, 10-dione) which can be reduced to a stable cytotoxic agent AQ4. The anti-tumour efficacy of AQ4N has been studied using male BDF mice bearing the T50/80 tumour. AQ4N in combination with single dose radiation (12 Gy) and also with two fractionated radiation regimens was examined (5 x 3 Gy, one fraction per day; or 10 x 2 Gy fractions, 2 fractions per day with an 8 h interval). Results show that in all combinations tested there was a marked increase in anti-tumour efficacy. This was also found in the single dose regimen for the bioreductive drug tirapazamine (SR 4233; 3-amino-1,2,4-benzotriazine-1, 4-dioxide). Normal tissue toxicity of drug-radiation combinations was measured by assessing function in the eccrine sweat gland of the mouse hind foot. When combined with 10 Gy radiation neither AQ4N nor tirapazamine showed any enhancement of functional loss as compared with radiation alone. This was in contrast to mitomycin C which had a marked effect on the radiation induced functional deficit. In conclusion, in our model, an increase in the therapeutic index was obtained for radiation treatment when either AQ4N or tirapazamine was administered concurrently.