Radiolabeled
nucleosides, specifically
5-iodo-2'-deoxyuridine (
IUdR) radioiodinated with the Auger-electronemitting 123I or 125I, have been shown to produce extensive DNA damage in mammalian cell systems in vitro. Such
nucleosides are cycle-dependent agents that are taken up by mitotically dividing cells in the S phase of the cell cycle. The degree of damage that occurs is related to the fact that these
nucleosides bind covalently to
DNA bringing the decaying Augerelectron-emitting
radionuclide in close proximity to the genome. The use of these radiohalogenated
nucleosides in vivo is associated with several problems. The first relates to their extremely short
biologic half-life in blood (T1/2 of minutes in humans). The second involves achieving therapeutic ratios in
tumor cells in the face of efficient hepatic dehalogenation. The third concerns the uptake of these
radiopharmaceuticals by actively proliferating normal cell renewal systems, thus potentially causing toxic side effects. The fourth, one shared with other cycle-dependent drugs, relates to the matter of labeling the whole
tumor cell population. To facilitate targeting to
tumors, investigators have been examining the direct introduction of these agents into the targeted area or into an arterial blood supply that immediately precedes the target. For example,
radiopharmaceutical administration could be intracavitary (bladder, spinal fluid, peritoneum), intralesional (
brain tumor, breast mass) or intra-arterial (liver, pancreas). In all these situations, the following conditions must be met: (a) once within the vicinity of the
tumor the agent can freely diffuse through the tissues and is selectively taken up by cancerous cells; (b) once the agent has left the target area it is converted quickly into a nontoxic form and/or excreted from the body; and finally, (c) the
biologic behavior of the agent is not altered by repeated
injections. We report herein our experience and that of others with [123I/125I/131I]
IUdR in cultured cells, animal
tumor-model systems, and patients. In vitro,
DNA incorporation of 123I- and 125I-labeled
IUdR leads to an exponential decrease in cell survival (no shoulder on the survival curve). However, the total number of decays needed to produce a given lethal effect with [123I]
IUdR is approximately twice that required with [125I]
IUdR. In vivo, the scintigraphic and
antineoplastic capabilities of radioiodinated
IUdR have been demonstrated in an intraperitoneal murine ovarian
tumor model following
intraperitoneal injection; in an intracerebral rat
gliosarcoma model after intracranial administration; in an intrathecal rat
gliosarcoma model after intrathecal infusion; and in a rat transitional cell
bladder cancer model following intravesicular infusion. [123I]
IUdR, [125I]
IUdR, and/or [131I]
IUdR have been administered to patients with brain, breast, colorectal, or
gastrointestinal cancers (intratumorally);
ovarian cancer (intraperitoneally);
bladder cancer (intravesically); liver
metastases from
colorectal cancer (through the hepatic artery, permanent intra-arterial
catheter). These studies have confirmed the observations made in animal models. The data indicate that
5-iodo-2'-deoxyuridine radiolabeled with an Auger electron emitter (123I or 125I) may be a useful agent for the scintigraphic diagnosis and/or
therapy of neoplastic diseases that are accessible to direct
radiopharmaceutical administration. This
radiopharmaceutical should serve as a prototype for, and facilitate the development of, other radiolabeled
nucleoside analogs. Further investigations are certainly warranted.