Therapeutic effects of radiolabeled 17-allylamino-17-demethoxygeldanamycin on human H460 nonsmall-cell lung carcinoma xenografts in mice.

Heat shock protein 90 (HSP90) is an exciting molecular target for cancer therapy because of this protein's key role in oncogenic signaling pathways. In this work, the binding property of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor now in phase II clinical trials, was used by labeling with radioisotope iodine-131 ((131)I), to observe the potential therapeutic effects on nonsmall-cell lung carcinoma (NSCLC) xenografts. The compound (131)I-17-AAG and BALB/c nude mice bearing H460 human NSCLC xenografts were prepared. Intratumoral and intravenous administration routes were used. The potential effects of labeled 17-AAG were evaluated by biodistribution studies, in vivo imaging, cancer-treatment studies, and histological analysis. Specific tumor uptake of (131)I-17-AAG was achieved in the xenograft models. Compared to intravenous (i.v.) application, tumor uptake was significantly improved with intratumoral injection of (131)I-17-AAG and competitively reduced with preinjection of unlabeled 17-AAG. All treatment groups established tumor-growth inhibition compared with the control group (p < 0.05), with a certain dose-dependent relationship. The 16-day inhibition ratios via intratumoral delivery were better than those via i.v. delivery (p < 0.05). No significant treatment-induced abnormalities appeared in the mice. Compared with the control group, HSP90alpha + expression and Ki-67+ expression of tumor tissues declined after treatments (p < 0.05), which correlated positively with tumor inhibition. Thus, (131)I-17-AAG treatment undoubtedly had inhibitive effects on human NSCLC xenografts in mice, and the combination of radionuclides and HSP90 inhibitors may be considered for cancer therapy.