Skip to main content
SpringerLink
Log in

Comparison of the efficacy of 177Lu-EDTMP, 177Lu-DOTMP and 188Re-HEDP towards bone osteosarcoma: an in vitro study

  • Published:
Journal of Radioanalytical and Nuclear Chemistry Aims and scope Submit manuscript

Abstract

Among the radiopharmaceuticals harnessed for palliation of bone pain in osseous metastases patients, 177Lu labeled phosphonates such as EDTMP (Ethylene diamine tetramethylene phosphonic acid) as well as DOTMP (1,4,7,10-tetraaza-cyclo-dodecane-1,4,7,10 tetraethylene phosphonic acid) and 188Re-labeled HEDP (1,1-hydroxyethylene diphosphonic acid) seem to be the most favorable for treatment of small and medium/large size bone lesions, respectively. A comparative assessment of 177Lu-EDTMP, 177Lu-DOTMP and 188Re-HEDP in osteosarcoma tumor cell line was carried out to evaluate their relative efficacy. It was found that 188Re-HEDP is more potent in induction of cell toxicity and apoptosis compared to the 177Lu-EDTMP and 177Lu-DOTMP, thus 188Re-HEDP might have great clinical significance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ogawa K, Washiyama K (2012) Bone target radiotracers for palliative therapy of bone metastases. Curr Med Chem 19:3290–3300

    Article  CAS  PubMed  Google Scholar 

  2. Luz MA, Aprikian AG (2010) Preventing bone complications in advanced prostate cancer. Curr Oncol 17:S65–S71

    PubMed  PubMed Central  Google Scholar 

  3. Chen YC, Sosnoski DM, Mastro AM (2010) Breast cancer metastasis to the bone: mechanisms of bone loss. Breast Cancer Res 12:215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Costa L, Major PP (2009) Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol 6:163–174

    CAS  PubMed  Google Scholar 

  5. DeNardo GL (1998) Bone pain palliation. Cancer Biother Radiopharm 13:407–411

    Article  CAS  PubMed  Google Scholar 

  6. Das T, Banerjee S (2017) Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons. Clin Exp Metastases 34:1–10

    Article  CAS  Google Scholar 

  7. Palma E, Correia JD, Campello MP, Santos I (2011) Bisphosphonates as radionuclide carriers for imaging or systemic therapy. Mol Biosys 7:2950–2966

    Article  CAS  Google Scholar 

  8. Paes FM, Serafini AN (2010) Systemic metabolic radiopharmaceutical therapy in the treatment of metastatic bone pain. Semin Nucl Med 40:89–104

    Article  PubMed  Google Scholar 

  9. Lewington VJ (2005) Bone-seeking radionuclides for therapy. J Nucl Med 46:38S–47S

    CAS  PubMed  Google Scholar 

  10. Thapa P, Nikam D, Das T, Sonawane G, Agarwal JP, Basu S (2015) Clinical efficacy and safety comparison of 177Lu-EDTMP with 153Sm-EDTMP on an equidose basis in patients with painful skeletal metastases. J Nucl Med 56:1513–1519

    Article  CAS  PubMed  Google Scholar 

  11. Shinto AS, Shibu D, Kamaleshwaran KK, Das T, Chakraborty S, Banerjee S, Thirumalaisamy P, Das P, Veersekar G (2014) 177Lu-EDTMP for treatment of bone pain in patients with disseminated skeletal metastases. J Nucl Med Technol 42:55–61

    Article  PubMed  Google Scholar 

  12. Das T, Shinto A, Kamaleshwaran KK, Banerjee S (2016) Theranostic treatment of metastatic bone pain with 177Lu-DOTMP. Clin Nucl Med 41:966–967

    Article  PubMed  Google Scholar 

  13. Argyrou M, Valassi A, Andreou M, Lyra M (2013) Rhenium-188 production in hospitals, by W-188/Re-188 generator, for easy use in radionuclide therapy. Int J Mol Imaging 2013:290750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dash A, Knapp FF Jr (2015) An overview of radioisotope separation technologies for development of 188 W/188Re radionuclide generators providing 188Re to meet future research and clinical demands. RSC Adv 5:39012–39036

    Article  CAS  Google Scholar 

  15. Mallia MB, Shinto AS, Kameswaran M, Kamaleshwaran KK, Kalarikal R, Aswathy KK, Banerjee S (2016) A Freeze-dried kit for the preparation of 188Re-HEDP for bone pain palliation: preparation and preliminary clinical evaluation. Cancer Biother Radiopharm 31:139–144

    Article  CAS  PubMed  Google Scholar 

  16. Sharma R, Kumar C, Mallia MB, Kameswaran M, Sarma HD, Banerjee S, Dash A (2017) In vitro Evaluation of 188Re-HEDP: a Mechanistic View of Bone Pain Palliations. Cancer Biother Radiopharm. 32:184–191

    Article  CAS  PubMed  Google Scholar 

  17. Guerra-Liberal FDC, Tavares AAS, Tavares JMRS (2016) Palliative treatment of metastatic bone pain with radiopharmaceuticals: a perspective beyond Strontium-89 and Samarium-153. Appl Radiat Isot 110:87–99

    Article  CAS  PubMed  Google Scholar 

  18. Kumar C, Korde A, Kumari KV, Das T, Samuel G (2013) Cellular toxicity and apoptosis studies in osteocarcinoma cells, a comparison of 177Lu-EDTMP and Lu-EDTMP. Curr Radiopharma 6:146–151

    Article  CAS  Google Scholar 

  19. Kumar C, Pandey BN, Samuel G, Venkatesh M (2013) Cellular internalization and mechanism of cytotoxicity of 131I-rituximab in Raji cells. J Environ Pathol Toxicol Oncol 32:91–99

    Article  CAS  PubMed  Google Scholar 

  20. Kumar C, Jayakumar S, Pandey BN, Samuel G, Venkatesh M (2014) Cellular and molecular effects of beta radiation from I-131 on human tumor cells a comparison with gamma radiation. Curr Radiopharm 7:138–143

    Article  CAS  PubMed  Google Scholar 

  21. Kumar C, Vats K, Lohar SP, Korde A, Samuel G (2014) Camptothecin enhances cell death induced by 177Lu- EDTMP in osteosarcoma cells. Cancer Biother Radiopharm 29:317–322

    Article  CAS  PubMed  Google Scholar 

  22. Kumar C, Pandey BN, Samuel G, Venkatesh M (2015) Doxorubicin enhances 131I-Rituximab induced cell death in Raji cells. J Can Res Ther 11:823–829

    Article  CAS  Google Scholar 

  23. Zhang W, Gao R, Yu Y, Guo K, Hou P, Yu M, Liu Y, Yang A (2015) Iodine-131 induces apoptosis in HTori-3 human thyrocyte cell line and G2/M phase arrest in a p53-independent pathway. Mol Med Rep 11:3148–3154

    Article  CAS  PubMed  Google Scholar 

  24. Lim SJ, Kim EH, Woo KS, Chung WS, Choi CW, Lim SM (2006) Induction of G2 arrest and apoptosis of Raji cells by continuous low dose beta irradiation with 188Re-perrhenate. Cancer Biother Radiopharm 21:314–320

    Article  CAS  PubMed  Google Scholar 

  25. Eriksson D, Blomberg J, Lindgren T, Löfroth PO, Johansson L, Riklund K, Stigbrand T (2008) Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells. Cancer Biother Radiopharm 23:541–550

    Article  CAS  PubMed  Google Scholar 

  26. Eriksson D, Löfroth PO, Johansson L, Riklund KA, Stigbrand T (2007) Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 Gy of ionizing radiation. Clin Cancer Res 13(18 Pt 2):5501 s-5508 s

  27. Yong KJ, Milenic DE, Baidoo KE, Brechbiel MW (2016) Mechanisms of cell killing response from low linear energy transfer (let) radiation originating from 177Lu radioimmunotherapy targeting disseminated intra peritoneal tumor xenografts. Int J Mol Sci 17(5):736

    Article  CAS  PubMed Central  Google Scholar 

  28. Kroger LA, DeNardo GL, Gumerlock PH, Xiong CY, Winthrop MD, Shi XB, Mack PC, Leshchinsky T, DeNardo SJ (2001) Apoptosis-related gene and protein expression in human lymphoma xenografts (Raji) after low dose rate radiation using 67Cu-2IT-BAT-Lym-1 radioimmunotherapy. Cancer Biother Radiopharm 16:213–225

    Article  CAS  PubMed  Google Scholar 

  29. Friesen C, Lubatschofski A, Kotzerke J, Buchmann I, Reske SN, Debatin KM (2003) Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukemia cells. Eur J Nucl Med Mol Imaging 30:1251–1261

    Article  CAS  PubMed  Google Scholar 

  30. Meng Z, Lou S, Tan K, Xu K, Jia Q, Zheng W (2012) Nuclear factor-kappa B inhibition can enhance apoptosis of differentiated thyroid cancer cells induced by 131I. PLoS ONE 7:e33597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumar C, Sharma R, Das T, Korde A, Sarma HD, Banerjee S, Dash A. (2018) 177Lu-DOTMP induces G2/M cell cycle arrest and apoptosis in MG63 cell line. J Labelled Comp Radiopharm https://doi.org/10.1002/jlcr.3651

  32. Moedritzer K, Irani RR (1996) Direct synthesis of α-aminomethyl phosphonic acid: mannich type reactions with o-phosphorus acid. J Org Chem 31:1603–1607

    Article  Google Scholar 

  33. Chakraborty S, Das T, Banerjee S, Balogh L, Chaudhari PR, Sarma HD, Polyák A, Máthé D, Venkatesh M, Janoki G, Pillai MRA (2008) 177Lu-EDTMP: a viable bone pain palliative in skeletal metastasis. Cancer Biother Radiopharm 23:202–213

    Article  CAS  PubMed  Google Scholar 

  34. Pillai MRA, Chakraborty S, Das T, Venkatesh M, Ramamoorthy N (2003) Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot 59:109–118

    Article  CAS  PubMed  Google Scholar 

  35. Das T, Sarma HD, Shinto A, Kamaleshwaran KK, Banerjee S (2014) Formulation, preclinical evaluation, and preliminary clinical investigation of an in-house freeze-dried EDTMP kit suitable for the preparation of 177Lu-EDTMP. Cancer Biother Radiopham 29:412–421

    CAS  Google Scholar 

  36. Das T, Chakraborty S, Unni PR, Banerjee S, Samuel G, Sarma HD, Venkatesh M, Pillai MRA (2002) 177Lu-labeled cyclic polyaminophosphonates as potential agents for bone pain palliation. Appl Radiat Isot 57:177–184

    Article  CAS  PubMed  Google Scholar 

  37. Das T, Pillai MRA (2013) Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl Med Biol 40:23

    Article  CAS  PubMed  Google Scholar 

  38. Naqvi SAR, Rasheed R, Ahmed MT, Zahoor AF, Khalid M, Mahmood S (2017) Radiosynthesis and preclinical studies of 177Lu-labeled sulfadiazine: a possible theranostic agent for deep-seated bacterial Infection. J Radioanal Nucl Chem 314:1023–1029

    Article  CAS  Google Scholar 

  39. ICRU Report 16: Linear Energy Transfer (1970) Volume os9, Issue 1, 15 June: 1-51

  40. Santivasi WL, Xia F (2014) Ionizing radiation-induced DNA damage, response, and repair. Antioxid Redox Signal 21(2):251–259

    Article  CAS  PubMed  Google Scholar 

  41. Mirkovic N, Meyn RE, Hunter NR, Milas L (1994) Radiation-induced apoptosis in a murine lymphoma in vivo. Radiother Oncol 33:11–16

    Article  CAS  PubMed  Google Scholar 

  42. He G, Siddik ZH, Huang Z, Wang R, Koomen J, Kobayashi R, Khokhar AR, Kuang J (2005) Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene 24(18):2929–2943

    Article  CAS  PubMed  Google Scholar 

  43. Mirzayans R, Andrais B, Scott A, Murray D (2012) New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. J Biomed Biotechnol 2012:170325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nicolini F, Burmistrova O, Marrero MT, Torres F, Hernández C, Quintana J, Estévez F (2014) Induction of G2/M phase arrest and apoptosis by the flavonoid tamarixetin on human leukemia cells. Mol Carcinog 53:939–950

    CAS  PubMed  Google Scholar 

  45. Chung TW, Lin SC, Su JH, Chen YK, Lin CC, Chan HL (2017) Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells. BMC Complement Altern Med 17:62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Norbury CJ, Zhivotovsky B (2004) DNA damage-induced apoptosis. Oncogene 23:2797–2808

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are thankful to staff members of the Radiochemical Section of Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC) for providing the 177LuCl3, produced in-house, used for the present study. The help rendered by the staff members of Animal House Facility, Radiation Biology and Health Sciences Division, BARC is also gratefully acknowledged.

Author information

Authors and Affiliations

  1. Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, 400085, India

    Chandan Kumar, Rohit Sharma, Kusum Vats, Madhav B. Mallia, Tapas Das & Ashutosh Dash

  2. Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, 400085, India

    H. D. Sarma

Authors
  1. Chandan Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rohit Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kusum Vats
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Madhav B. Mallia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tapas Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. D. Sarma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ashutosh Dash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chandan Kumar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, C., Sharma, R., Vats, K. et al. Comparison of the efficacy of 177Lu-EDTMP, 177Lu-DOTMP and 188Re-HEDP towards bone osteosarcoma: an in vitro study. J Radioanal Nucl Chem 319, 51–59 (2019). https://doi.org/10.1007/s10967-018-6283-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10967-018-6283-5

Keywords

Search

Navigation