Effective cancer therapy with the alpha-particle emitter [211At]astatine in a mouse model of genetically modified sodium/iodide symporter-expressing tumors.

Abstract

Purpose: The sodium/iodide symporter (NIS) gene is currently explored in several trials to eradicate experimental cancer with radiodine ( 131 I) by its h-emission. We recently characterized NIS-specific cellular uptake of an alternative halide, radioastatine ( 211 At), which emits high-energy a-particles.The aim of this study was to investigate in vivo effects of the high linear energy transfer (LET) emitter 211 At on tumor growth and outcome in nude mice. Experimental Design: We administered radioastatide in a fractionated therapy scheme to NMRI nude mice harboring rapidly growing solid tumors established from a papillary thyroid carcinoma cell line genetically modified to express NIS (K1-NIS). Animals were observed over 1year. Tumor growth, body weight, blood counts, survival, and side effects were measured compared with control groups without therapy and/or lack of NIS expression. Results: Within 3 months, radioastatide caused complete primary tumor eradication in all cases of K1-NIS tumor-bearing nude mice (n = 25) with no tumor recurrence during 1 year follow-up. Survival rates of the K1-NIS/ 211At group were 96% after 6 months and 60% after1year, in contrast to those of control groups (maximum survival 40 days). Conclusion: Our study indicates that 211 At represents a promising substrate for NIS-mediated therapy of various cancers either with endogenous or gene transfer-mediated NIS expression.

Functional sodium iodide symporter expression in breast cancer xenografts in vivo after systemic treatment with retinoic acid and dexamethasone

“…The well known additional antiproliferative and radiosensitizing effects of retinoids in breast cancer cells [42][43][44][45] as well as the bystander effect caused by the crossfire effect of b-particles emitted by 131 I are able to potentiate the therapeutic effect of 131 I in vivo [46,47]. Should limited iodide accumulating capacity and short iodide retention limit therapeutic efficacy of 131 I in breast cancer, the application of alternative radionuclides, including the high energy a-emitter 211 Astatine ( 211 At) and the potent b-emitter 188 Rhenium ( 188 Re), that are also transported by NIS, can be considered for application following atRA/Dex-mediated induction of endogenous NIS expression in breast cancer due to their higher energy and shorter half-life, thereby offering the possibility of higher energy deposition in a shorter time period [48][49][50][51][52][53]. Stimulation of the tumor absorbed radiation dose and the therapeutic effect of NIS-mediated radionuclide therapy has already been demonstrated for 188 Re in NIS-expressing mammary adenocarcinomas in a transgenic mouse model [48,49,51,52].…”

Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with 211At-MX35-F(ab′)2: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival

“…The therapeutic potential of a-emitters for macroscopic tumors has been sparsely investigated, and the dose levels required for tumor eradication are mostly unknown. A few studies have reported complete remission at absorbed doses of 12-21 Gy (14,29,30). Other studies reported antitumor effects that were close to, but not, curative (TFF, 60%-95%) for doses of 9-28 Gy (31-37).…”

Therapeutic Effect of Sodium Iodide Symporter Gene Therapy Combined With External Beam Radiotherapy and Targeted Drugs That Inhibit DNA Repair

“…Measles virus expressing NIS is already in the clinic and would seem to be an ideal initial model. The assessment of alternative radioisotopes, such as 186 Re, 188 Re, or 211 At, [18][19][20] would offer the prospect of integrating this approach within a standard outpatient regimen of radiation delivery.…”