Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Jun;77(12):2061–2068. doi: 10.1038/bjc.1998.348

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions.

S H Cunningham 1, R J Mairs 1, T E Wheldon 1, P C Welsh 1, G Vaidyanathan 1, M R Zalutsky 1
PMCID: PMC2150394  PMID: 9649115

Abstract

Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [131I]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electron-emitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 123I-, 125I-, 131I- and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([123I]MIBG and [125I]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [131I]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml(-1) administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Biedler J. L., Roffler-Tarlov S., Schachner M., Freedman L. S. Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res. 1978 Nov;38(11 Pt 1):3751–3757. [PubMed] [Google Scholar]
  2. Bogenmann E. A metastatic neuroblastoma model in SCID mice. Int J Cancer. 1996 Jul 29;67(3):379–385. doi: 10.1002/(SICI)1097-0215(19960729)67:3<379::AID-IJC12>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  3. Bruchelt G., Girgert R., Buck J., Wolburg H., Niethammer D., Treuner J. Cytotoxic effects of m-[131I]- and m-[125I]iodobenzylguanidine on the human neuroblastoma cell lines SK-N-SH and SK-N-LO. Cancer Res. 1988 Jun 1;48(11):2993–2997. [PubMed] [Google Scholar]
  4. Charlton D. E. The range of high LET effects from 125I decays. Radiat Res. 1986 Aug;107(2):163–171. [PubMed] [Google Scholar]
  5. Clerc J., Halpern S., Fourré C., Omri F., Briançon C., Jeusset J., Fragu P. SIMS microscopy imaging of the intratumor biodistribution of metaiodobenzylguanidine in the human SK-N-SH neuroblastoma cell line xenografted into nude mice. J Nucl Med. 1993 Sep;34(9):1565–1570. [PubMed] [Google Scholar]
  6. De Kraker J., Hoefnagel C. A., Caron H., Valdés Olmos R. A., Zsiros J., Heij H. A., Voûte P. A. First line targeted radiotherapy, a new concept in the treatment of advanced stage neuroblastoma. Eur J Cancer. 1995;31A(4):600–602. doi: 10.1016/0959-8049(95)00063-o. [DOI] [PubMed] [Google Scholar]
  7. Gaze M. N., Huxham I. M., Mairs R. J., Barrett A. Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging. Int J Cancer. 1991 Apr 1;47(6):875–880. doi: 10.1002/ijc.2910470615. [DOI] [PubMed] [Google Scholar]
  8. Gaze M. N., Mairs R. J., Boyack S. M., Wheldon T. E., Barrett A. 131I-meta-iodobenzylguanidine therapy in neuroblastoma spheroids of different sizes. Br J Cancer. 1992 Dec;66(6):1048–1052. doi: 10.1038/bjc.1992.408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gaze M. N., Wheldon T. E., O'Donoghue J. A., Hilditch T. E., McNee S. G., Simpson E., Barrett A. Multi-modality megatherapy with [131I]meta-iodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: feasibility study of a new strategy for advanced neuroblastoma. Eur J Cancer. 1995;31A(2):252–256. doi: 10.1016/0959-8049(94)e0036-4. [DOI] [PubMed] [Google Scholar]
  10. Gaze M. N., Wheldon T. E. Radiolabelled mIBG in the treatment of neuroblastoma. Eur J Cancer. 1996 Jan;32A(1):93–96. doi: 10.1016/0959-8049(95)00511-0. [DOI] [PubMed] [Google Scholar]
  11. Gelfand M. J. Meta-iodobenzylguanidine in children. Semin Nucl Med. 1993 Jul;23(3):231–242. doi: 10.1016/s0001-2998(05)80104-7. [DOI] [PubMed] [Google Scholar]
  12. Guerreau D., Thedrez P., Fritsch P., Saccavini J. C., Metivier H., Nolibe D., Masse R., Coornaert S., Chatal J. F. In vitro therapeutic targeting of neuroblastomas using 125I-labelled meta-iodobenzylguanidine. Int J Cancer. 1990 Jun 15;45(6):1164–1168. doi: 10.1002/ijc.2910450629. [DOI] [PubMed] [Google Scholar]
  13. Haimovitz-Friedman A., Kan C. C., Ehleiter D., Persaud R. S., McLoughlin M., Fuks Z., Kolesnick R. N. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994 Aug 1;180(2):525–535. doi: 10.1084/jem.180.2.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hartmann O., Lumbroso J., Lemerle J., Schlumberger M., Ricard M., Aubert B., Coonaert S., Merline L., Olive D., De Lumley L. Therapeutic use of 131I-metaiodobenzylguanidine (MIBG) in neuroblastoma: a phase II study in nine patients. Med Pediatr Oncol. 1987;15(4):205–211. doi: 10.1002/mpo.2950150414. [DOI] [PubMed] [Google Scholar]
  15. Hoefnagel C. A. Metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours. Eur J Nucl Med. 1994 Jun;21(6):561–581. doi: 10.1007/BF00173045. [DOI] [PubMed] [Google Scholar]
  16. Hoefnagel C. A., Smets L., Voûte P. A., de Kraku J. Iodine-125-MIBG therapy for neuroblastoma. J Nucl Med. 1991 Feb;32(2):361–362. [PubMed] [Google Scholar]
  17. Howell R. W. Radiation spectra for Auger-electron emitting radionuclides: report No. 2 of AAPM Nuclear Medicine Task Group No. 6. Med Phys. 1992 Nov-Dec;19(6):1371–1383. doi: 10.1118/1.596927. [DOI] [PubMed] [Google Scholar]
  18. Humm J. L. Dosimetric aspects of radiolabeled antibodies for tumor therapy. J Nucl Med. 1986 Sep;27(9):1490–1497. [PubMed] [Google Scholar]
  19. Jarvis W. D., Kolesnick R. N., Fornari F. A., Traylor R. S., Gewirtz D. A., Grant S. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):73–77. doi: 10.1073/pnas.91.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kassis A. I., Fayad F., Kinsey B. M., Sastry K. S., Taube R. A., Adelstein S. J. Radiotoxicity of 125I in mammalian cells. Radiat Res. 1987 Aug;111(2):305–318. [PubMed] [Google Scholar]
  21. Larsen R. H., Bruland O. S., Hoff P., Alstad J., Lindmo T., Rofstad E. K. Inactivation of human osteosarcoma cells in vitro by 211At-TP-3 monoclonal antibody: comparison with astatine-211-labeled bovine serum albumin, free astatine-211 and external-beam X rays. Radiat Res. 1994 Aug;139(2):178–184. [PubMed] [Google Scholar]
  22. Link E. M., Brown I., Carpenter R. N., Mitchell J. S. Uptake and therapeutic effectiveness of 125I- and 211At-methylene blue for pigmented melanoma in an animal model system. Cancer Res. 1989 Aug 1;49(15):4332–4337. [PubMed] [Google Scholar]
  23. Link E. M., Carpenter R. N. 211At-methylene blue for targeted radiotherapy of human melanoma xenografts: treatment of cutaneous tumors and lymph node metastases. Cancer Res. 1992 Aug 15;52(16):4385–4390. [PubMed] [Google Scholar]
  24. Link E. M., Carpenter R. N. 211At-methylene blue for targeted radiotherapy of human melanoma xenografts: treatment of micrometastases. Cancer Res. 1990 May 15;50(10):2963–2967. [PubMed] [Google Scholar]
  25. Link E. M., Carpenter R. N., Hansen G. [211At]methylene blue for targeted radiotherapy of human melanoma xenografts: dose fractionation in the treatment of cutaneous tumours. Eur J Cancer. 1996 Jun;32A(7):1240–1247. doi: 10.1016/0959-8049(96)00023-8. [DOI] [PubMed] [Google Scholar]
  26. Mairs R. J., Angerson W., Gaze M. N., Murray T., Babich J. W., Reid R., McSharry C. The distribution of alternative agents for targeted radiotherapy within human neuroblastoma spheroids. Br J Cancer. 1991 Mar;63(3):404–409. doi: 10.1038/bjc.1991.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mairs R. J., Cunningham S. H., Russell J., Armour A., Owens J., McKellar K., Gaze M. N. No-carrier-added iodine-131-MIBG: evaluation of a therapeutic preparation. J Nucl Med. 1995 Jun;36(6):1088–1095. [PubMed] [Google Scholar]
  28. Mairs R. J., Gaze M. N., Watson D. G., Skellern G. G., Constable P., McKellar K., Owens J., Vaidyanathan G., Zalutsky M. R. Carrier-free 131I-meta-iodobenzylguanidine: comparison of production from meta-diazobenzylguanidine and from meta-trimethylsilylbenzylguanidine. Nucl Med Commun. 1994 Apr;15(4):268–274. doi: 10.1097/00006231-199404000-00157. [DOI] [PubMed] [Google Scholar]
  29. Mairs R. J., Livingstone A., Gaze M. N., Wheldon T. E., Barrett A. Prediction of accumulation of 131I-labelled meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction. Br J Cancer. 1994 Jul;70(1):97–101. doi: 10.1038/bjc.1994.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Makrigiorgos G. M., Berman R. M., Baranowska-Kortylewicz J., Bump E., Humm J. L., Adelstein S. J., Kassis A. I. DNA damage produced in V79 cells by DNA-incorporated iodine-123: a comparison with iodine-125. Radiat Res. 1992 Mar;129(3):309–314. [PubMed] [Google Scholar]
  31. Mastrangelo R. The treatment of neuroblastoma with 131I-MIBG. Med Pediatr Oncol. 1987;15(4):157–158. doi: 10.1002/mpo.2950150403. [DOI] [PubMed] [Google Scholar]
  32. Mastrangelo R., Tornesello A., Riccardi R., Lasorella A., Mastrangelo S., Mancini A., Rufini V., Troncone L. A new approach in the treatment of stage IV neuroblastoma using a combination of [131I]meta-iodobenzylguanidine (MIBG) and cisplatin. Eur J Cancer. 1995;31A(4):606–611. doi: 10.1016/0959-8049(95)00048-n. [DOI] [PubMed] [Google Scholar]
  33. O'Donoghue J. A., Bardiès M., Wheldon T. E. Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nucl Med. 1995 Oct;36(10):1902–1909. [PubMed] [Google Scholar]
  34. Obeid L. M., Linardic C. M., Karolak L. A., Hannun Y. A. Programmed cell death induced by ceramide. Science. 1993 Mar 19;259(5102):1769–1771. doi: 10.1126/science.8456305. [DOI] [PubMed] [Google Scholar]
  35. Sastry K. S. Biological effects of the Auger emitter iodine-125: a review. Report No. 1 of AAPM Nuclear Medicine Task Group No. 6. Med Phys. 1992 Nov-Dec;19(6):1361–1370. doi: 10.1118/1.596926. [DOI] [PubMed] [Google Scholar]
  36. Schwabe D., Sahm S., Gerein V., Happ J., Kropp-von Rabenau H., Maul F., Baum R. P., Manegold K., Nitz C., Hör G. 131-Metaiodobenzylguanedine therapy of neuroblastoma in childhood. One year of therapeutic experience. Eur J Pediatr. 1987 May;146(3):246–250. doi: 10.1007/BF00716467. [DOI] [PubMed] [Google Scholar]
  37. Shapiro B., Gross M. D. Radiochemistry, biochemistry, and kinetics of 131I-metaiodobenzylguanidine (MIBG) and 123I-MIBG: clinical implications of the use of 123I-MIBG. Med Pediatr Oncol. 1987;15(4):170–177. doi: 10.1002/mpo.2950150406. [DOI] [PubMed] [Google Scholar]
  38. Sisson J. C., Hutchinson R. J., Shapiro B., Zasadny K. R., Normolle D., Wieland D. M., Wahl R. L., Singer D. A., Mallette S. A., Mudgett E. E. Iodine-125-MIBG to treat neuroblastoma: preliminary report. J Nucl Med. 1990 Sep;31(9):1479–1485. [PubMed] [Google Scholar]
  39. Sisson J. C., Shapiro B., Hutchinson R. J., Shulkin B. L., Zempel S. Survival of patients with neuroblastoma treated with 125-I MIBG. Am J Clin Oncol. 1996 Apr;19(2):144–148. doi: 10.1097/00000421-199604000-00011. [DOI] [PubMed] [Google Scholar]
  40. Sisson J. C., Shapiro B., Hutchinson R. J., Zasadny K. R., Mallette S., Mudgett E. E., Wieland D. M. Treatment of neuroblastoma with [125I]metaiodobenzylguanidine. J Nucl Biol Med. 1991 Oct-Dec;35(4):255–259. [PubMed] [Google Scholar]
  41. Soule H. D., Vazguez J., Long A., Albert S., Brennan M. A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst. 1973 Nov;51(5):1409–1416. doi: 10.1093/jnci/51.5.1409. [DOI] [PubMed] [Google Scholar]
  42. Strickland D. K., Vaidyanathan G., Zalutsky M. R. Cytotoxicity of alpha-particle-emitting m-[211At]astatobenzylguanidine on human neuroblastoma cells. Cancer Res. 1994 Oct 15;54(20):5414–5419. [PubMed] [Google Scholar]
  43. Tritschler H. J., Medori R. Mitochondrial DNA alterations as a source of human disorders. Neurology. 1993 Feb;43(2):280–288. doi: 10.1212/wnl.43.2.280. [DOI] [PubMed] [Google Scholar]
  44. Vaidyanathan G., Zalutsky M. R. 1-(m-[211At]astatobenzyl)guanidine: synthesis via astato demetalation and preliminary in vitro and in vivo evaluation. Bioconjug Chem. 1992 Nov-Dec;3(6):499–503. doi: 10.1021/bc00018a006. [DOI] [PubMed] [Google Scholar]
  45. Vaidyanathan G., Zalutsky M. R. No-carrier-added synthesis of meta-[131I]iodobenzylguanidine. Appl Radiat Isot. 1993 Mar;44(3):621–628. doi: 10.1016/0969-8043(93)90179-e. [DOI] [PubMed] [Google Scholar]
  46. Vergote I., Larsen R. H., de Vos L., Nesland J. M., Bruland O., Bjørgum J., Alstad J., Tropé C., Nustad K. Therapeutic efficacy of the alpha-emitter 211At bound on microspheres compared with 90Y and 32P colloids in a murine intraperitoneal tumor model. Gynecol Oncol. 1992 Dec;47(3):366–372. doi: 10.1016/0090-8258(92)90141-5. [DOI] [PubMed] [Google Scholar]
  47. Voûte P. A., Hoefnagel C. A., de Kraker J. 131I-meta-iodobenzylguanidine in diagnosis and treatment of neuroblastoma. Bull Cancer. 1988;75(1):107–111. [PubMed] [Google Scholar]
  48. Weber W., Weber J., Senekowitsch-Schmidtke R. Therapeutic effect of m-[131I]- and m-[125I]iodobenzylguanidine on neuroblastoma multicellular tumor spheroids of different sizes. Cancer Res. 1996 Dec 1;56(23):5428–5434. [PubMed] [Google Scholar]
  49. Wheldon T. E., Livingstone A., Wilson L., O'Donoghue J., Gregor A. The radiosensitivity of human neuroblastoma cells estimated from regrowth curves of multicellular tumour spheroids. Br J Radiol. 1985 Jul;58(691):661–664. doi: 10.1259/0007-1285-58-691-661. [DOI] [PubMed] [Google Scholar]
  50. Wheldon T. E., O'Donoghue J. A., Barrett A., Michalowski A. S. The curability of tumours of differing size by targeted radiotherapy using 131I or 90Y. Radiother Oncol. 1991 Jun;21(2):91–99. doi: 10.1016/0167-8140(91)90080-z. [DOI] [PubMed] [Google Scholar]
  51. Wieland D. M., Wu J., Brown L. E., Mangner T. J., Swanson D. P., Beierwaltes W. H. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J Nucl Med. 1980 Apr;21(4):349–353. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES