EFFECT OF INTRA-PERITONEAL FLUDARABINE ON RAT SPINAL-CORD TOLERANCE TO FRACTIONATED-IRRADIATION

The effect of fludarabine ta-D-arabinosyl-2-fluoroadenine-5'-monophosp hate), an adenine nucleoside analogue, on the tolerance of the spinal cord to fractionated irradiation was studied in a rat model. Anestheti zed female Fisher 344 rats received irradiation to 2 cm of the cervica l spine with a telecobalt unit (dose rate 1.14 Gy/min). Radiation was administered in two, four or eight fractions spread over a 48-h period with or without fludarabine. Animals assigned to combined therapy rec eived two daily intraperitoneal injections of fludarabine (150 mg/kg) given 3 h prior to the first daily radiation fraction, It was found th at fludarabine reduced the iso-effect dose required to induce leg pare sis at 9 months after irradiation for all fractionation schedules. Dos e modification factors of 1.23, 1.29 and greater than 1.27 were obtain ed for two, four and eight fractions, respectively. Fitting the data w ith the direct analysis method of Thames et al, with an incomplete rep air model [18] showed that the potentiating effect of fludarabine may be mediated through reduction in the number of 'tissue-rescuing units' (1nK), Alpha and beta values were slightly but not significantly decr eased, whereas the alpha/beta ratio was unchanged. These features sugg est that fludarabine did not significantly inhibit cellular repair pro cesses but rather reduced the spinal cord tolerance by a fixed additiv e toxic effect on the same target cells. In rodent models, the combina tion of fludarabine and fractionated radiation has previously been fou nd to yield a therapeutic gain, i.e., the drug enhanced tumor response to a greater extent than it reduced normal tissue tolerance. However, given our results, caution should be exercised in extrapolating these findings to the clinic. Normal tissue reactions will have to be monit ored rigorously in phase I clinical studies.