RADIATION ENHANCEMENT WITH IODINATED DEOXYURIDINE

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A technique for radiation enhancement of conventional photon radiotherapy is outlined. High Linear Energy Transfer (LET) radiations in the form of Auger electron distributions are generated by a photon beam through photoactivation of stable iodine incorporated as an analog of thymidine (Tyd) in DNA. Of the several halogenated deoxyribonucleosides evaluated, iodinated deoxyuridine (IdUrd) is chosen as the only Tyd analog providing effective photoactivation in situ. This mechanism is combined with radiation sensitization produced by IdUrd to produce an overall radiation enhancement. Calculations show that 5% replacement of Tyd in tumor DNA should multiply the biological effectiveness of low energy photons by a factor of 2. Higher replacements would provide higher gains. Enhancement results from chemical sensitization by IdUrd, where it is known that effects of irradiation are multiplied by factors of from 1.5 to 3 as replacement varies from 5 to 50%. Additional enhancement results from the stimulation of Auger cascades in DNA. Five percent replacement has been obtained in human tumor in vivo. At least 15% has been obtained in murine tumors. We have been able to document the various radiobiological parameters used in our analysis (sensitization, photoactivation) using single cell cultures. In particular, our data show that damage from sensitization (as well as photoactivation) does not repair. Thus it is anticipated that use of low dose rates associated with "permanent" implants of Sm-145 sources (38-45 KeV x-rays; T 1/2 = 34 d) will yield an additional increase in therapeutic efficacy by a factor of from 3 to 8, compared to that obtained with acute dose rates. The expectation is that previous favorable clinical results with BrdUrd and high energy x-rays can be further improved through the use of IdUrd and suitable lower energy activating photons (35 - 50 keV). Protracted irradiations with implanted sources such as obtained from Sm-145 may provide unique advantages at selected sites such as brain, or head and neck tumors. The experiments described here are designed to complete our compilation of relevant parameters, and to test the therapeutic modality in two animal tumor models.