In vivo targeting of human neuroblastoma xenograft by anti-GD2/anti-Fc gamma RI (CD64) bispecific antibody.

Antidisialoganglioside (GD2) monoclonal antibodies can target in vitro and in vivo neuroblastoma cells. However, their in vivo use is limited by the presence of high levels of circulating IgG which hamper the recruitment of effector cells through the high affinity Fc gamma RI (CD64). A bispecific Fab' x Fab' antiGD2/antiFc gamma RI antibody (7A4 bis 22), which binds outside the IgG binding site of Fc gamma RI, was therefore developed. This antibody binds both human GD2+ neuroblastoma and Fc gamma RI+ activated macrophages in vitro. It can localise a GD2 positive neuroblastoma xenografted on Nu/Nu mice. Scintigraphy tumour/muscle ratios showed that targeting with this antibody has an excellent selectivity for the tumour over normal tissues. Furthermore, although its whole body clearance is more rapid than that of the 7A4 parental antibody over the first 48 h, its selective tumour uptake is similar, as shown by immunoscintigraphy imaging. Thus, such a bispecific antibody may represent an efficient tool for in vivo therapy of neuroblastoma through its ability to recruit Fc gamma RI+ effector cells even in presence of circulating IgG and to bind concomitantly GD2+ tumour cells.

Imaging and biodistribution of 125I tyramine oligonucleotide in nude mice bearing human breast tumor. Preliminary report.

Although the range of applications for antisense oligonucleotides is vast, current research concentrates mainly on virology and oncology. We have conducted in vivo and in vitro investigations of radiolabelling and biodistribution of a 22-mer phosphodiester oligonucleotide injected in athymic mice bearing xenograft of human mammary tumor (coculture: MCF7 and fibroblasts strain AF-11). Tumor/healthy tissue ratio of the 22-mer phosphodiester oligonucleotide fixation is high during the 24 hours after injection instead of fast elimination.

Strong uptake of 111In-pentetreotide by an MIBG-negative, xenografted neuroblastoma.

We investigated the distribution of 111In-pentetreotide (Octreoscan, Mallinckrodt) in nude mice xenografted with a human neuroblastoma cell line (SKLAN, derived from the LAN1 line). These cells develop into solid tumours in nude mice and can be grafted repeatedly in grafts of 10(8) cells. Animals were sequentially explored by scintigraphy 2, 4, 24 and 48 hr after i.v. injection of 2.5-4 MBq of the tracer and killed at various times up to 48 hr. 111In-pentetreotide was rapidly and strongly taken up by all tumours, with a tumour/muscle (T/M) ratio on resected samples of 20.0 +/- 5.7 at 2 hr, 23.7 +/- 3.0 at 4 hr, 75.6 +/- 12.6 at 24 hr and 78.7 +/- 12.4 at 48 hr, for tumours ranging from 0.5 to 8 g. Scintigraphy results were quantitatively in agreement. Pre-injection of a 15-20 times larger quantity of unlabelled octreotide s.c. reduced the tumour uptake by a factor of 2. For comparison, nude mice xenografted with the same cell line were also studied with 123I-MIBG (4 MBq). At 24 hr, the T/M ratio was 0.62 +/- 0.18. Two other cell lines (glioblastoma ROM and small-cell lung carcinoma SC41) which were similarly tested with 111In-pentetreotide (2.5-4 MBq) gave T/M ratios at 24 hr of 4.8 +/- 2.8 and 38.4 +/- 21.8, respectively. Pentetreotide seems to have a high affinity for this MIBG-negative neuroblastoma cell line, which exhibited a clearly higher tumour uptake than the 2 other lines. This work provides new experimental arguments in favour of the particular interest of somatostatin analogues in neuroblastoma and confirms our first clinical results.

Biodistribution of iodine-125 tyramine transforming growth factor alpha antisense oligonucleotide in athymic mice with a human mammary tumour xenograft following intratumoral injection.

The Watson-Crick base pairing rule provides the underlying principle for the antisense (AS) approach to inhibiting gene expression. Transforming growth factor alpha (TGFalpha) was the first growth factor to be associated with tumorigenesis, thus making the TGFalpha (mRNA) a potential target for AS therapy and offering the potential for monitoring of the progression of malignancy by non-invasive imaging with radiolabelled AS phosphodiester. Probe labelling and biodistribution were studied in the present report. A 23-mer oligonucleotide sequence was synthesized and grafted in 5' with a tyramine group which was further radioiodinated. The radiolabelled AS was injected intratumorally in mammary tumour-bearing BALB/c mice (3 weeks after inoculation of 7.10(6)NS2T2A mammary cells). Biodistribution was monitored by sequential scintigraphy and organ radioactivity after autopsy. The 5' tyramine group allowed specific and stable radiolabelling of the AS with 125I. The 125I AS oligonucleotide was rapidly cleared from the tumour by intestine and kidneys. Four hours after intratumoral injection, 6.5%+/-1.5% of the dose was retained in the tumour as non-degraded 125I AS. It is concluded that 5' tyraminylated AS provides information on the biodistribution of AS oligonucleotide following intratumoral injection. These data will contribute to the pharmacology of AS oligonucleotides which can be used for therapy.

The 1951-98 experience of the Paris Institut Curie Radiopathology Unit: a preliminary report.

From 1 January 1951 to 30 June 1998, 696 patients presented spontaneously or were referred to the French Institut Curie Radiopathology Unit following a more or less severe accidental irradiation. Of these, 568 patients came from France, while 128 were sent by various foreign countries. The very great majority of irradiation accidents occurred in the workplace, particularly in industry. Interestingly, 'non-nuclear' industry was responsible for three times more events than the nuclear industry. While incidental irradiation of the public by lost radioactive sources was exceedingly rare in France, it seemed to be more frequent in our cohort of foreign patients. Radiation phobia accounted for about 10% of cases in the French cohort, but the number of cases did not seem to increase with time. Overall, the accrual of patients over time appears to be stable, with 10 to 25 new cases consulting each year. Fortunately, a majority of cases corresponded to low-level irradiation (and even no irradiation at all). In the French cohort, only 21.6% of patients, showing deterministic effects, required some form of treatment, with 4.9% considered as 'severe' cases. Not unexpectedly, more patients required treatment in the foreign cohort (35.2%), with 24.2% of severe cases, including four deaths. The main features of this database are consistent with the data previously reported by the IAEA, UNSCEAR and REAC/TS. Although the number of severe cases is small, it should still be considered to be too high, especially as most of these accidents could have been easily avoided if a few basic radioprotection rules had been fully respected.