Scintigraphic evaluation of functional hepatic mass in patients with advanced breast cancer.

Recent studies suggest a high specificity of 99mTc-galactosyl neoglycoalbumin (99mTc-NGA) receptor scanning in vivo by providing both morphological and functional diagnosis of liver disease. In 22 patients with advanced breast cancer 99mTc-NGA (150 MBq; 50 nmol) was exclusively trapped by the liver, the images showing 'cold spots' in areas of liver metastases formation. A two-tailed analysis was performed: the time activity curves recorded for the liver and precordial area were subjected to a kinetic receptor-calculating model allowing an estimation of the NGA-receptor concentration of the liver (i.e. hepatic binding protein, HBP) as well as calculation of the residual functional liver volume (RFLV) via the S.P.E.C.T.-study. In breast cancer patients with liver metastases a significantly (P < 0.01) lower HBP-concentration was estimated (0.65 +/- 0.16 vs 0.82 +/- 0.17 mumol l-1) as evidenced by a lower 99mTc-NGA-accumulation in the liver resulting also in a significantly (P < 0.001) lower RFLV (739 +/- 348 vs 1336 +/- 184 ml). In four amonafide-treated patients (800 mg m-2 intravenous infusion over 3 h) approximately one week after one chemotherapy cycle a significant (P < 0.05) increase in HBP-concentration (0.56 +/- 0.10 vs 0.72 +/- 0.06 mumol l-1) of the liver was found corresponding with an increase in RVLF (546 +/- 297 vs 670 +/- 265 ml). These regulatory mechanisms at the HBP level measured in vivo provide further evidence that 99mTc-NGA should have promise as a clinically useful receptor radiopharmaceutical for both quantification of liver function and assessment of liver morphology.

Antiradiation mixture and ionic-bond product of AET and adenyl nucleotides.

These experiments continued our line of inquiry into low-toxicity high-effectiveness radiomodifying agents obtained by binding radioprotective substances to biogenic and biologically active components or antidotes. Testes for toxicity and radioprotective effects were three preparations combining within one molecule AET and an adenyl nucleotide (AMP, ADP, or ATP). Ionic-bond formation was shown to have advantages over concomitant administration of AET and adenosine phosphoric acids as mixtures. The evidence obtained supports the rational foundation of the concept being developed by our laboratory.

Evaluation of somatostatin receptors in human cancer.

The binding of 123I-Tyr-3-octreotide (SDZ-204-090; specific activity 1 mCi/nmol), a new somatostatin-receptor binding radiopharmaceutical, to human tumour membrane fractions was evaluated in presence of unlabeled Tyr-3-octreotide and octreotide (SMS-201-995; Sandostatin). Tumour tissue was obtained intraoperatively from 15 patients with different endocrine tumours (insulinoma, carcinoide, phaechromocytoma, hypophysal adenoma) and breast cancer. In equilibrium experiments, membrane fractions (200 micrograms protein/ml) were incubated with increasing concentrations of 123I-Tyr-3-octreotide (0.03-30 nM) in presence or absence of 5 microM of unlabeled agonist. Binding capacities ranged from 1-20 pmol/mg protein (Kd 4-100 nM). The IC50 values (2.5-112 nM versus 0.02-69 nM) were different for the octreotide and Tyr-3-octreotide indicating that octreotide was the better competitor as Tyr-3-octreotide for 123I-Tyr-3-octreotide binding sites. In ductal breast cancer high numbers of in vitro binding sites for the radiolabel were found. In initial clinical studies 123I-Tyr-3-octreotide was i.v.-injected (3 mCi) to 5 acromegaly patients with hypophyseal adenomas. Following rapid uptake by the liver, positive tumour imaging was obtained in 3 patients which correlated to computer tomographic findings. Positive images were obtained just some minutes after injection. Our results support recent data suggesting that the 123I-Tyr-3-octreotide would be a suitable receptor-radiopharmaceutical for the localization of endocrine tumours.

[The antiradiation properties of betamide under conditions of sublethal and lethal gamma irradiation]. / Issledovanie protivoluchevykh svoistv betamida v usloviiakh subletal'nogo i letal'nogo gamma-oblucheniia.

Bone marrow cellularity in the femur, mass and cellularity of the spleen and small intestine, and nucleic acid concentration in the leukocyte mass of blood were investigated after the intraperitoneal administration of betamide (500 mg/kg) 15 min before gamma irradiation of mice with doses of 4, 7 and 9 Gy. The number of myelokaryocytes and splenocytes in the protected animals was shown to exceed considerably that in the controls on days 3 and 9 after irradiation with the three doses. With betamide injected on day 9 following irradiation the number of nucleated cells of the small intestine was larger and the nucleic acid concentration in leukocytes higher than the same indices in the irradiated control.

123I-tyrosine-(A14)-insulin: preparation and preliminary clinical studies.

Insulin was radioiodinated with 123I (123I-tyrosine-(A14)-insulin) to a specific activity of 1 micrograms/mCi, corresponding to 0.025 I.U. of insulin/mCi. This preparation was used for in vitro binding experiments with adipose tissue, showing active binding to the two subunits of the known insulin receptor. In a preliminary clinical investigation, 5 adipose patients with (n = 2) and without (n = 3) diabetes mellitus Type II, were subject to in vivo injection of the same radiolabeled product using 3 mCi/patient. During the first minutes of dynamic imaging, the liver was the major organ of tracer uptake in all patients. Furthermore, the pancreas, and in one patient the kidneys, were visualised. Further studies on insulin in vivo kinetics and quantification are under way.

[The prevention and treatment of experimental radiation injuries to the skin by using the Nucliderm-gel preparation]. / Profilaktika i lehcenie éksperimental;'nykh luchevykh povrezhdenii kozhi s pomoshch'iu preparata nukliderm-gel'.

Radiopreventive and radiotherapeutic efficacy of nuclyderm-gel was studied on tails of mice exposed to fractionated gamma-radiation of 90 Gy (15 + 30 + 45 Gy) and 75 Gy (45 + 30 Gy). Daily seven-day treatment with nuclyderm-gel prior to irradiation with increasing doses (15 + 30 + 45 Gy) and the subsequent continuous therapy were shown to delay and reduce skin reactions. Nuclyderm-gel was particularly effective when used therapeutically. The treatment of exposed areas, with the three-fold dose fractionation, was the optimum therapy scheme.

Antiradiation properties of alpha tocopherol, anthocyans, and pyracetam administered combined as a pretreatment course.

The effects of an pretreatment course (2 x 5 days) combining vitamin E 20 mg/kg, anthocyans 50 mg/kg, and pyracetam 200 mg/kg on animal survival after lethal irradiation (8 Gy) and blood formation after sublethal irradiation (6 Gy) were studied in mice. Assessments were based on records of an integral criterion, 30-day survival, of spleen weight and cellularity, and of bone-marrow cellularity. Pretreatment with the mixture distinctly raised survival rate (50%) in the protected population. The effect observed was shown to result from potentiating interactions between mixture components. Blood-forming organs experienced less radiation damage, and recovery processes in them were stimulated.

Electrophoretic mobility of erythrocytes from adeturone-pretreated rats exposed to gamma or high-energy protons.

Change in electrophoretic mobility (EM) of erythrocytes was studied 6 hours after rats were exposed to a dose range (0.5-4 Gy) of high-energy protons (9 GeV/nucleon) or gamma rays (0.660 MeV), with or without adeturone pretreatment (300 mg/kg body weight). With either of the two radiation types used, EM of the cells was observed to undergo significant dose-related decline. As indicated by our findings, adeturone pretreatment failed to contribute to maintenance of normal erythrocyte surface charge in the case of proton irradiation, proving, nevertheless, effective against gamma-ray exposure at all dose levels used.

[The course of skin radiation reactions after treatment with the preparation nucliderm-gel]. / Techenie luchevykh reaktsii kozhi posle obrabotki preparatom nukliderm-gel'.

The process of epithelialization and the antiseptic effect of nucliderm-gel applied locally have been studied on 63 oncologic patients subjected to radiotherapy. In all cases under study, nucliderm-gel promotes skin epithelialization and has a high antiseptic effect as compared with the drugs applied hitherto.

[Effect of adeturon on postradiation macromolecular synthesis in the peripheral blood leukocytes of gamma ray-irradiated rats]. / Vliianie adeturona na postradiatsionnyi sintez makromolekul v leikotsitakh perifericheskoi krovi obluchennykh gamma-luchami krys.

DNA, RNA and protein syntheses were studied in peripheral blood leucocytes of irradiated (1-7 Gy) rats. Adeturon was shown to produce a pronounced protective effect on DNA synthesis progressively inhibited by the doses applied. The protective effect of the agent was not manifest with the slightly increased synthesis of RNA. There was a trend toward normalization of the increased protein synthesis.

Adeturone protection of hemopoiesis in lethally irradiated mice and rats.

Experiments were carried out to investigate the possibility of providing chemical protection to blood forming organs and increasing animal survival rates in lethally irradiated H mice and Wistar rats. A 300 mg/kg dose of the radioprotective agent was injected intraperitoneally 15-30 min prior to irradiation with 8.0 Gy gamma rays. Recorded were 30-day survival rates and the state of hemopoiesis on days 3 and 10 postradiation as judged by spleen weight and total counts of spleno- and myelokaryocytes. At 8.0 Gy exposure was observed to cause severe spleen and bone-marrow hypoplasia on day 3 postradiation. Adeturone pretreatment provided slight protection to rat spleen and mouse bone marrow; by day 10, however, both animal species exhibited a vigorous proliferative response of nucleated cells in the bone marrow, which resulted in 75% survival rate among animals exposed to a lethal radiation dose.

Cistiside-M, a new protective agent.

The toxicological and radiopharmacological properties of the agent Cistiside-M (2-mercaptoethylamine adenosine-5-phosphate) were investigated on male mice, lines C57Bl and H. The compound was administered intraperitoneally in doses from 1000 to 125 mg/kg, 15 min prior to lethal gamma-irradiation using a 137Cs source in the 6 to 15 Gy range. The radioprotective effect was assessed by the integral indices of 30-day survival, mean survival time, coefficient of protection alpha, S30 and the dose-reduction factor (DRF). The compound was characterized by low toxicity and good antiradiation effect in a wide dose range. Maximum degree of radioprotection (75% survival) was established when the agent was administered in a dose of 1000 mg/kg. DRF was 1.6. The dose of 250 mg/kg was interesting--with 50% survival rate and increase of the therapeutic index to 5.6. The low toxicity and the considerable radioprotective effect of the compound are due to its complex structure.

[Radiation injuries to mice in relation to the modes of administration of adeturon]. / Radiatsionnoe porazhenie myshei v zavisimosti ot sposobov primeneniia adeturona.

In experiments with mice the influence of adeturon, a preparation obtained in Bulgaria, on the survival rate, leucocytes dynamics, cellularity of bone marrow and spleen, and on nucleic acids in the peripheral blood has been investigated. The comparative analysis of the results obtained indicates that the protective and therapeutic administration of adeturon is more effective than a single injection of the drug immediately after irradiation.

[Effect of the radioprotector adeturon on radiation injury in mice with Lewis carcinoma of the lung]. / Vliianie radioprotektora adeturona na radiatsionnoe porazhenie myshei s kartsinomoi legkikh L'iuisa.

A study was made of the radioprotective effect of Adeturon, a protective agent obtained in Bulgaria, on mice with Luis lung tumors exposed to fractionated radiation. The effect of the radioprotector on a radiation-induced injury to normal tissue was estimated by the number of leucocytes in the peripheral blood and its count, cellularity of bone marrow and spleen and the mass of the latter, and by the number of exogenous and endogenous CFUs. A pronounced radioprotective effect of Adeturon was implemented through maintaining or normalizing the indices under study impaired by tumor inoculation or irradiation.

S-[(N,N'-diarylamidino)methyl] diethyldithiocarbamates and related amides as potential radioprotectants.

A series of symmetrically and unsymmetrically N,N'-diaryl-substituted amidinomethyl diethyldithiocarbamates and corresponding amides have been synthesized and tested for potential radioprotective activity. Antiradiation data for 10 amidines are presented. Half of the amidines showed low toxicity and radioprotective activity, based on both protective index (PI) and 30-day survival (greater than 35%) after lethal irradiation (800-rad X-rays). All (N-arylcarbamoyl)methyl diethyldithiocarbamates investigated were nonprotective.

Effect of Eleutherococcus extract on the radioprotective action of adeturone.

The effect of successive prophylactic administration of the adaptogen Eleutherococcus and the chemical radioprotector Adeturone on the radiation injury in rats is investigated. The experiments were carried out on sexually mature male Wistar rats weighing 170 +/- 10 g. For 14 days the animals drank water containing Eleutherococcus extract (Medexport), 5 g/kg body weight. On the 7th and 14th days the daily dose of the extract was administered totally using a probe. One hour prior to the last intake, the rats were irradiated with 3 Gr using a 137Cs source, 15 min earlier part of them were injected intraperitoneally with 300 mg/kg Adeturone. The effect of the independent and successive administration of the two agents on the postradiation damage and recovery was tested on the 1st, 3rd, 10th, 20th and 30th days after the irradiation by the change in the leucocyte count and in the quantity of nucleic acids in the leucocytic mass of the blood. The independent application of the adaptogen and radioprotector have a favourable effect only on the course of the recovery processes. Successive administration of the two agents results in mutual potentiation of the effects and guarantees a high degree of protection. This is probably due to an increase in the natural radiation resistance and to the rats' capacity for adaptation during the acute phase of the radiation stress.