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Biomedical subjects

A I Kassis

Publications and source records attributed to A I Kassis.

At least 73 records · Page 4Linked to original sources
PubMed1991

Potential for tumor therapy with iodine-125 labeled immunoglobulins.

Because of the high intranuclear toxicity of Auger-electron emitters, the use of radioiodinated (123I, 125I) 5-iodo-2'-deoxyuridine (IUdR)-antibody conjugates for cancer therapy has been examined. The results have demonstrated that all the conditions necessary for labeling DNA in vivo are present: uptake of the radiolabeled immunoglobulin by target cells, its subsequent internalization, the degradation of the IUdR-protein conjugate by lysosomal enzymes, and the incorporation of the radionucleoside into DNA.

Humans↗
PubMed1991

Embolization of platelets after endothelial injury to the aorta in rabbits. Assessment with 111indium-labeled platelets and angiography.

This study exploits the ability of a collateral arterial network to trap platelet aggregates in order to document the frequency of macroembolization in rabbits after endothelial damage. Two weeks after ligation of the right superficial femoral artery, endothelial injury was induced in the distal aorta; within 3 hours the rabbits were studied using either angiography or 111indium-labeled (111In) platelet scintigraphy. Angiography indicated visible aggregates in the thigh region in eight of 19 and arterial occlusion in three of 19 rabbits. The collateral-dependent thigh also showed more 111In-labeled platelet activity than the contralateral side (P less than .001), whether platelets were injected before or 2 hours after injury. Radioactivity in the limbs of rabbits with no injury was distributed symmetrically. Blood pool volume, assessed with technetium-99m-labeled red blood cells, was the same in both thighs, and could not account for these observations. The findings indicate that platelet activation and aggregation after endothelial injury lead to microembolization much more frequently than it leads to macroaggregate formation and visible artery occlusion.

Animals↗
PubMed1991

Antigen-binding site protection during radiolabeling leads to a higher immunoreactive fraction.

It is generally accepted that the immunointegrity of an antibody (Ab) depends on the preservation of its antigen-binding sites. Our goal was to radiolabel an antibody at several iodine:antibody molar ratios under conditions protecting its combining site and to compare its immunoreactive fraction (IRF) and electrophoretic mobility with those of the same antibody radiolabeled without protection. The data indicate that an antibody radiolabeled while its antigen-binding site is occupied by its antigen had the same IRF, regardless of the number of iodine atoms per antibody molecule. On the other hand, even at an I:Ab ratio of 1:1, the IRF of the same antibody radiolabeled without protection was lower than that of a protected one and decreased with increasing I:Ab ratios. In addition, the iodination of these Ab changes their electrophoretic mobility; however, when the Ab is labeled in the protected state, the degree of change is less. The binding of an antibody to its antigen prior to radiolabeling, therefore, enhances its immuno-integrity and prevents major conformational changes as reflected by electrophoresis.

Animals↗
PubMed1990

Specific uptake of the auger electron-emitting thymidine analogue 5-[123I/125I]iodo-2'-deoxyuridine in rat brain tumors: diagnostic and therapeutic implications in humans.

Glial neoplasms of the human central nervous system are malignancies that have defied treatment. Part of the problem lies in the limitations of current diagnostic techniques which are unable to identify small collections of neoplastic glia within normal parenchyma and in the difficulty of sterilizing these tumors because of limited selectivity of the cytotoxic agents available. The thymidine analogue 5-iodo-2'-deoxyuridine (IdUrd) radiolabeled with 123I and 125I was injected directly into an intracerebral rat 9L gliosarcoma and found to be a sensitive and specific agent for the detection of this neoplasm in rats. External gamma camera imaging (123I) visualized tumors as small as 0.5 mm in diameter. Autoradiography (125I) indicated that IdUrd was incorporated into the DNA of neoplastic glia only. Since 123I emits gamma-photons suitable for scintigraphy, [123I]IdUrd holds promise for the diagnosis of brain tumors in humans as well. Furthermore, since 123I and 125I are Auger electron emitters that have demonstrated antineoplastic effects, direct administration of [123I]IdUrd or [125I]IdUrd into tumors may also have potential for the treatment of central nervous system malignancies.

Animals↗
PubMed1990

Cellular radiation dosimetry and its implications for estimation of radiation risks. Illustrative results with technetium 99m-labeled microspheres and macroaggregates.

Radiation absorbed doses at the cellular level were calculated for routine, human lung perfusion examinations after the intravenous injection of technetium 99m-labeled microspheres or macroaggregated albumin. In such studies, more than 90% of these particles are trapped in the precapillary arterioles of the lung, resulting in an extremely inhomogeneous distribution of radionuclide. We used a computer program that accounted for the inhomogeneity of radiopharmaceutical distribution and calculated the dose to individual lung cells. Absorbed doses to individual lung cells were found to vary by a factor of about 30,000. We believe that such findings call for a reevaluation of the justification for dosimetry at the organ level and an examination of the implications of absorbed doses calculated at the cellular level for the estimation of radiation risks.

Dose-Response Relationship, Radiation↗
PubMed1990

Auger electron emitters: insights gained from in vitro experiments.

This paper outlines the evolution of the current rationale for research into the biological effects of tissue-incorporated Auger electron emitters. The first section is a brief review of the research conducted by several groups in the last fifteen years. The second section describes the in vitro model used in our studies, dosimetric calculations, experimental techniques and recent findings. The third section focuses on the use of Auger electron emitters as in vitro microprobes for the investigation of the radiosensitivity of distinct subcellular components. Examination of the biological effects of the Auger electron emitter 125I located in different cellular compartments of a single cell line (V 79 hamster lung fibroblast) verifies that DNA is the critical cell structure for radiation damage and that the sensitive sites are of nanometer dimensions. The data from incorporation of several Auger electron emitters at the same location within DNA suggest that there are no saturation effects from the decay of these isotopes (i.e. all the emitted energy is biologically effective) and provide some insight into which of the numerous physical mechanisms accompanying the Auger decay are most important in causing cell damage. Finally the implications of Auger electron emission for radiotherapy and radiation protection in diagnostic nuclear medicine are detailed and further research possibilities are suggested.

Cell Survival↗
PubMed1990

(3H/14C)beta-methylheptadecanoic acid subcellular distribution and lipid incorporation in mouse heart.

Beta-methylfatty acids are transported into myocardial cells as other fatty acids would be, but are incapable, for example, of undergoing complete catabolism. Our previous studies have established the structure-location relationship and the imaging characteristics of these analogs. In the present study in mouse myocardium, microautoradiography and electron microscopy were used to show the distribution of [7,8-3H] beta-methylheptadecanoic acid [( 3H]BMHA) in mitochondria and lipid droplets. Thin-layer chromatography demonstrated the presence of [1-14C] beta-methylheptadecanoic acid [( 14C]BMHA) and its metabolites in various lipid pools. These studies complement our earlier findings which showed that similarities exist in the initial metabolic fate of BMHA and physiological fatty acids.

Animals↗
PubMed1990

Human anti-murine antibody responses in ovarian cancer patients undergoing radioimmunotherapy with the murine monoclonal antibody OC-125.

Human anti-murine antibody (HAMA) responses were monitored in 23 patients with recurrent or persistent epithelial ovarian carcinoma undergoing single-dose intraperitoneal radioimmunotherapy (RIT) with the murine monoclonal antibody OC-125. Sera of patients receiving escalating doses of OC-125 F(ab')2 (10-70 mg) radiolabeled with 18 to 141 mCi of iodine-131 were assayed for HAMA by a protein A-based radioimmunoassay. Overall, 70% of patients (16/23) developed HAMA within 10 to 46 days (median = 29) postinfusion, with peak values (23 +/- 6 to 325 +/- 10 micrograms/ml) at 32 to 102 days (median = 38). HAMA was undetectable prior to infusion in all cases and persisted up to 76 weeks. Of patients receiving a dose of 123 mCi or less, 80% (16/20) developed HAMA, whereas in the 140-mCi group, none of the three patients had detectable levels. Two patients in the 140-mCi group demonstrated dose-limiting bone marrow toxicity (severe thrombocytopenia and neutropenia). It is concluded that a single intraperitoneal dose of monoclonal antibody leads to a high incidence of HAMA production. The results also suggest that the likelihood of HAMA formation in patients who either had undergone recent chemotherapy or had received the highest dose of the radioimmunoconjugate is reduced. These observations may be of significance in designing multiple-dose therapy trials as HAMA has been demonstrated to decrease antibody-to-tumor binding and may potentially increase renal, hepatic, and hematologic toxicity associated with radioimmunotherapy.

Adult↗
PubMed1990

Synthesis and biological activity of the intercalating agent 3-acetamido-5-[123/125I]iodo-6-aminoacridine.

3-Acetamido-5-iodo-6-aminoacridine (3), a derivative of the known intercalating agent proflavine (3,6-diaminoacridine) (1) was synthesized, and no-carrier-added 123I and 125I labeled compounds prepared. Compound 3 was taken up by live cells and localized in the nucleus. The intracellular concentration of [125I]3 was 7-fold greater in human prostate carcinoma (PC-3) cells than in normal Chinese hamster lung fibroblast (V-79) cells.

Acridines↗
PubMed1990

Mutation induction by 125iodoacetylproflavine, a DNA-intercalating agent, in human cells.

Survival and the induction of mutations at the hprt and tk loci were measured in TK6 human lymphoblastoid cells following treatment with the DNA-intercalating agent 125iodoacetylproflavine (125IAP). 125IAP was readily taken up into the cells, was localized to the nucleus, and was released rapidly following resuspension of the cells in fresh medium. Treatment with 125IAP for 24 h yielded a D0 of 110 decays/cell and an induced mutant fraction of 0.13 x 10(-6) per decay at the hprt locus and 0.4 x 10(-6) per decay at the tk locus. Molecular analyses of 125IAP-induced hprt mutants by Southern blot revealed a high proportion of large-scale changes at this locus. When these results are compared with those observed with 125IdUrd, 125IAP shows a reduced effectiveness per decay, related perhaps to the non-covalent nature of intercalator binding, resulting in reduced energy deposition in the DNA.

Acridines↗
PubMed1990

5-iodo-2'-deoxyuridine-protein conjugates: synthesis and enzymatic degradation.

Several halogenated analogs of thymidine and cytidine possess antineoplastic and antiviral activity. They are also powerful sensitizers of bacterial and mammalian cells to lethal effects of x-irradiation. An important factor limiting the effectiveness of these agents in therapy is their extremely short half-life in circulation due to rapid hepatic dehalogenation. An approach to this problem is to deliver the drug directly to its target using monoclonal antibodies. This study evaluates the lysosomotropic delivery systems of halogenated pyrimidines using 5-iodo-2'-deoxyuridine [IUdR] as a model. IUdR, derivatized and activated at either the 3'- or the 5'-position forms covalent adducts with the epsilon-amino groups of the lysine residues in proteins (bovine serum albumin [BSA], and immunoglobulins [IgG]). Two methods suitable for conjugation of IUdR to proteins involving either the formation of acyl-imidazoles in the reaction of IUdR succinates with N,N'-carbonyldiimidazole or the preparation of N-succinimidyl esters of IUdR succinates were established. Both derivatives express comparable reactivity toward proteins. The degree of IUdR incorporation is easily controlled by the ratio of reagents. The succinate "arm" linking IUdR to protein is susceptible to lysosomal hydrolysis in vitro releasing intact IUdR. The half-life of the IUdR-IgG conjugate in the presence of the lysosomal enzymes was shown to be approximately twice that of the IUdR-BSA conjugate.

Antineoplastic Agents↗
PubMed1990

Platelet activation and aggregation after endothelial injury. Assessment with indium-111-labeled platelets and angiography.

Although platelet activation and aggregation after endothelial injury are well documented, the time course of platelet deposition and the relationship between platelet aggregation and the release of vasoactive products have not been fully clarified in vivo. To study the effect of platelet vasoactive products, a collateral blood supply was induced by ligating the superficial femoral artery in male New Zealand white rabbits. Two weeks later, endothelial injury to the distal abdominal aorta was produced by cytologic brush or mimicked with a metal coil embolus. Platelet aggregation was assessed with indium-111 (111In)-labeled platelets, and scintigraphy demonstrated significant, progressive platelet deposition up to 3 hours after injury and evidence of residual activity 24 hours later. Angiography showed that the time course of peripheral vasoconstriction matched closely that of platelet deposition, indicating release of vasoactive substances from the aggregating platelets. These pathophysiologic changes secondary to endothelial injury may have significant implications for intravascular interventional procedures.

Angiography↗
PubMed1990

Inhomogeneous deposition of radiopharmaceuticals at the cellular level: experimental evidence and dosimetric implications.

We have undertaken an experimental examination of the conventional internal dosimetry assumptions of homogeneity of radionuclide deposition in tissues. The distribution of radiolabeled Microlite has been quantitated in mouse liver at the millimeter (multicellular) and the micrometer (cellular) levels. Measurements of radioactivity in 1-mm3 tissue samples indicate homogeneous radionuclide distribution; those derived from autoradiographs of 0.5-micron tissue sections show that, relative to other cells, the colloid was concentrated 200- to 1000-fold in liver macrophages. The dosimetric implications of such inhomogeneous radionuclide distribution in human liver, where similar radionuclide distribution is expected, are discussed on the basis of a recently developed model for calculating the dose at the cellular level, and the estimates are compared to conventional internal dosimetry predictions. It is demonstrated that during routine diagnostic examinations with 99mTc-Microlite, conventional dosimetry underestimates the dose to labeled human liver cells by factors of 8-30.

Animals↗
PubMed1989

Absence of preferential uptake of [125I]iododihydrorhodamine 123 by four human tumor xenografts.

The biodistribution of [125I]iododihydrorhodamine 123 has been studied over a 96-h period in four human tumor xenograft models: HT-29 colon adenocarcinoma, PC-3 prostate carcinoma, HT-1080 fibrosarcoma, and PaCa-2 pancreatic carcinoma. Elimination of radioactivity in the tumor-bearing nude mice was rapid during the first 24 h and slow thereafter. The lack of uptake in the thyroid indicated there was little, if any, deiodination of the molecule. Activity was found mainly in the liver and spleen. Accumulation of radioactivity was low in all four tumors examined. At 4 h postinjection, as well as at 24 and 48 h, however, the total radioactive content in each of the four tumors was directly proportional to the weight of the tumor sample. This correlation was independent of tumor type, route of injection (i.v./i.p.) or dose (1.2-6 microCi/mouse). This was not true for any of the normal tissues, suggesting that this accumulation may be governed by certain intrinsic characteristics of the cancers tested.

Adenocarcinoma↗
PubMed1989

Influence of human antimurine antibody on CA 125 levels in patients with ovarian cancer undergoing radioimmunotherapy or immunoscintigraphy with murine monoclonal antibody OC 125.

Human antimurine antibody responses interfere with CA 125 antigen determinations by crosslinking the murine antiovarian carcinoma monoclonal antibody OC 125 with the second murine radiolabeled antibody used in the CA 125 radioimmunoassay. Serial CA 125 levels in 22 patients with epithelial ovarian carcinoma undergoing either radioimmunotherapy or radioimmunoscintigraphy with iodine 131-labeled F(ab')2 fragments of OC 125 were followed up for up to 96 weeks after infusion. Fourteen radioimmunoscintigraphy patients received 131I-labeled monoclonal antibody by the intraperitoneal (n = 5) or intravenous (n = 9) route: 10 of 14 had sera drawn at appropriate time points for human antimurine antibody detection; 8 of 10 had 1.3- to 363-fold increases in CA 125; 4 of 8 had detectable human antimurine antibody (18.5 to 22 and 575 to 36 micrograms/ml). Eight radioimmunotherapy patients received 131I-labeled monoclonal antibody by the intraperitoneal route: 8 of 8 displayed an apparent 4.8- to 3725-fold increase in CA 125 levels within 7 to 42 days after monoclonal antibody infusion; 6 of 8 had detectable human antimurine antibody (13 to 4 and 319 to 31 micrograms/ml). Adsorption of immunoglobulin G resulted in a 21% to 98% reduction in CA 125 antigen levels in 4 of 4 patients tested. In patients with demonstrable human antimurine antibody, CA 125 antigen levels obtained by the clinical CA 125 radioimmunoassay are spuriously elevated.

Adsorption↗
PubMed1989

Intraperitoneal radiolabeled OC 125 in patients with advanced ovarian cancer.

Twenty patients with recurrent or persistent epithelial ovarian cancer failing conventional therapies were treated with a single intraperitoneal injection of iodine-131-labeled OC 125 monoclonal antibody. Rare acute side effects were nausea and mild diarrhea. At doses up to 120 mCi of iodine-131, median white blood cell and platelet count nadirs were 3.6k/microliters and 187k/microliters, respectively. Two patients acquired thyroid toxicities despite thyroid blockage with "cold" iodine. One patient had transient TSH elevation while remaining clinically euthyroid, and 1 patient developed activation of a thyroid nodule and clinical hyperthyroidism. Dose-limiting toxicity has not yet been observed. Twelve of 20 patients are alive 3 to 17 months following therapy. Tumor progression was noted in the majority of patients, although 3 patients had documented decreases in tumor burden of short duration. We conclude that, at the doses examined, iodine-131 OC 125 can be safely administered intraperitoneally.

Adenocarcinoma↗
PubMed1989

Synthesis of 125I labeled N-succinimidyl p-iodobenzoate for use in radiolabeling antibodies.

A new method is reported for the synthesis of N-succinimidyl p-([125/127I]iodobenzoate (NS-p-IB) from N-succinimidyl p-(tri-n-butylstannyl)benzoate via an iodination-destannylation reaction. The tin precursor was obtained in 70% overall yield from p-bromobenzoyl chloride after a four-step synthesis. The radiochemical yield of NS-p-[125I]IB was 75%. Conjugation of NS-p-[125I]IB to rabbit IgG or bovine serum albumin gave yields of 52 and 60% respectively. In vitro the radiolabeled proteins in serum at 37 degrees C showed less than 1% deiodination by 24 h. In vivo the stability of mouse IgG (MIgG) labeled with NS-p-[125I]IB was superior to MIgG radioiodinated in the presence of chloramine-T.

Animals↗