Relationship between biodistribution of a novel thymidine phosphorylase (TP) imaging probe and TP expression levels in normal mice

Abstract

Objective Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway and its expression is upregulated in a wide variety of solid tumors. In mice, we previously observed high and specific accumulation levels of our TP imaging probe, radioiodinated 5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil (IIMU) not only in high-TP-expressing tumors, but also in the liver and small intestine. To clarify the reason for the high accumulation levels of radioiodinated IIMU in the liver and small intestine, we investigated the expression levels of TP in mice in comparison with the biodistribution of radioiodinated IIMU ( 123 I-IIMU).Methods BALB/cCrSlc mice were injected with 123 I-IIMU, and the radioactivity levels [%ID/g (normalized to a mouse of 25 g body weight)] in the tissues of interest were determined 0.5, 1, 3 and 24 h after the injection (n=5, each time point). To determine the expression levels of TP, BALB/cCrSlc and ddy mice (n=3/each strain)were euthanized, and the heart, liver, lung, spleen, kidney, stomach, small intestine, large intestine and brain were collected. The mRNA and protein expression levels of TP in these organs were examined by quantitative reverse transcription-polymerase chain reaction and western blot analyses, respectively. Immunoblotting showed intense immunoreactive bands of the TP protein for the liver and small intestine, whereas no notable bands were detected for other tissues. Similar expression profiles of TP mRNA and protein were observed in ddy mice. ConclusionWe confirmed TP expression in various tissues of mice at the mRNA and protein levels: high TP expression levels were observed in the liver and small intestine. These high TP expression levels are consistent with the high accumulation levels of 123 I-IIMU in these tissues. Our results may provide important information about the physiological accumulation of 123 I-IIMU, which may be useful for the clinical diagnostic imaging of TP.

The Thymidine Phosphorylase Imaging Agent 123I-IIMU Predicts the Efficacy of Capecitabine

“…5B). In our previous studies, we investigated the biodistribution of 125 I-IIMU and 123 I-IIMU in mice (25,27). The radiolabeled tracers mainly accumulated in the liver and small intestine, consistent with our present results.…”

“…The radiolabeled tracers mainly accumulated in the liver and small intestine, consistent with our present results. Furthermore, we confirmed messenger RNA and protein levels of TP in various mouse tissues (27). We observed high TP expression in the liver and intestine, which corresponded to the observed high accumulation of radiolabeled IIMU (Supplemental Table 1).…”

“…1) as a noninvasive TP imaging probe (24). 125 I-IIMU accumulated in cancer cells and tumor tissues depending on TP expression levels (25)(26)(27), suggesting that radiolabeled IIMU enables TP-specific image acquisition. Because TP is responsible for capecitabine activation, we hypothesized that 123 I-IIMU, as an imaging probe for SPECT, could be used to predict capecitabine efficacy in cancer patients.…”

Preclinical investigation of potential use of thymidine phosphorylase-targeting tracer for diagnosis of nonalcoholic steatohepatitis

“…In our previous studies, we clearly demonstrated that TYMP mRNA and protein were more highly expressed in the normal liver and small intestine than in the other organs including the heart, lung, stomach, spleen, kidney, large intestine, muscle, and brain [12]. Radiolabeled IIMU also accumulated mostly in the liver and small intestine of mice [9,10,12].…”

“…Thymidine phosphorylase (TYMP) is induced by TNF-α and is also identical to the platelet-derived endothelial cell growth factor (PD-ECGF) [7,8]. We previously synthesized radioiodine-labeled [10][11][12][13], and was safely administered in humans [14].…”