Increased thermal response to ultrasound in the Walker carcinosarcoma treated with vasoactive drugs.

In order to evaluate the potential of a highly selective Ca2+ entry blocker (nisoldipine) and of 5-hydroxytryptamine (5-HT) as adjuvant in hyperthermia treatment, we studied the differential flow response and time-course of tumor and normal tissue temperature following the administration of the two substances and during ultrasound heating. In 12 rats bearing Walker 256 carcinomas i.p. injection of 0.2-0.4 mg/kg nisoldipine caused a reduction in the tumor-to-muscle flow relationship of 4.4 +/- 1.9 (SD) to 1.74 +/- 0.86 as determined by intraarterial 133Xe injection; i.p. injection of 2-8 mg/kg 5-HT (N = 13) caused a respective reduction from 3.9 +/- 2.67 to 1.3 +/- 1.59. During a 20-min period of 41 degrees C normal tissue temperature-controlled ultrasound heating without drugs, tumor temperature attained 40.8 +/- 0.9 degrees C (N = 16). Nisoldipine or 5-HT injection at continuing 41 degrees C normal tissue temperature controlled energy delivery produced an instantaneous further increment of tumor temperature, eventually to 44.0 +/- 1.14 degrees C or 44.2 +/- 1.26 degrees C, respectively, after a period of 20 min. Injection of 0.9% NaCl (N = 4) solution caused only insignificant changes. Blood pressure and muscle perfusion were distinctly influenced by nisoldipine, but not by 5-HT. Since both drugs instantaneously increased the temperature differential between tumor and normal tissue, though by different vasoaction, they should be considered as adjuvants in hyperthermia.

Selective drug-induced reduction of blood flow in tumor transplants.

The effect of a calcium antagonist and a physiologic amine on tumor and muscle perfusion was investigated with the aim of improving the preconditions for external hyperthermia treatment of cancer. Nisoldipine (0.04-4.0 mg/kg) and 5-hydroxy tryptamine (5-HT) (0.2-8.0 mg/kg) were administered i.p. in Sprague-Dawley rats bearing Walker 256 carcinoma, Yoshida sarcoma, or a homologous tumor transplant derived from a spontaneous leiomyosarcoma of the uterus. At the maximum dosage used, nisoldipine injection caused a decrease of the regional washout rate of Xenon-133 of 63 +/- 8% (SEM) in the Walker carcinoma and an increase of 80 +/- 41% in the muscle of the hind leg. 5-HT (8 mg/kg) caused a drop of 79 +/- 29% in the Walker carcinoma and only a slight fall of the washout rate in muscle of 14 +/- 4.8%. Tumor-to-muscle uptake ratios of 11C-butanol fell from 5.63 +/- 1.98 to 3.32 +/- 1.21, and from 5.3 +/- 0.56 to 2.98 +/- 0.30, after injection of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT, respectively. Similar reaction patterns and percentage changes were observed in different tumor lines at constant doses of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT. Both drugs representing two different rationales of vasomotor action were able to reduce blood flow specifically in transplanted tumors; nisoldipine increased muscle blood flow and decreased arterial blood pressure, whereas 5-HT acted without substantial systemic effects.

Effect of methotrexate on perfusion and nitrogen-13 glutamate uptake in the Walker-256 carcinosarcoma.

The tissue uptake of [13N]glutamate (glu) was related to that of [11C]butanol (but), a highly diffusible perfusion tracer. In 25 rats bearing Walker-256 carcinomas tumor-to-muscle glu uptake averaged 6.34 +/- 2.84 (s.d.) prior to interventions and the respective uptake of but was 6.79 +/- 3.08 (y = 0.03 + 0.94x). One hour after selective intraarterial administration of methotrexate (mtx), glu uptake fell by 47%, whereas blood flow remained within the pretreatment range (N = 9). Four hours after mtx, perfusion was reduced by approximately 40%, and 2 days later both perfusion and glu uptake reached extremely low levels. No significant difference in the effect of 10 and 50 mg/kg mtx was observed. Regional tissue mtx uptake estimations using 77Br-labeled bromomethotrexate did not reveal any significant uptake in muscle. The relationship between tumor-to-muscle uptake of glu and but (13N/11C-index) was 0.94 +/- 0.015 (s.e.m., N = 25) before intervention. After methotrexate (1 hr, 4 hr, and 2 days) this index was 0.58 +/- 0.06 (N = 9), and 0.85 +/- 0.04 (N = 11) and 1.03 +/- 0.05 (N = 5), respectively. These values demonstrate an early mtx-induced uncoupling of glu uptake with respect to perfusion.

Evaluation of complicating osteomyelitis with Tc-99m MDP, In-111 granulocytes, and Ga-67 citrate.

Studies with gallium-67 and three-phase bone imaging (TPBS), though very sensitive, are not very specific in evaluating suspected osteomyelitis (OM) that is superimposed upon other diseases causing increased bone turnover. A total of 57 patients with suspected OM were studied; this included 48 with increased bone turnover. All of the patients were studied with granulocytes labeled with In-111 acetylacetone (In-111 GRAN), TPBS and 29 of these patients had Ga-67 studies as well. In-111 GRAN had a sensitivity of 100% in acute OM and 60% in chronic OM, with a specificity of 96%. Gallium-67 was excellent in ruling out OM when the study was normal, or in ruling in OM when the relative uptake of Ga-67 exceeded the uptake of Tc-99m MDP, or when the Ga-67 in bone had a different distribution from the TPBS. Unfortunately, these criteria were met in only 28% of our subjects. We conclude that when added to TPBS, the In-111 GRAN study plays an important role in detecting complicating OM.

Synthesis, antitumor activity, distribution and toxicity of 4-[4-[bis(2-chloroethyl)amino]phenyl]-1-hydroxybutane-1 1-bisphosphonic acid (BAD), a new lost derivative with increased accumulation in rat osteosarcoma.

The aim of this study was to investigate whether the newly synthesized bisphosphonic acid-linked N-Lost derivative BAD retains bone-seeking and cytostatic properties. The paper describes experiments on mutagenicity in vitro and on toxicity in vivo. BAD is characterized by very low mutagenic activity toward histidine auxotrophic Salmonella typhimurium strains. Cytotoxic effects were tested in rat osteosarcoma and in Walker carcinosarcoma 256B. The LD50 of i.v. injected BAD was 146 mg/kg. Acute toxicity is probably caused by calcium complexing of the bisphosphonate part of the molecule. Labeling experiments showed moderate accumulation in bone and osteosarcoma, as well as in lung metastases. BAD effected high tumor growth inhibition in osteosarcoma and Walker carcinosarcoma-bearing rats and marked prolongation of survival; histologic and radiographic examination revealed rapid calcification of osteosarcoma and lung metastases. BAD-pretreatment produced protective effects against osteolysis induced by intratibially implanted Walker carcinosarcoma ascites cells. The cytostatic efficacy of equitoxic doses of BAD in rat osteosarcoma is comparable to that of dacarbazine and in Walker carcinosarcoma to that of melphalan.

A chemical dosimeter for the determination of the photodynamic activity of photosensitizers.

Uric acid a known singlet oxygen scavenger, was investigated as a chemical dosimeter in physiological aqueous solution for use in photodynamic therapy. The uric acid test takes the decrease in uric acid (UA) absorbance at 293 nm after laser light irradiation of a solution containing UA and a photosensitizer as a rapid evaluation of relative photodynamic activities of the photosensitizer. A uric acid test standard procedure was defined. To compare photodynamic activity of different photosensitizers or irradiation conditions a proposal for a photodynamic activity scale based on the uric acid test is given. Examples of uric acid test operation are given by comparing the changes in UA absorbance decrease with respect to irradiation wavelength and to photosensitizer concentration of Photofrin II with that of two other photosensitizers (5,10,15,20-tetrakis-[4-hydroxyphenyl]-21H,23H-porphyrin (TOP) and 5,10,15,20-tetrakis-[4-carboxyphenyl)-21H, 23H-porphyrin (TCPP), both derivatized with methoxypolyethyleneglycol (TOP-MPV and TCPP-AMP) as a macromolecular carrier). The photodynamic activity of the three photosensitizers using the proposed photodynamic activity scale is given.

[Leukocyte scintigraphy of inflammatory processes in the spinal column]. / Leukozytenszintigraphie bei entzündlichen Prozessen der Wirbelsäule.

Scintigraphic studies with labelled leucocytes in 30 patients with suspected inflammatory processes in the spinal column showed false negative results in all cases, even in acute inflammatory lesions. This is in contrast to the good results in detecting inflammatory bone processes in the non-axial parts of the skeleton, where an accuracy of 88% was found. These findings demonstrate that scintigraphy with labelled leucocytes is not suitable for diagnosing bacterial inflammatory diseases in the spinal column.

A new radioiodine exchange labeling technique.

A new technique of radioiodine exchange labeling is presented. The method was developed with respect to the short physical half lives of 123I and 121I, the altered activity concentrations and varying impurities, which hamper the previously introduced labeling methods. The described "one step reaction" is applicable to a series of organic compounds with different physicochemical and physiological behaviour as well as to all radioisotopes of iodine.

Position dependent renogram changes of the mobile kidney.

The present study evaluates the isotope renograms, obtained in prone and upright position of 87 patients with 93 mobile kidneys. Scintiphotos were made to determine the extent of renal movement. The transient position abnormality of the kidney was compared to the position dependent isotope renogram changes. It was possible to describe three types of floating kidney each with a characteristic motion and position dependent function disturbance. One form of renal ptosis, ptosis with ventral rotation, was commonly associated with a 2nd phase renogram abnormality and with hypertension.

Radioiodination of proteins and lipoproteins using N-bromosuccinimide as oxidizing agent.

In an attempt to improve conditions for radioiodination of sensitive proteins we used N-bromosuccinimide as a mild oxidizing agent. Under gentle conditions we increased the average labeling efficiency of a wide variety of proteins to above 97%. There was no loss of binding activity of low density lipoprotein particles, which are most sensitive to oxidation. Depending on high labeling efficiency, our method reduces preparation time as well as radioactive waste, costs, and irradiation exposure to personnel.