Whole-body hyperthermia and ADPRT inhibition in experimental treatment of brain tumors.

Malignant primary brain tumors have hitherto been incurable. One reason for this may be the migrating tumor cells that spread into the surrounding normal brain, creating the basis for inevitable recurrences. Therefore, local therapy may have a temporary effect, but for a cure, the treatment must reach all the tumor cells. Whole-body hyperthermia (WBH) is such a general treatment, which we have studied in a rat glioma model. Cells of the RG2 rat glioma cell line were inoculated in the right caudate nucleus of Fischer-344 rats, which were then either controls or treated with WBH, induced by a radiant heat device for 4-5 sessions of 30 min at body temperature 42 degrees C (rectal), and/or nicotinamide (NAM), an effective radiosensitizer in animal tumor models and an inhibitor of ADPRT (poly adenosine diphosphate ribosyl transferase), a chromatin-bound enzyme suggested to be important in the DNA repair system. We have shown that WBH 42 degrees C alone, or in combination with NAM, has no effect upon tumor growth if a larger number of RG2 cells (5,000) are inoculated. If only 1,000 cells are inoculated, a significant inhibitory effect (p < 0.05) is observed on tumor growth as compared to the untreated control animals. Thus, WBH is feasible, and in some circumstances effective, in a rat glioma model. WBH in combination with other therapies influencing cell metabolism may be of value in future postoperative treatment of human malignant brain tumors.

99mtc-unithiol complex, a new radiopharmaceutical for kidney scintigraphy III. Studies of labelling unithiol with 99mtc.

Labelling of 2, 3-dimercaptopropane sodiumsulphonate (Unithiol) with 99mTc resulted in essentially three components in the GCS pofile: the top zone, a low-molecular Complex A and a high-molecular Complex B. In the presence of tin metal a fourth component, Complex C, could be distinguished. Complex A was relatively independent of pH, the proportion of Complex B increased with increasing pH. Methods were developed for preparing, with over 80% labelling efficiency, either Complex A or Complex B, each having high stability in the preparation vials and in human blood.

Biophysical aspects of Am-241 and Pu-241 in the environment.

Most of plutonium released by nuclear explosions is Pu-241 which decays to Am-241. We have studied the deposition of Pu-241 and Am-241 in lichens collected since 1958 in the central part of Sweden (62.3 degrees N, 12. 4 degrees E). Comparative studies with Pu-isotopes, Pu-239 + 240 and Pu-238 were also performed. In 1972 the total accumulated deposition of Pu-241 was 8 mCi/km2 of Pu-239 + 240 1 mCi/km2 and of Am-241 0.2 mCi/km2. About 80% of the Am-241 activity has been formed in situ from decay of Pu-241. The biological mean-residence time for all Pu-isotopes were about 6 years and for Am-241 4 years. The spatial distribution of Am-241 in the lichen carpet is quite different from that of Pu-241. The activity concentrations of Am-241 and Pu-241 have been studied in reindeer liver and bone. The average concentrations found were in liver 0.6 and 40 pCi/kg, in bone 0.2 and 6 pCi per kg for Am-241 and Pu-241 respectively. The activity content of Am-241 and Pu-241 in the Lapps due to their reindeer diet was estimated to be in liver 1.0 E-4 and 1.0 E-2 pCi/kg, in bone (3-9) E-5 and 1.0 E-2 pCi/kg for Am-241 and Pu-241 respectively. The estimated values for the fractions of ingested activity retained were in liver 7 E-6 and 14 E-6, in bone 20 E-6 for Am-241 and Pu-241 respectively. The fraction of ingested activity of Pu retained in reindeer liver is about 2-3 times higher than that of Am.

Comparative labelling and biokinetic studies of 99mTc-EDTA(Sn) and 99mTc-DTPA(Sn).

Gelchromatography column scanning has been used to study the fractions of 99mTc-pertechnetate, 99mTc-chelate and reduced hydrolyzed 99mTc in preparations of 99mTc-EDTA(Sn) and 99mTc-DTPA(Sn). The labelling yield of 99mTc-EDTA(Sn) chelate was as high as 90--95% when 100 mumol EDTA-H4 and 0.5 mumol SnCl2 was incubated with 10 ml 99mTc-eluate for 30--60 min at room temperature. The study of the influence of the pH-value on the fraction of 99mTc-EDTA shows that pH 2.8--2.9 gave the best labelling yield. In a comparative study of the labelling kinetics of 99mTc-EDTA(Sn) and 99mTc-DTPA(SN) at different temperatures (7, 22 and 37degreesC), no significant influence on the reduction step was found. The rate constant for complex formation, however, increased more rapidly with increased temperature for 99mTc-DTPA(Sn). At room temperature only a few minutes was required to achieve a high labelling yield with 99mTc-DTPA(Sn) whereas about 60 min was required for 99mTc-EDTA(Sn). Comparative biokinetic studies in rabbits showed that the maximum activity in kidneys is achieved after 12 min with 99mTc-EDTA(Sn) but already after 6 min with 99mTc-DTPA(Sn). The long-term disappearance of 99mTc-DTPA(Sn) from the kidneys is about five times faster than that for 99mTc-EDTA(Sn).

99mTc-DTPA(Sn) dry-kit preparation. Quality control and clearance studies.

The preparation technique for 99m-Tc-DTPA(Sn)-complex has been studied in detail in order to find the optimal conditions for preparation. The concentration of DTPA should be at least 10 mM, and that of Sn(II) less than 1 mM, in order to obtain a reproducible high-labelling yield. A dry sterile kit was prepared of 39.3 mg H-5DTPA and 2.3 mg SnCl-2 with 2H-2O in a 10 ml vial. The 99m-Tc-DTPA(Sn) was prepared by adding the 99m-Tc-eluate to the vial. After 1 min the solution was sterile-filtered and was ready for use. The plasma clearance of 99m-Tc-DTPA(Sn) in man determined by blood-sampling up to 200 minutes after administration shows a good correlation to endogenous creatinine clearance (r plus 0.93). The plasma disappearance curve studied during 24 h is, however, a sum of three exponentials corresponding to biological half-times of 18 plus or minus 8 min, 105 plus or minus 9 min and 17 plus or minus 4 h. The slow third component representing about 2% is assumed to be due to binding of 99m-Tc to plasma proteins. The absorbed radiation dose calculated for whole body is 8 mrad/mCi, kidneys 50 mrad/mCi, bladder 300 mrad/mCi, ovaries 17 mrad/mCi and testes 11 mrad/mCi. This agent is a valuable radiopharmaceutical for renovascular clinical problems. Scintigraphic imaging of the aorta, kidneys, ureters and bladder (for residual urinary volume-determination) could be performed.