Rhenium-188 as an alternative to Iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS)

doi:10.1016/S0969-8051(01)00279-7

Nuclear Medicine and Biology

Volume 29, Issue 1, January 2002, Pages 13-18

https://doi.org/10.1016/S0969-8051(01)00279-7 Get rights and content

Abstract

The sodium-iodide symporter (NIS), which transports iodine into the cell, is expressed in thyroid tissue and was recently found to be expressed in approximately 80% of human breast cancers but not in healthy breast tissue. These findings raised the possibility that therapeutics targeting uptake by NIS may be used for breast cancer treatment. To increase the efficacy of such therapy it would be ideal to identify a radioactive therapy with enhanced local emission. The feasibility of using the powerful beta-emitting radiometal ¹⁸⁸Re in the form of ¹⁸⁸Re-perrhenate was therefore compared with ¹³¹I for treatment of NIS-expressing mammary tumors. In the current studies, using a xenografted breast cancer model induced by the ErbB2 oncogene in nude mice, ¹⁸⁸Re-perrhenate exhibited NIS-dependent uptake into the mammary tumor. Dosimetry calculations in the mammary tumor demonstrate that ¹⁸⁸Re-perrhenate is able to deliver a dose 4.5 times higher than ¹³¹I suggesting it may provide enhanced therapeutic efficacy.

Introduction

Breast cancer remains the major cause of cancer death in women in the developed world. Novel therapeutic modalities are needed for patients with tumors resistant to conventional therapies such as chemotherapy, hormonal treatment and external radiation. Recently Tazebay et al have discovered [31] that more than 80% of mammary cancers but not normal/healthy breast tissue in humans express the sodium/iodide symporter (NIS) which these authors named mammary gland NIS (mgNIS). Kilbane et al [11] have found an expression of NIS to be a feature of both fibroadenomata and breast carcinoma tissues. NIS mediates iodide accumulation in the thyroid gland [2], and the capability to concentrate and organify iodide allows the use of radioactive iodine isotope ¹³¹I for the treatment of differentiated thyroid cancers and hyperthyroidism 10, 24. Thus, the presence of the endogenous sodium/iodide symporter in mammary tumors might open a new avenue in treatment of breast cancer [31].

At this time, no studies have formally assessed the functional significance of endogenous NIS in mammary tumors for therapy with ¹³¹I. However, it has been pointed out by Daniels and Harber [5] that organification of iodide is unlikely to occur in breast cancer cells as the thyroid is the only organ known to organify iodide, a process that involves the conversion of inorganic iodide to an organic form by conjugation to tyrosine residues on the protein thyroglobulin, a precursor to iodinated forms of thyroid hormone [30]. The organification process causes radioiodine to be retained within the gland for several days [16]. This relatively long retention time which matches the physical half-life of ¹³¹I (8 days) allows a significant radiation dose to be delivered to the tumor.

Several studies have reported transfection of NIS into different non-thyroid or undifferentiated thyroid tumors for the purpose of subsequent therapy with ¹³¹I 1, 3, 15, 17, 21, 27. In all of these studies, although ¹³¹I uptake in NIS-expressing tumors was substantial (up to 27% injected dose in [27]), the residence times of ¹³¹I in the tumors were relatively short and no tumor shrinkage was observed 1, 3, 27. In a recent report by Spitzweg et al [28], impressive therapeutic results were seen in NIS-transfected prostate tumor xenografts in mice when treated with a very high single 3 mCi dose of ¹³¹I. However, as no biodistribution and no dose-escalation studies were reported, it is unclear why such high dose was administered. The lack of therapeutic gains observed by other investigators 1, 3, 27 can be attributable to the long physical half-life (8 days) and decay properties of ¹³¹I, as the beta-particles emitted by ¹³¹I are low energy (E_average=0.134 MeV) and have an optimal tissue range of only 2.6–5.0 mm [22]. If there is no prolonged biological retention of ¹³¹I in NIS-transfected or NIS-expressing tumors, an isotope with a shorter physical half-life and superior to ¹³¹I decay properties which can be transported by NIS may provide a better therapeutic option. This is especially true in case of tumors larger than 5.0 mm in diameter which cannot be covered by the range of ¹³¹I beta-particles.

A short-lived isotope of technetium ^99mTc is used in ∼ 90% of all diagnostic nuclear medicine procedures. It has been long recognized by nuclear medicine practitioners that due to their common ionic characteristics, iodide and ^99mTc-pertechnetate (^99mTcO₄^-) behave similarly following intravenous administration [23]. Like iodide, ^99mTcO₄^- localizes in the thyroid, salivary glands, gastric mucosa, and choroid plexus of the brain. It is trapped but not organified in the thyroid gland and is used in nuclear medicine as an alternative to Na ¹²³I for assessing the thyroid condition.

Rhenium is a chemical analogue of technetium and exhibits practically identical chemical and biodistribution properties [6]. Because of chemical similarity to pertechnetate, the perrhenate anion (¹⁸⁸ReO₄^-) is concentrated in thyroid and stomach [14], apparently, by endogenous NIS. We have demonstrated that co-injected ^99mTcO₄⁻, ¹²⁵I⁻ and ¹⁸⁸ReO₄^- have similar uptake and biodistribution in NIS-expressing and non-expressing tissues in healthy mice, with the exception of the thyroid gland where only ¹²⁵I^- is retained by organification [32]. 188-Rhenium (¹⁸⁸Re), a powerful beta-emitting radionuclide (E_average = 0.764 MeV) with a 16.7 h half-life has been recently used in a number therapeutic applications in humans including cancer radioimmunotherapy, palliation of skeletal bone pain, and endovascular brachytherapy to prevent restenosis after angioplasty 8, 12, 25 as well as in the pre-clinical development of novel therapeutics 4, 19.

In this study we investigate the utility of ¹⁸⁸Re in treatment of NIS-expressing mammary tumors in a mouse model. We report the results of comparative ¹²⁵I and ¹⁸⁸Re biodistribution in a mouse breast cancer model and use these data to extrapolate the dosimetry calculations to humans.

Section snippets

Radioisotopes

¹²⁵I in the form of sodium iodide was purchased from NEN, Boston, MA. ¹⁸⁸Re in the form of Na perrhenate Na¹⁸⁸ReO₄ was eluted from the ¹⁸⁸W/¹⁸⁸Re generator (Oak Ridge National Laboratory (ORNL), Oak Ridge, TN).

Animal model

To investigate the binding of ¹²⁵I and ¹⁸⁸Re to NIS-expressing mammary tumors, a xenografted mammary adenocarcinoma model in nude mice was used. As erbB-2 (Neu) is one of the better known human breast cancer oncogenes, we used a mammary tumor cell line (NAFA) induced by oncogenic Neu. The

Results

In this study we have investigated the uptake of ¹⁸⁸ReO₄^- compared with ¹²⁵I^- in mice bearing mgNIS-expressing mammary tumors. The biodistribution results are given in Table 1. The tumors exhibited increased uptake of ¹²⁵I^- and ¹⁸⁸ReO₄^- in comparison with the tissues that do not express NIS (liver, muscle, spleen, kidney). The uptake in the tumors plateaued over the initial 2 h and then decreased over 24 h period. There was no statistically significant difference between ¹²⁵I^- and ¹⁸⁸ReO₄^-

Discussion

Several different approaches to circumvent the problem of insufficient radiation dose to the NIS-expressing tumors have been suggested. Boland et al [1] proposed to improve the efficiency of NIS gene transfer and thus the iodide uptake capacity of the target tissue by the use of modified vectors and/or higher viral doses. The same authors proposed to increase the biological half-life of radioiodide in the tumor tissues by coupling transfer of the NIS gene with the delivery of a gene involved in

Conclusion

We have demonstrated the feasibility of using a powerful beta-emitting radiometal ¹⁸⁸Re, in ¹⁸⁸Re-perrhenate form in place of ¹³¹I for treatment of NIS-expressing mammary tumors. Similar to radioiodine, ¹⁸⁸Re-perrhenate exhibited NIS-dependent uptake into the tumors, but, like ^99mTc-pertechnetate, no long-term organification and accumulation in the thyroid gland. Dosimetry calculations performed by extrapolation of biodistribution data to humans, showed that ¹⁸⁸Re-perrhenate is able to deliver

Acknowledgements

This work was supported by AECOM grant 95269593 (to E.D.) and R01CA70897, R01CA75503, R01CA77552, the Komen Foundation, Breast Cancer Alliance, Inc., and Cancer Center Core National Institutes of Health grant 5-P30-CA13330–26 (to R.G.P.). The authors would like to thank Prof. N.Carrasco, Albert Einstein College of Medicine, for insightful comments.

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Rhenium-188 as an alternative to Iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS)

Abstract

Introduction

Section snippets

Radioisotopes

Animal model

Results

Discussion

Conclusion

Acknowledgements

Biochim. Biophys. Acta.

Int. J. Rad. Appl. Instrum.

Endocrinol. Metab. Clin. N. Am.

Radiother. Oncol.

Nucl. Med. Biol.

Cell

Semin. Radiation Oncol.

Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy

Cancer Res.

Expression and activity of human Na+/I- symporter in human glioma cells by adenovirus-mediatd gene delivery

Gene Ther.

188-Re(V)DMSA revisited - preparation and biodistribution of potential radiotherapeutic agent with the low kidney uptake

Nucl. Med. Commun.

Will radioiodine be useful in treatment of breast cancer?

Nature Med.

Principles and Practice of Nuclear Medicine

Intracoronary beta-irradiation with a liquid 188-Re-filled balloonsix-month results from a clinical safety and feasibility study

Circulation

188W/188Re generator for biomedical applications

Radiochim.

Tissue iodine content and serum-mediated 125-I uptake-blocking activity in breast cancer

J. Clin. Endocrinol. Metab.

Rhenium-188 - a generator-derived radioisotope for cancer therapy

Cancer Biother. Radiopharm.

Expression and activity of human Na⁺/I^- symporter in human glioma cells by adenovirus-mediatd gene delivery