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

Abstract

Summary Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [1311]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 electronemitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 1231-, 1251-, 1311-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 ([1231]MIBG and [1251]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [1311]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-' 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.Keywords: meta-iodobenzylguanidine; neuroblastoma; tageted radiotherapy; astatine Meta-iodobenzylguanidine (MIBG) is a structural analogue of the neuroadrenergic blocking drugs bretylium and guanethidine. It is selectively accumulated by an active mechanism in cells of neural crest origin. Radiolabelled MIBG allows the scintigraphic imaging of neural crest tumours (Weiland et al, 1980) and ['311]MIBG is used in the treatment of neuroblastoma and phaeochromocytoma (Hartmann et al, 1987;Mastrangelo, 1987;Schwabe et al, 1987;Voute et al, 1988). Clinical experience since 1984 has demonstrated its potential, with an objective response rate of 35% in patients with progressive heavily pretreated disease (Hoefnagel, 1994). Clinical studies are now evaluating the role of ['311]MIBG at an earlier stage in therapy, either as a first line treatment or in combination with other treatment modalities (DeKraker et al, 1995;Gaze et al, 1995;Mastrangelo et al, 1995).Although many patients show beneficial responses to ['311]MIBG treatment, a significant number subsequently relapse from previously undetected tumour sites (Sisson et al, 1989). This suggests that microtumours below the limit of clinical detectability have survived ['311]MIBG therapy. A possible explanation for the rela...

Megatherapy combining I131 metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma

“…4 In fact, it has been demonstrated that I 131 MIBG therapy effectiveness and toxicity may depend on the tumour size. Beta particles with a path length of 800 m may irradiate neighbouring cells, especially when the tumour size decreases.…”

“…Ten were females and seven were males. Median age at diagnosis was 3 years (range [1][2][3][4][5][6][7][8][9]. Median time between diagnosis and megatherapy was 7 months (range 4-46).…”

Experimental targeted radioiodide therapy following transfection of the sodium iodide symporter gene: Effect on clonogenicity in both two-and three-dimensional models

“…A recent report indicated that Auger electron -emitting radionuclides may also be capable of cell kill by means other than bombardment of nuclear DNA. 12 Although the short range of Auger electrons results in the absence of a bystander effect, single-cell toxicity would be of great use in circumstances such as the ex vivo purging of bone marrow or peripheral blood stem cells before autologous rescue, where it is desirable to minimize damage to normal hemopoietic cells.…”

Combining a targeted radiotherapy and gene therapy approach for adenocarcinoma of prostate

“…36 In addition to underdosing of small tumour deposits, long-range bemissions may damage surrounding normal tissues. [37][38][39] Owing to their short path length, radionuclides that decay by the emission of a-particles, such as the heavy halogen astatine-211 ( 211 At), offer the prospect of combining cell-specific molecular targeting with radiation having a range in tissue of only 50-80 mm. 40,41 Moreover, a-particles are much more radiotoxic than bemitting radionuclides and their cytocidal efficiency is independent of cell cycle status and oxygen concentra- Because of the anatomical position of the prostate gland, prostate cancer is an attractive target for this novel treatment strategy which combines gene transfer and radionuclide therapy.…”