Oligoradionuclidetherapy using radiolabelled antisense oligodeoxynucleotide phosphorothioates.

Abstract

Radiolabelled antisense oligodeoxynucleotides have been used for in vivo biokinetic studies in AIDS and cancer patients. The therapeutic possibilities are still unknown and the major question in therapeutic use of radio-oligonucleotide is the optimal source of radiation. We studied the pharmacokinetics and in vivo tissue distribution for oligodeoxynucleotide phosphorothioates by using the data from three different radionuclides: sulphur-35 (t1/2 = 87.4 days, maximum beta-energy = 167 keV), phosphorus-33 (t1/2 = 24.4 days, maximum beta-energy = 250 keV) and phosphorus-32 (t1/2 = 14.3 days, maximum beta-energy = 2270 keV). The absorbed doses of 32P-, 33P- and 35S-labelled oligonucleotides were estimated using the published biodistribution data for several oligonucleotides in two animal models for both tumour xenografts and AIDS. The local energy absorption of 33P turned out to be higher than that of 32P if the mass was smaller than approximately 300 micrograms, and the local absorption of 35S was higher than that of 32P when the mass was <80 micrograms. In a mouse tumour xenograft model an i.v. injected activity seemed to achieve sufficient radiation doses in the tumour: in a 1 g tumour 4.9 Gy for 32P, 5.1 Gy for 33P and 5.5 Gy for 35S were calculated when the kidney dose was kept as 5 Gy. In the same model in smaller tumours the doses were for a 1 mg tumour 0.73 Gy (32P), 5.1 Gy (33P) and 5.5 Gy (35S), and for a 1 microgram tumour 0.08 Gy (32P), 3.1 Gy (33P) and 3.9 Gy (35S). Thus, 33P and 35S have more beneficial radiotherapeutic characteristics than 32P. Relative advantage factors (33P and 35S versus 32P) for kidney and liver doses using these nuclides varied from 0.997 to 1.001 for a 1 g tumour and there was no difference in the radiation dose to normal organs. Therefore, we conclude that in oligonucleotide radiotherapy tumours >1 g should be treated with 32P, whereas smaller tumours should be treated with 33P or 35S. There is no significant difference between 33P and 35S, and either radionuclide could be selected according to labelling properties.