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PubMed2004

Targeting of a head and neck squamous cell carcinoma xenograft model using the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker.

OBJECTIVE: High rates of local recurrence and distant metastases following surgery of high-grade head and neck squamous cell carcinoma (HNSCC) necessitate the use of adjuvant systemic treatment. Radioimmunotargeting might be a possible treatment modality in this case. The nuclear properties of 131I make it a suitable isotope for treatment of minimal residual disease and small metastases, but the conventional radioiodine label has poor cellular retention and its radiocatabolites accumulate in the thyroid. We attempted to overcome these problems by using closo-dodecaborate derivatives for attachment of radioiodine. MATERIAL AND METHODS: We investigated the feasibility of targeting an SCC25 HNSCC xenograft in vivo using a benzylisothiocyanate derivative of closo-dodecaborate (DABI) as radioiodine linker and the chimeric anti-CD44v6 antibody U36. 125I was used in biodistribution studies. RESULTS: The use of DABI enabled tumor targeting and decreased the radioactivity uptake of the thyroid. CONCLUSION: Tumor localization of DABI-labeled U36 was similar to its para-iodobenzoate-labeled counterpart, presumably due to the strong dependence of targeting efficiency on tumor size.

Animals↗

PubMed2006

Cellular processing in the SW1222 cell line of mAb A33 directly and indirectly radiohalogenated.

Investigations into the cellular processing of radiolabeled monoclonal antibodies (mAbs) for their further use in radioimmunodiagnosis and cancer therapy are needed in order to understand the fate of internalized and catabolized mAbs. The anti-colorectal cancer mAb, A33, was labelled with 76Br and 125I using the direct Chloramine-T method, or by labelling N-succinimidyl para-(tri-methylstannyl) benzoate and its further conjugation to the mAb. The cellular processing of the four conjugates was investigated in SW1222 cells in vitro. Uptake of mAb was rapid, peaking after 14-16 h. Intracellular degradation was slow and the early loss of radioactivity was due to dissociation of cell-surface bound mAb. The indirect labelling resulted in stronger binding of the mAb as well as prolonged intracellular retention of the radiolabel. Direct and indirect halogen radiolabelling results in different cell-processing patterns of radiolabels, and radioactive catabolic products follow different routes of cellular excretion. The results of this cellular study indicate that indirect labelling is preferable to the direct Chloramine-T method.

Antibodies, Monoclonal↗

PubMed1985

Studies directed toward labeling analysis of angiotensin II in plasma.

We assay a 1-mL plasma sample containing angiotensin II (103 pg by radioimmunoassay) for the hormone by the following sequence of steps: add 125I-labeled val5-angiotensin II as an internal standard, extract on a C18 Sep Pak column, extract on an antibody affinity column, label the extract with an 125I Bolton-Hunter reagent, separate on a Bio Gel P2 column, and repetitively separate on a reversed-phase "high-performance" liquid-chromatographic column, detecting the eluting compounds by counting radioactivity. The fact that we measured 46 pg of angiotensin II-like substance per milliliter in a sample of pooled plasma is encouraging for the further development of this methodology. In particular, replacing the radioisotope with a more suitable chemical label such as an electrophoric (electron-capturing) release tag should be useful.

Angiotensin II↗

PubMed1996

The transfer of interleukin-8 across the human placenta perfused in vitro.

OBJECTIVE: To assess the placental transfer of interleukin (IL)-8 in vitro. METHODS: Eighteen placentas obtained immediately after delivery were perfused with a mixture of 125I-labeled IL-8 (IL-8*) and unlabeled IL-8 in two different concentrations. Antipyrine was coinfused in all experiments as a reference compound. Fetal-to-maternal and maternal-to-fetal perfusions were performed. Radioactivity was measured in a gamma counter at the end of each perfusion experiment. In four experiments, unlabeled IL-8 was analyzed in addition to labeled IL-8 to exclude a change in the IL-8/IL-8* ratio resulting from membrane transfer. RESULTS: Two of the 18 experiments had to be discarded because of poor transfer of antipyrine. There was only faint accumulation of radioactivity in the transplacental compartment, regardless of whether the test substance was added maternally or fetally. Because measurement of unlabeled IL-8 yielded negative results, the radioactivity is clearly attributable to free iodine 125, which is generated during IL radiolabeling or which disassociates from IL-8 in small amounts after radiolabeling. CONCLUSION: Interleukin-8 does not appear to cross the placenta by simple diffusion, regardless of the concentration or the perfusion rate. The impermeability of the placenta to the diffusion of IL-8 might explain why there is insufficient correlation between serum and amniotic fluid cytokine concentrations of pregnant women and the presence of the amnion infection syndrome.

Biological Transport↗

PubMed1976

Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes.

The addition of 0.1 mug/ml of phorbol myristate acetate (PMA) to a suspension of resting human neutrophils causes a marked stimulation of all aspects of cellular oxidative metabolism normally associated with phagocytosis. PMA induces a greatly increased rate of glucose oxidation via the hexose monophosphate shunt, increased production of superoxide anion and of hydrogen peroxide, increased cellular chemiluminescence, and increased iodination of protein material. The time course of hexose monophosphate shunt activation and of chemiluminescence are similar to those observed following phagocytosis of opsonized zymosan; the levels of activation achieved in all cases approximate those seen following phagocytosis. These phenomena are not simply reflections of altered cellular permeability, since PMA actually inhibits the uptake of radioactive 2-deoxyglucose and of uniformly labeled amino acids. The addition of PMA similarly inhibits the uptake of 14C-labeled bacteria, suggesting a competition between the effect of the chemical and the process of phagocytosis. These results suggest that PMA activates the cell in the same manner as does phagocytosis. This compound should provide a useful tool for elucidating the metabolic events underlying the phenomena of phagocytosis and bacterial killing by polymorphonuclear leukocytes.

Amino Acids↗

PubMed1980

Proteins iodinated by the chloramine-T method appear to be degraded at an abnormally rapid rate after endocytosis.

Proteins labeled with either (3)H by reductive methylation or (125)I by the chloramine-T method were incubated with Xenopus laevis oocytes; the incorporation and acid precipitability of the proteins were then studied. The uptake rates of both specifically incorporated (vitellogenin) and nonspecifically incorporated proteins (bovine serum albumin and X. laevis serum proteins lacking albumin) were not influenced by the method of labeling. However, (125)I-labeled proteins were apparently degraded at rates far exceeding their (3)H-labeled counterparts, based on the generation of acid-soluble radioactivity. Thus, after a 3-hr incubation, 3-5 times more (125)I-labeled bovine serum albumin and X. laevis serum proteins lacking albumin were degraded than the corresponding (3)H-labeled proteins (95% compared to 30% and 75% compared to 15%, respectively), whereas after a 24-hr incubation, the degradation of (125)I-labeled vitellogenin was 15 times greater than that of [(3)H]vitellogenin labeled in vivo (60% compared to 4%). Moreover, examination of the relative amounts of (3)H- compared to (125)I-labeled bovine serum albumin deposited into the exogenously derived yolk platelet compartment of the oocyte revealed 7 times more acid-precipitable (3)H-labeled protein, indicating that the observed discrepancies were not due to reincorporation of the (3)H-labeled ligands. Passage of dissolved oocytes previously exposed to (125)I-labeled bovine serum albumin (chloramine-T method) over a column of Bio-Gel P-10 revealed some breakdown of bovine serum albumin to intermediate molecular weight components and the presence of a large amount ( approximately 90%) of labeled low molecular weight compounds, which analysis showed to be 72% free iodine. The evolution of either iodotyrosine or free iodine would nevertheless be perceived as protein degradation by most analytical procedures (e.g., acid precipitation or autoradiography). We conclude, therefore, that apparent degradation rates observed for endocytotically incorporated proteins may vary depending on the method used to label the protein and caution should be exercised when interpreting results obtained with labeled, particularly chloramine-T labeled, proteins.

Animals↗

PubMed1983

Synthesis of radioiodinated metyrapone--a potential adrenal imaging agent.

Metyrapone has been labelled with radioiodine selectively in the 4'-position of ring B. The synthesis of 123I-(131)-metyrapone involves four intermediate compounds. 4'-Bromo-metyrapone serves as a stable precursor that is labelled before use. Studies of the biodistribution of [131I]metyrapone in rats indicate the highest concentration in the adrenal gland 10 min after the injection with a fast elimination of the radioactivity. However, the absolute uptake in the normal adrenal is low. When [123I]metyrapone was used in a patient with bilateral hyperplasia, faint adrenal images were obtained.

Adrenal Glands↗

PubMed1990

In vitro covalent binding of new brain tracer, para-125I-amphetamine, to rat liver and lung microsomes.

p-125I-amphetamine (I-Amp) is retained significantly in liver and lung during brain tomoscintigraphy. To attempt to explain this clinical observation, we have investigated the interaction of I-Amp with rat liver and lung microsomal proteins. Studies using spectral shift technique indicate that low concentration of I-Amp gives a type I complex and high concentration appears very stable type II complex with cytochrome P-450 Fe III. In the presence of NADPH, I-Amp gives rise to a 455 nm absorbing complex with similar properties to the Fe-RNO complexes. This complex formation was greatly enhanced with phenobarbital treated liver microsomes. The in vitro binding study shows that I-Amp and/or its metabolites was covalently bound to macromolecules in the presence of the molecular oxygen and NADPH-generating system. Incubation in the presence of glutathione, cystein and radical scavengers decreases binding. Mixed function oxydase (MFO) inhibitors diminish the amount of covalent binding and alter the extent of metabolite formation. The total covalent binding level increased with liver microsomes from PB pretreated rats as it was observed with the 455nm complex formation. The radioactivity distribution on microsomal proteins was examinated with SDS polyacrylamide gel electrophoresis and autoradiography. This experiment proves that the radiolabelled compounds are bound on the cytochrome P-450. The radioactivity bound increased when the PB induced rat liver microsomes were used. All these results indicate that I-Amp was activated by an oxydative process dependent on the MFO system which suggests a N-oxydation of I-Amp and the formation of reactive entities which covalently bind to proteins.

Amphetamine↗

PubMed1984

In vivo specific uptake of labeled insulin by turtle (Chrysemys dorbigni) thyroid gland.

Insulin labeled with 125I was injected into turtles to study its specific uptake by the thyroid gland. The gel filtration behavior of labeled material in blood and thyroid gland was determined in order to ascertain if the uptake is specific. Most animals were pretreated with KI to saturate the gland with iodide. Maximum specific uptake of radioactivity by the thyroid gland was only detected in animals pretreated with KI. A significant dose-related reduction (ED50 = 0.5 micrograms/kg) was observed when unlabeled insulin was administered simultaneously with 125I-insulin. Prolactin, glucagon and growth hormone (2 mg/kg) did not affect 125I-insulin uptake. Most of the radioactive material extracted from the turtle thyroid 15 min after 125I-insulin injection coeluted with 125I-insulin on Sephadex G-50. This peak decreased as a function of time after 125I-insulin administration. Similar elution patterns were found for thyroid extracts from turtles previously treated with KI. The labeled hormone in the gland was rapidly degraded or processed to both higher and lower molecular weight compounds. Prior administration of KI suppressed the former, whereas when unlabeled insulin was injected simultaneously with 125I-insulin the amount of degradation products was reduced. The demonstration of radioactive degradation products is consistent with the intracellular receptor-mediated degradation hypothesis. These findings indicate the presence of specific insulin-binding sites in the thyroid gland.

Animals↗

PubMed1980

Induction of surface glycoprotein expression by cyclic AMP in Chinese hamster ovary cells.

Surface expression of a membrane glycoprotein of 135,000 molecular weight (P135) was inducible by adenosine 3',5' -cyclic monophosphate in Chinese hamster ovary cells, CHO-K1 clone. Cells were cultured in the presence or absence of cyclic AMP derivatives, chemicals influencing cytoplasmic cyclic AMP levels, or inhibitors of protein or RNA synthesis. Surface proteins wre radiolabeled by a lactoperoxidase-catalyzed iodination reaction and analyzed by two-dimensional polyacrylamide gel electrophoresis. Surface expression of P135 increased 3---5-fold inthe presence of N6,O2' -dibutyryl cyclic AMP or 8-parachlorophenylthio cyclic AMP. Induction was also observed after treatment with prostaglandins E1 and F2 alpha, but not with sodium butyrate. Phosphodiesterase inhibitor, Roche compound Ro20-1724, enhanced the effect of N6,O2' -dibutyryl cyclic AMP. Metabolic incorporation of [35S]methionine into P135 was increased by N6,O2' -dibutyryl cyclic AMP. The induction was sensitive to inhibitors of protein and RNA biosynthesis. These results are consistent with a proposal that cyclic AMP controls the synthesis of this protein. Metabolic incorporation of a radioactive precursor suggested that P135 was a glucos-amine-containing glycoprotein. P135 appeared to be strongly associated with cell membrane because it was resistant to extraction of plasma membrane by cole 0.1 N NaOH.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗

PubMed1996

The role of the sheath in resistance of Haemonchus contortus infective-stage larvae to proteolytic digestion.

Surface iodinated larvae of Haemonchus contortus were incubated in the presence of the fungal protease, proteinase K, and proteolysis quantified by scintillation counting of released radioactivity. No radioactivity was released from live ensheathed infective-stage larvae (L3(2M)). In contrast, 58% of the radioactivity was released from ecdysed, second molt (2M) cuticles (sheaths) of L3(2M) and 48% from live exsheathed third-stage larvae (L3). When L3(2M) larvae were killed by heat (80 degrees C for 10 min) prior to proteinase K incubation, 61% of the radioactivity was released, whereas less than 7% was released from larvae killed by the metabolic inhibitors NaN3 or KCN. Proteinase K released 44% of the radioactivity from live L3(2M) larvae which had been preincubated with 1% sodium dodecylsulfate (SDS), whereas no radioactivity was released from L3(2M) larvae preincubated with either 1% Triton X-100, 0.2% CTAB, 50% methanol, 50% ethanol, or water. Following incubation with proteinase K, only L3(2M) larvae which had been heat-killed or preincubated with SDS showed visible damage to the sheath. Material released from L3(2M) larvae by exposure to either heat or SDS contained a 98,000 M(r) protein by SDS-PAGE autoradiography. These results indicate that viable L3(2M) larvae are resistant to attack by proteinase K and that this resistance is dependent on structural properties of the sheath.

Animals↗

PubMed1997

A non-radioactive and two radioactive assays for selenophosphate synthetase activity.

Selenophosphate synthetase catalyzes the formation of monoselenophosphate (SePO3(3-)) from ATP and selenide (reaction 1). [formula: see text] In one assay frequently used, [8-14C]AMP formation from [8-14C]ATP is estimated after separation of the nucleotides by thinlayer chromatography. An alternative non-radioactive assay in which the AMP product is estimated using AMP deaminase is described. The highly oxygen-labile selenophosphate product can be estimated in an assay employing [gamma-32P]ATP. The 32P-labeled selenophosphate is converted to [32P]orthophosphate by treatment with iodine and estimated after removal of residual [32P]ATP on charcoal.

Adenosine Monophosphate↗

PubMed1993

Synthesis of A-ring fluorinated derivatives of (17 alpha,20E/Z)-[125I]iodovinylestradiols: effect on receptor binding and receptor-mediated target tissue uptake.

We have prepared a series of 2- and 4-fluoro derivatives of the isomeric (17 alpha,20E)- and (17 alpha, 20Z)iodovinylestradiols (IVE2) and also the analogs substituted with either a 7 alpha-methyl (7 alpha-Me-IVE2) or 11 beta-methoxy group (11 beta-OMe-IVE2) and evaluated their in vitro and in vivo properties. Electrophilic substitution of the estrone derivatives with N-fluoropyridinium salt gave the 2- and 4-fluoro analogs which were subsequently converted to the 17 alpha-ethynyl derivatives. The tributylstannyl intermediates were obtained from the corresponding 17 alpha-ethynyl analogs using azobisisobutyronitrile or triethylborane as catalyst. All 12 products were also prepared as their no-carrier-added [125I]iodovinyl analogs via destannylation of the tributylstannyl precursors. Binding affinity for the estrogen receptor (ER) was in general higher for the 4-F derivatives as compared to the 2-F derivatives, while the 20Z isomers of the same compounds showed somewhat higher ER binding affinity as compared to the 20E isomers. The combination of an A-ring fluoro and 7 alpha- or 11 beta-substituent decreased ER binding affinity. Substitution of a fluoro atom at C-4 on either the 17 alpha-ethynylestradiol or isomeric 17 alpha-IVE2 enhanced the affinity of the parent molecule for the ER. A-ring fluorination of all other analogues tested had no effect or depressed ER binding affinity. Varying incubation conditions showed substantial differences in ER binding kinetics between the 20E and 20Z isomers. Tissue distribution in immature female rats showed that the highest uterus uptake and uterus to blood/nontarget ratios in the IVE2 series were obtained with the 4-F-(17 alpha,20Z)IVE2 isomer. The combination of A-ring fluoro and 7 alpha- or 11 beta-substitution decreased uterus uptake but had little or no effect on uterus to blood/nontarget ratios. The highest uterus to blood ratios were observed for the 4-F-(17 alpha,20E)11 beta-OMe-IVE2 (75 at 6 h and 125 at 12 h pi) reflecting rapid blood clearance and in vivo stability, as confirmed by the low levels of thyroid radioactivity. The lack of correlation between ER binding affinities and uterus uptake, and/or uptake ratios, suggests that other factors, including nonspecific binding and metabolic processes, also are involved in the tissue localization process. Our data suggest that 4-F substitution onto (17 alpha,20Z)IVE2 and (17 alpha,20E)11 beta-OMe-IVE2 enhances the potential of these compounds to function as SPECT imaging agents of ER-rich tissues.

Animals↗

PubMed1982

Protection of methionine in peptides during iodination by sulfonium salt formation.

A method for the prevention of methionine oxidation during iodination of tyrosine containing peptides is reported. The methionine containing peptide is converted into the corresponding S-tert.-butylsulfonium derivative, which is iodinated using iodine monochloride. After removal of the S-tert.-butyl group and purification, sulfoxide-free 3,5 diiodotyrosine (Dit) peptides were obtained. Dit8-substance P, Dit8-physalaemin 6-11 and Dit1, Met5-enkephalin were synthesized by this route. Tritium labeling of Dit1, Met5-enkephalin yielded 3H-enkephalin with a specific radioactivity of 38 Ci/mmol.

Enkephalin, Methionine↗

PubMed1975

Growth hormone covalently bound to sepharose or glass. Analysis of ligand release rates and characterization of soluble radiolabeled products.

Purified boveine growth hormone labeled enzymatically with iodine-125 was covalently coupled to cyanogen bromide activated Sepharose 4B gel and to diazotized zirconia-clad glass beads. Under the conditions employed, an average of 0.8 and 7.3 mg of hormone were bound per ml of Sepharose and glass, respectively. When the conjugates were incubated in Krebs-Ringer bicarbonate buffer (pH 7.4), three separate radioactive species were detected in the incubation supernatant by chromatography on Sephadex G-75. The elution volumes of two of the species were identical with those of 125-I-labeled growth hormone and Na-125I controls, while the third component eluted as a moleucle of intermediate size. The rate of release of each species from the solid matrix was linear with time over 4 days and increased with temperature from 4 to 37 degrees. Although significantly less growth hormone was released from glass (0.14%/day) than from Sepharose (0.40%/day) at 37 degrees, active hormone in amounts sufficient to be detectable in a biological assay was nevertheless liberated from the former after as little as 4 hr of incubation. By contrast, the rate of release of 125-Iminus- and the intermediate-size compound from glass was significantly greater than from Sepharose, suggesting that protein bound to glass supports is more susceptible to degradation from exposure to ionizing radiation.

Animals↗

PubMed1987

Immunoscintigraphy of colorectal carcinoma with F (ab')2 fragments of anti-CEA monoclonal antibody.

A monoclonal antibody to carcinoembryonic antigen (CEA) (F023C5), belonging to IgG1 class, was obtained by cell fusion technique. Preliminary screening on different tissues was performed with immunoperoxidase staining, which showed good specificity of the antibody for gastric and colorectal carcinomas. F(ab')2 fragments were subsequently prepared and labeled with 131I and 111In. After immunoreactivity check the radiopharmaceuticals were injected intravenously. Sixteen patients with 22 primary or secondary localizations of colorectal carcinoma were studied following the recommendations of the ethical Committee of the Istituto Nazionale Tumori, Milan, Italy. Serial scans were performed after injection of the two radioactive reagents. In vivo pharmacokinetics of the compound was studied. Radioactivity level in surgical specimens was measured, and immunostaining was performed. All tumors were found to express the antigen. Eleven out of 12 tumor localizations of the gastrointestinal tract and three out of ten liver metastases were imaged. Specificity of tumor uptake was assessed by simultaneous injection of an irrelevant antibody.

Antibodies, Monoclonal↗

PubMed1992

Pharmacokinetics of the SPECT benzodiazepine receptor radioligand [123I]iomazenil in human and non-human primates.

The pharmacokinetics of [123I]iomazenil (Ro 16-0154) in 5 healthy human volunteers were compared to those in 2 hypothermic and 3 normothermic anesthetized monkeys. Following intravenous injection in humans and monkeys, [123I]iomazenil rapidly diffused outside the vascular bed and was cleared from the arterial plasma triexponentially. The clearance half-times in hypothermic animals were protracted to values closer to those of the human. [123I]Iomazenil was metabolized mainly to a polar radiometabolite (not extracted by ethyl acetate) in the human whereas an additional lipophilic radiometabolite was detected in the monkey. In vitro and in vivo studies showed that [123I]iomazenil established equal concentrations in association with the cellular and plasma component of the blood, indicating that the plasma clearance of [123I]iomazenil mirrors that of the blood. Analysis of organs from a monkey given [123I]iomazenil showed that the parent compound was actively taken up by peripheral organs; the polar radiometabolite accumulated mainly in the bile and the kidneys whereas the non-polar radiometabolite accumulated in the urine and kidneys. Greater than 90% of the radioactivity in the different regions of the brain was unchanged parent [123I]iomazenil.

Adult↗

PubMed1988

Radiohalogenation of a monoclonal antibody using an N-succinimidyl 3-(tri-n-butylstannyl)benzoate intermediate.

N-Succinimidyl 3-(tri-n-butylstannyl)benzoate (ATE) was elevated for its utility in the radiohalogenation of monoclonal antibodies. The F(ab')2 fragment of monoclonal antibody OC 125 was labeled with 125I using the ATE reagent and with 131I using a conventional electrophilic iodination method (Iodogen). N-Succinimidyl 3-[125I]iodobenzoate was synthesized from ATE in greater than 90% yield and purified using a disposable silica gel cartridge. About 60-65% of the radioiodinated product was coupled to the F(ab')2 fragment after a 30-min reaction. Two procedures were investigated, one involving exposure of antibody to 35 nmol of ATE and the other to 240 nmol of ATE. Using Scatchard analyses, affinity constants for binding to CA 125 antigen for OC 125 F(ab')2 labeled using the low ATE, Iodogen, and high ATE procedures were determined to be (5.2 +/- 1.0) x 10(10), (2.5 +/- 0.9) x 10(10), and (4.2 +/- 2.4) x 10(9) M-1, respectively. Paired-label studies in athymic mice bearing OVCAR-3 tumors treated with injections of antibody labeled via both ATE and Iodogen demonstrated that use of the ATE method (a) reduced thyroid uptake to less than 0.1% of the injected dose, more than 100 times less than that observed with Iodogen; (b) resulted in more rapid clearance of activity from normal tissues; and (c) with the low ATE preparations, increased the uptake of radioactivity in tumor from 27 to 49%. At 96 h, tumor:tissue ratios were generally at least 4-fold higher when antibody was labeled via ATE. These results suggest that the ATE method may be a valuable approach for the radiohalogenation of antibodies.

Animals↗