OLIGORADIONUCLIDETHERAPY USING RADIOLABELED ANTISENSE OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATES

Radiolabelled antisense oligodeoxynucleotides have been used for in vi vo biokinetic studies in AIDS and cancer patients. The therapeutic pos sibilities are still unknown and the major question in therapeutic use of radio-oligonucleotide is the optimal source of radiation. We studi ed the pharmacokinetics and in vivo tissue distribution for oligodeoxy nucleotide phosphorothioates by using the data from three different ra dionuclides: sulphur-35 (t(1/2) = 87.4 days, maximum beta-energy = 167 keV), phosphorus-33 (t(1/2) = 24.4 days, maximum beta-energy = 250 ke V) and phosphorus-32 (t(1/2) = 14.3 days, maximum beta-energy 2270 keV ). The absorbed doses of P-32-, P-33- and S-35-labelled oligonucleotid es 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 P-33 turned out to be higher than that of P-32 if the mass was smaller than similar to 300 mu g, and th e local absorption of S-35 was higher than that of P-32 when the mass was <80 mu g In a mouse tumour xenograft model an i.v. injected activi ty seemed to achieve sufficient radiation doses in the tumour: in a 1 g tumour 4.9 Gy for P-32, 5.1 Gy for P-33 and 5.5 Gy for S-35 were cal culated when the kidney dose was kept as 5 Gy. In the same model in sm aller tumours the doses were for a 1 mg tumour 0.73 Gy (P-32), 5.1 Gy (P-33) and 5.5 Gy (S-35), and for a 1 mu g tumour 0.08 Gy (P-32), 3.1 Gy (P-33) and 3.9 Gy (S-35). Thus, P-33 and S-35 have more beneficial radiotherapeutic characteristics than P-32. Relative advantage factors (P-33 and S-35 versus P-32) for kidney and liver doses using these nu clides varied from 0.997 to 1.001 for a 1 g tumour and there was no di fference in the radiation dose to normal organs. Therefore, we conclud e that in oligonucleotide radiotherapy tumours >1 g should be treated with P-32, whereas smaller tumours should be treated with P-33 or S-35 . There is no significant difference between P-33 and S-35, and either radionuclide could be selected according to labelling properties.