EVIDENCE FOR A THERAPEUTIC GAIN WHEN AQ4N OR TIRAPAZAMINE IS COMBINEDWITH RADIATION

The use of bioreductive drugs as an adjunct to radiotherapy in the tre atment of cancer is presently being tested in several clinical trials worldwide. We have developed a novel bioreductive compound AQ4N -N-oxi de)ethyl]amino}5,8-dihydroxy-anthracene-9,10 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 bear ing 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 t ested there was a marked increase in anti-tumour efficacy. This was al so found in the single dose regimen for the bioreductive drug tirapaza mine (SR 4233; 3-amino-1,2,Cbenzotriazine-1,4-dioxide). Normal tissue toxicity of drug-radiation combinations was measured by assessing func tion in the eccrine sweat gland of the mouse hind foot. When combined with 10 Gy radiation neither AQ4N nor tirapazamine showed any enhancem ent of functional loss as compared with radiation alone. This was in c ontrast to mitomycin C which had a marked effect on the radiation indu ced functional deficit. In conclusion, in our model, an increase in th e therapeutic index was obtained for radiation treatment when either A Q4N or tirapazamine was administered concurrently.