Abstract
1492
Objectives: Integrin αvβ3 is over-expressed in tumor-induced angiogenic vessels and various malignant human tumors. The aim was to assess therapeutic response with an In-111-labeled peptidomimetic integrin αvβ3 antagonist. Methods: 2-p-isothiocyanatobenzyl-DOTA (SCN-Bz-DOTA) was conjugated to the amino end group of 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-β-alanine hydrochloride (IAC), an αvβ3 antagonist. The resulting IAC-SCN-Bz-DOTA was radiolabeled with In-111, purified on a Sep-Pak C-18 cartridge and confirmed for its binding to αvβ3 as described before (J Nucl Med 2006;47(S1):101P). Groups of nude mice (n=5 per time point) implanted s.c. with A431/K5 tumors expressing mesothelin were treated with i.p. taxol alone at 50 mg/kg, i.v. immunotoxin SS1P alone at 0.2 mg/kg or the two agents together when the tumor size was 200 mm3. A day later, the mice received i.v. IAC-SCN-Bz-DOTA-In-111 (2.0 μCi/<0.1 μg in 0.2 ml of PBS containing 1% BSA) and were euthanized at 1 hr postinjection. Results: The combination therapy was synergistic, using doses at which either agent alone causes stabilization of tumor growth as reported previously (Clin Cancer Res 2006;12:4695). The biodistribution of the radiolabel in the control animals without therapeutic treatment showed 3.5±0.6, 1.7±0.2, 3.2±0.6, 3.0±0.5, 4.3±0.8, 5.3±0.4, 5.0±0.3, 3.2±0.2, 0.7±0.1, and 1.9±0.1% ID/g in tumor, blood, liver, spleen, stomach, intestine, kidney, lung, muscle, and bone. The tumor uptake of the radiolabel was decreased to 0.8% ID/g upon co-injection with 200 ug of cold c(RGDyK), indicating a receptor-mediated uptake. Biodistribution in blood and major organs was similar between the control and the drug treated animals. However, the tumor uptake (% ID) of the radiolabel decreased propotionally to the therapeutic response reflected by shrinkage of the tumor size. Conclusions: The level of αvβ3 receptor expression measured by the uptake of the radiolabeled antagonist was found to be a reliable surrogate marker for the therapeutic response of tumors.
- Society of Nuclear Medicine, Inc.