Synthesis and application of 131I-fulvestrant as a targeted radiation drug for endocrine therapy in human breast cancer

Yin,Guobing; Zeng,Bin; Peng,Zhiping; Liu,Ying; Sun,Lu; Liu,Changan

doi:10.3892/or.2018.6212

Synthesis and application of 131I-fulvestrant as a targeted radiation drug for endocrine therapy in human breast cancer

Authors:
- Guobing Yin
- Bin Zeng
- Zhiping Peng
- Ying Liu
- Lu Sun
- Changan Liu
View Affiliations

Affiliations: Department of Breast, Thyroid, Pancreatic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China, Graduate School, Chongqing Medical University, Chongqing 400010, P.R. China, Department of Radiological Medicine and Oncology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
Published online on: January 11, 2018 https://doi.org/10.3892/or.2018.6212
Pages: 1215-1226

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of this study was to label fulvestrant (an endocrine therapy drug for breast cancer) with radioiodine and to evaluate the effect of 131I-fulvestrant on inhibiting the growth of human breast cancer and its influence on major organs in nude mice. Fulvestrant was labeled with radioiodine using a modified chloramine T method, and its chemical properties were assessed using traditional methods. The binding affinity of 131I-fulvestrant was measured by radioligand binding assays, and its antiproliferative activity was determined by MTT assays. The ability of 131I-fulvestrant to kill MCF-7 and MDA-MB-231 cells was also detected by MTT assays. We established MCF-7 cell xenografts in nude mice and monitored tumor growth and critical organ function. When the labeling reactions were conducted for 5 min at room temperature at pH 7.5, the radiochemical yield of the 131I labeling to fulvestrant was 62.34±1.8%, the radiochemical purity was 98.6±3.4%, and the half maximal inhibitory concentration (IC50) at 48 h was 35 µCi. 131I-fulvestrant was stable, and its binding affinity to estrogen receptor-positive (ER+) MCF-7 cells was also retained. In addition, 131I-fulvestrant exhibited similar cytotoxicity in MCF-7 and MDA-MB-231 cells, although MCF-7 cells showed a slightly more pronounced response. 131I-fulvestrant continuously exerted a tumor suppressive effect on MCF-7 cells but not on MDA-MB-231 cells (P<0.05). Upon intravenous injection of 131I-fulvestrant into nude mice, the radioactivity distribution corresponded to ER expression patterns and was primarily confined to the tumor. 131I-fulvestrant exhibited a precise growth inhibition effect on MCF-7 breast cancer cells, and its effects on general conditions of nude mice and their major organs were manageable. Therefore, radioiodine labeling of fulvestrant was successful and could be used to develop novel drugs for breast cancer by superimposing the benefits of radiotherapy and endocrine therapy.

View Figures

View References

1	Pitoia F and Miyauchi A: 2015 American thyroid association guidelines for thyroid nodules and differentiated thyroid cancer and their implementation in various care settings. Thyroid. 26:319–321. 2016. View Article : Google Scholar : PubMed/NCBI
2	Higashi T, Kudo T and Kinuya S: Radioactive iodine (¹³¹I) therapy for differentiated thyroid cancer in Japan: Current issues with historical review and future perspective. Ann Nucl Med. 26:99–112. 2012. View Article : Google Scholar : PubMed/NCBI
3	Sawka AM, Straus S, Gafni A, Meiyappan S, David D, Rodin G, Brierley JD, Tsang RW, Thabane L, Rotstein L, et al: Thyroid cancer patients' involvement in adjuvant radioactive iodine treatment decision-making and decision regret: An exploratory study. Support Care Cancer. 20:641–645. 2012. View Article : Google Scholar : PubMed/NCBI
4	Haymart MR, Banerjee M, Stewart AK, Koenig RJ, Birkmeyer JD and Griggs JJ: Use of radioactive iodine for thyroid cancer. JAMA. 306:721–728. 2011. View Article : Google Scholar : PubMed/NCBI
5	Tuttle RM, Rondeau G and Lee NY: A risk-adapted approach to the use of radioactive iodine and external beam radiation in the treatment of well-differentiated thyroid cancer. Cancer Contr. 18:89–95. 2011. View Article : Google Scholar
6	Sacks W, Fung CH, Chang JT, Waxman A and Braunstein GD: The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: A systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid. 20:1235–1245. 2010. View Article : Google Scholar : PubMed/NCBI
7	Hosseinzadeh M, Eivazi Ziaei J, Mahdavi N, Aghajari P, Vahidi M, Fateh A and Asghari E: Risk factors for breast cancer in Iranian women: A hospital-based case-control study in tabriz, iran. J Breast Cancer. 17:236–243. 2014. View Article : Google Scholar : PubMed/NCBI
8	Howard-Anderson J, Ganz PA, Bower JE and Stanton AL: Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 104:386–405. 2012. View Article : Google Scholar : PubMed/NCBI
9	Gradilone A, Raimondi C, Naso G, Silvestri I, Repetto L, Palazzo A, Gianni W, Frati L, Cortesi E and Gazzaniga P: How circulating tumor cells escape from multidrug resistance: Translating molecular mechanisms in metastatic breast cancer treatment. Am J Clin Oncol. 34:625–627. 2011. View Article : Google Scholar : PubMed/NCBI
10	Chen WJ, Wang H, Tang Y, Liu CL, Li HL and Li WT: Multidrug resistance in breast cancer cells during epithelial-mesenchymal transition is modulated by breast cancer resistant protein. Chin J Cancer. 29:151–157. 2010. View Article : Google Scholar : PubMed/NCBI
11	Dall G, Vieusseux J, Unsworth A, Anderson R and Britt K: Low dose, low cost estradiol pellets can support MCF-7 tumour growth in nude mice without bladder symptoms. J Cancer. 6:1331–1336. 2015. View Article : Google Scholar : PubMed/NCBI
12	Yang ZY, Wang MW, Zhang YP, Xu JY, Yuan HY and Zhang YJ: The biodistribution and imaging of 16α-(18F) fluroroestradiol (18F-FES) in rats and breast tumor-bearing nude mice. Shanghai Medical Imaging. 20:234–238. 2011.
13	Turner NC, Neven P, Loibl S and Andre F: Advances in the treatment of advanced oestrogen-receptor-positive breast cancer. Lancet. 389:2403–2414. 2017. View Article : Google Scholar : PubMed/NCBI
14	Dalmau E, Armengol-Alonso A, Muñoz M and Seguí-Palmer MÁ: Current status of hormone therapy in patients with hormone receptor positive (HR⁺) advanced breast cancer. Breast. 23:710–720. 2014. View Article : Google Scholar : PubMed/NCBI
15	James R, Thriveni K, Krishnamoorthy L, Deshmane V, Bapsy PP and Ramaswamy G: Clinical outcome of adjuvant endocrine treatment according to Her-2/neu status in breast cancer. Indian J Med Res. 133:70–75. 2011.PubMed/NCBI
16	Al-Mubarak M, Sacher AG, Ocana A, Vera-Badillo F, Seruga B and Amir E: Fulvestrant for advanced breast cancer: A meta-analysis. Cancer Treat Rev. 39:753–758. 2013. View Article : Google Scholar : PubMed/NCBI
17	Wardell SE, Nelson ER, Chao CA and McDonnell DP: Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: Implications for treatment of advanced disease. Clin Cancer Res. 19:2420–2431. 2013. View Article : Google Scholar : PubMed/NCBI
18	Mishra AK, Abrahamsson A and Dabrosin C: Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ERα positive breast cancer by up-regulation of ERβ. Oncotarget. 7:56876–56888. 2016. View Article : Google Scholar : PubMed/NCBI
19	He S, Wang M, Yang Z, Zhang J and Zhang Y, Luo J and Zhang Y: Comparison of 18F-FES, 18F-FDG, and 18F-FMISO PET imaging probes for early prediction and monitoring of response to endocrine therapy in a mouse xenograft model of ER-positive breast cancer. PLoS One. 11:e01599162016. View Article : Google Scholar : PubMed/NCBI
20	Fernandes SA, Gomes GR, Siu ER, Damas-Souza DM, Bruni-Cardoso A, Augusto TM, Lazari MF, Carvalho HF and Porto CS: The anti-oestrogen fulvestrant (ICI 182,780) reduces the androgen receptor expression, ERK1/2 phosphorylation and cell proliferation in the rat ventral prostate. Int J Androl. 34:486–500. 2011. View Article : Google Scholar : PubMed/NCBI
21	Wang MH, Xu YJ, Wang ZZ, Liu M, Li Z, Weng W and Fan W: Radiolabeling of paclitaxel with ¹²⁵I. J Isotopes. 21:82–87. 2008.
22	Wang L, Mi C and Wang W: Establishment of lymph node metastasis of MDA-MB-231 breast cancer model in nude mice. Zhonghua Yi Xue Za Zhi. 95:1862–1865. 2015.(In Chinese). PubMed/NCBI
23	Nofiele JT and Cheng HL: Establishment of a lung metastatic breast tumor xenograft model in nude rats. PLoS One. 9:e97950. 2014. View Article : Google Scholar : PubMed/NCBI
24	Nishihara E, Nagayama Y, Inoue S, Hiroi H, Muramatsu M, Yamashita S and Koji T: Ontogenetic changes in the expression of estrogen receptor α and β in rat pituitary gland detected by immunohistochemistry. Endocrinology. 141:615–620. 2000. View Article : Google Scholar : PubMed/NCBI
25	Giacinti L, Giacinti C, Gabellini C, Rizzuto E, Lopez M and Giordano A: Scriptaid effects on breast cancer cell lines. J Cell Physiol. 227:3426–3433. 2012. View Article : Google Scholar : PubMed/NCBI
26	Liu L, Ma H, Tang Y, Chen W, Lu Y, Guo J and Duan JA: Discovery of estrogen receptor α modulators from natural compounds in Si-Wu-Tang series decoctions using estrogen-responsive MCF-7 breast cancer cells. Bioorg Med Chem Lett. 22:154–163. 2012. View Article : Google Scholar : PubMed/NCBI
27	Ko YM, Wu TY, Wu YC, Chang FR, Guh JY and Chuang LY: Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells. J Ethnopharmacol. 137:1283–1290. 2011. View Article : Google Scholar : PubMed/NCBI
28	Mendoza RA, Enriquez MI, Mejia SM, Moody EE and Thordarson G: Interactions between IGF-I, estrogen receptor-α (ERα), and ERβ in regulating growth/apoptosis of MCF-7 human breast cancer cells. J Endocrinol. 208:1–9. 2011. View Article : Google Scholar : PubMed/NCBI
29	Hong W, Chen L, Li J and Yao Z: Inhibition of MAP kinase promotes the recruitment of corepressor SMRT by tamoxifen-bound estrogen receptor alpha and potentiates tamoxifen action in MCF-7 cells. Biochem Biophys Res Commun. 396:299–303. 2010. View Article : Google Scholar : PubMed/NCBI
30	Kelkar MG, Senthilkumar K, Jadhav S, Gupta S, Ahn BC and De A: Enhancement of human sodium iodide symporter gene therapy for breast cancer by HDAC inhibitor mediated transcriptional modulation. Sci Rep. 6:193412016. View Article : Google Scholar : PubMed/NCBI
31	Renier C, Do J, Reyna-Neyra A, Foster D, De A, Vogel H, Jeffrey SS, Tse V, Carrasco N and Wapnir I: Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy. Oncotarget. 7:54811–54824. 2016. View Article : Google Scholar : PubMed/NCBI
32	Chatterjee S, Thaker N and De A: Combined 2-deoxy glucose and metformin improves therapeutic efficacy of sodium-iodide symporter-mediated targeted radioiodine therapy in breast cancer cells. Breast Cancer (Dove Med Press). 7:251–265. 2015.PubMed/NCBI
33	Poole VL and McCabe CJ: Iodide transport and breast cancer. J Endocrinol. 227:R1–R12. 2015. View Article : Google Scholar : PubMed/NCBI
34	Jan KC, Ku KL, Chu YH, Hwang LS and Ho CT: Tissue distribution and elimination of estrogenic and anti-inflammatory catechol metabolites from sesaminol triglucoside in rats. J Agric Food Chem. 58:7693–7700. 2010. View Article : Google Scholar : PubMed/NCBI
35	Younes M and Honma N: Estrogen receptor β. Arch Pathol Lab Med. 135:63–66. 2011.PubMed/NCBI
36	Ur Rahman MS and Cao J: Estrogen receptors in gastric cancer: Advances and perspectives. World J Gastroenterol. 22:2475–2482. 2016. View Article : Google Scholar : PubMed/NCBI