5-¹²⁵I-iododeoxyuridine as prototype for radionuclide therapy with Auger emitters

Abstract

MANY of the physical and biological requirements for treating cancer with internally emitting radionuclides are met by 5-¹²⁵I-iododeoxyuridine (¹²⁵IUdR). The decay of ¹²³I is associated with a highly localised deposition of energy¹. Cascades of very low energy and thus densely ionising Auger electrons are released. In addition, a charge transfer reaction takes place leaving the resultant tellurium nucleus with a transient mean net charge of +9 (ref. 2). These unique physical characteristics can be used for cell destruction by labelling DNA with ¹²⁵IUdR, a thymidine analogue. The marked radiotoxicity of ¹²⁵I incorporated into DNA as ¹²⁵IUdR has been demonstrated by lethality, mutations and DNA strand breaks in bacteria and bacteriophage^3–7, by lethality and chromosome aberrations in mammalian cells cultured in vitro^8–10, and by diminished survival of prelabelled tumour cells assayed in vivo¹¹. The intranuclear location is of major importance: ¹²⁵I located extracellularly⁹ or bound to cell membranes is much less toxic (unpublished work of R. L. Warters and K. G. Hofer). These findings suggested that ¹²⁵IUdR might have significant anti-neoplastic activity. We tested this hypothesis in a murine ascites tumour model^12,13. In a pilot study using therapeutic doses of ¹²⁵IUdR, the agent substantially augmented the median and absolute survival of treated animals. The critical factors affecting treatment of a 1-d-old ascites tumour model with ¹²⁵IUdR are detailed here.