Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (uCi) of tumor activity per gram per 100 uCi injected activity compared to 4.5 uCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. Tumor dose found in normal organs is less than 20% of the tumor dose, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibodies QCI054 and ZME018, which define a tumor-associated and a second melanoma-associated antigen, respectively, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5, QCI054, and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Average absorbed doses of 3770 +/- 445 (mean +/- SEM), 2043 +/- 134, and 645 +/- 48 cGy in tumor, 353 +/- 41, 243 +/- 22, and 222 +/- 13 cGy in a contralateral control intramuscular site, 980 +/- 127, 815 +/- 41, and 651 +/- 63 cGy in liver, and 275 +/- 14, 263 +/- 11, and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 uCi 90Y-radiolabeled P96.5, QCI054, and ZME018, respectively. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5, QCI054, or ZME018. Striking tumor regression and prolonged survival were measured following administration of 90Y-labeled P96.5. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3 percent 28 and 58 days following 100 and 200 uCi 90Y-radiolabeled P96.5 administration, respectively. The time required to achieve four times the initial tumor volume was 6.1 +/- 0.9 days for buffer; 43 +/- 12 and 63 +/- 10 days for 50 and 100 uCi 90Y-radiolabeled P96.5; 7 +/- 2, 20 +/- 1, and 53 +/- 4 for 50, 100, and 200 uCi 90Y-radiolabeled QCI054; and 9 +/- 1, 13 +/- 1, and 29 +/- 3 days for 50, 100, and 200 uCi 90Y-radiolabeled ZME018, respectively. Average tumor regrowth failed to occur 180 days following administration of 200 uCi 90Y-labeled P96.5.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Targeting and therapy of human glioma xenografts in vivo using radiolabeled antibodies. 217 Mar 1

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. IIIIn-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCi of tumor activity/g/100 microCi injected activity compared to 4.5 microCi following administration of 100 microCi radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate the deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The dose found in normal organs is less than 20% of that in the tumor, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, demonstrates positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5 and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters. Average absorbed doses of 3770 +/- 445 (SEM) and 645 +/- 48 cGy in tumor, 353 +/- 41 and 222 +/- 13 cGy in a contralateral control i.m. site, 980 +/- 127 and 651 +/- 63 cGy in liver, and 275 +/- 14 and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 microCi 90Y-radiolabeled P96.5 and ZME018, respectively. Calculations of absorbed dose by the medical internal radiation dose method confirmed thermoluminescent dosimeter absorbed dose measurements. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5 or ZME018. Tumor regression was measured in 1 of 12, 9 of 10, and 12 of 12 compared to 0 of 10, 1 of 10, and 2 of 10 animals following administration of 50, 100, or 200 microCi 90Y-labeled P96.5 and ZME018, respectively. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3% 28 and 58 days following 100 and 200 microCi 90Y-radiolabeled P96.5 administration, respectively. In contrast, no average decrease in tumor volume was noted following 50, 100, or 200 microCi 90Y-labeled ZME018.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Targeting and therapy of human glioma xenografts in vivo utilizing radiolabeled antibodies. 240 87

Human melanoma xenografts were produced in the subcutis, kidney, cecum and liver of different nude mice. An 111In-labeled anti-(human melanoma) monoclonal antibody (96.5) or an 111In-labeled nonspecific control monoclonal antibody (ZCE-025) was injected intravenously in separate groups of mice. Radioactive antibody accumulation was measured in tumor, blood, viscera, and carcasses. mAb 96.5 targeted specifically to tumor tissue regardless of site of growth. Tumors in the liver exhibited significantly (P less than 0.05) higher tumor-to-blood ratios (45 +/- 6, mean +/- SEM) than xenografts at other visceral organs, the lowest value being found for subcutaneous melanoma (2.6 +/- 0.5). The differences in tumor-to-blood ratio were due to significant alterations of antibody biodistribution, since the actual antibody concentration in the different tumor sites was similar. The percentage of recovered anti-melanoma antibody per milliliter of blood in mice with visceral lesions (4.6 +/- 1.1% ml) was significantly lower than that found in mice with subcutaneous tumors (9.5 +/- 1.4%/ml, P less than 0.05). Moreover, significantly higher levels (18.2 +/- 3.2%/g, 31.0 +/- 5.1%/g, respectively) of the melanoma mAb 96.5 were found in normal liver and spleen tissue recovered from mice with visceral tumors as compared to tissue from mice with subcutaneous tumors (9.2 +/- 0.9%/g, 13.5 +/- 1.9%/g, respectively; P less than 0.05). These results demonstrate that the presence of visceral tumor can significantly affect tumor-to-blood ratios, blood levels, and biodistribution of 111In-labeled mAb 96.5.
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PMID:Altered biodistribution of indium-111-labeled monoclonal antibody 96.5 to tumors and normal tissues of nude mice bearing human melanoma xenografts in visceral organs. 262 18

Tissue-type plasminogen activator is a new thrombolytic agent that dissolves intravascular thrombi in coronary and peripheral vessels with less pronounced systemic lysis than that produced by streptokinase. Plasminogen activator was shown to induce reperfusion, and to salvage ischemic myocardium, by lysing experimentally induced coronary artery thrombi. The effect of a melanoma cell-derived tissue-type plasminogen activator was studied in cat myocardium rendered ischemic by coronary artery ligation for 2 hours and reperfused for another 4 hours. Plasminogen activator was infused at a rate of 500 IU X kg-1 X min-1 for the first 30 minutes of reperfusion. The marked increase in plasma creatine kinase activity during reperfusion was significantly lower in plasminogen activator-treated cats at 4, 5 and 6 hours, with 7.7 +/- 1.5 X 10(-3) IU X mg protein-1 (n = 8) in the plasminogen activator group versus 17.8 +/- 3.5 X 10(-3) IU X mg protein-1 (n = 7) in the vehicle group at 6 hours (mean +/- SEM). The area at risk in the two ischemic groups was not different, being 14.6 +/- 1.5 and 16.6 +/- 1.4% of total left ventricular mass for the treated and untreated groups, respectively. However, the mass of necrotic tissue determined histochemically was significantly lower in the plasminogen activator-treated group, accounting for 29.5 +/- 3.9% of the area at risk compared with 46.8 +/- 4.2% of area at risk in cats receiving only the vehicle (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beneficial effects of tissue-type plasminogen activator in acute myocardial ischemia in cats. 308 17

Physiochemical properties of an estrogen binding protein were characterized in three human melanoma cell lines, UISO-MEL-1, UISO-MEL-2, and UISO-MEL-4. Estrogen binding to melanoma cytosol was saturable, specific for estrogens, and represented by a single class of high-affinity, limited-capacity binding sites (Kd 5.5 x 10(-10) M, 2.7 +/- 0.5 fmol/mg of cytosol protein, UISO-MEL-2; 2.2 x 10(-10) M, 7.8 +/- 3.3, UISO-MEL-4) (SEM). UISO-MEL-1 cytosols did not bind estradiol. The binding protein in UISO-MEL-2 and -4 sedimented at 8.5S and 9.2S, respectively, in the presence of 10 mM sodium molybdate. Solid-phase radioimmunoassay with a monoclonal antibody specific for human estrogen receptor (H222 sp lambda) showed good correlation (r = 0.84) with a hydroxyapatite biochemical assay of identical melanoma cytosols. Exposure of UISO-MEL-2 to estradiol produced a time- and temperature-dependent increase in total nuclear receptor for estrogen in vitro. Estradiol treatment of athymic mice also significantly increased cytosol progesterone receptor content in UISO-MEL-2 and UISO-MEL-4 xenografts. Estradiol had no effect on the plating efficiency or growth of any melanoma cell line or normal melanocytes in vitro. Tamoxifen also had no effect on melanoma growth in vitro. In contrast, chronic exposure of athymic mice carrying estrogen receptor-positive UISO-MEL-2 to estradiol resulted in a sex-dependent increase in tumor latency and overall inhibition of tumor growth. Taken together, these observations suggest that a subset of human melanomas contains limited amounts of an estrogen binding protein similar to that observed in other estrogen-responsive tissues. The lack of effect of estradiol on melanocyte and melanoma growth in vitro, coupled with a decrease in tumor growth in athymic mice, suggests that, while inhibition may be receptor mediated, possible indirect actions of estradiol must also be considered.
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PMID:Effect of 17 beta-estradiol on the growth of estrogen receptor-positive human melanoma in vitro and in athymic mice. 319 86

Basic LM, TEM, SEM, and FFR appearances of a pure line of normal human melanocytes derived from foreskin, and a human melanoma line, in cell culture are described. Normal melanocyte cultures exhibit side by side, cells of widely different melanogenic activities--possible clones--and melanosomes of bizarre shape and internal structure are frequent. Aggregates of melanosomes, with or without associated amorphous material, and with no discernible limiting membrane are present within many cells, and occasional simple specialised contacts occur between apposed cells. On replicas of plasma membrane of normal melanocytes, particle densities and diameters on P and E fracture faces were within the ranges for cells in general, and equivalent data for the melanoma cells were not significantly different. Similarly, there was no difference in density of distribution or diameter of nuclear pores between the normal and the tumoural cells.
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PMID:Transmission and scanning electron microscopy and freeze-fracture replication of normal human melanocytes and human melanoma cells in tissue culture. 323 99

Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. The objectives of this report are to address two issues relevant to IL-2/LAK therapy. (a) Can IL-2/LAK therapy be accomplished outside of previously identified centers of expertise? (b) What are the relevant laboratory/clinical parameter correlations? The six institutions in the National Cancer Institute extramural trial treated 83 evaluable patients with renal cancer, malignant melanoma, or colon cancer with IL-2/LAK by a uniform protocol. Patients received 5 days of IL-2 priming, then daily leukaphereses for 5 days starting 48 h after IL-2 to harvest cells. Mononuclear cells were isolated, then cultured in roller bottles in 1-liter aliquots for 3 to 4 days at a cell density of 1.5 x 10(6) per ml with recombinant IL-2, 1500 units per ml. Cells were harvested and administered to patients with additional IL-2. Administration of IL-2 regularly induced lymphopenia and rebound lymphocytosis. Leukapheresis yields and numbers of LAK cells generated in culture and reinfused into patients correlated directly with peak lymphocyte counts achieved by IL-2 administration. Mean mononuclear cell recovery per 5 days of leukapheresis (+/- SEM) was 14.3 +/- 0.8 x 10(10). Average volume of cells cultured per patient was 95 liters (range, 41 to 235). Mean yield of cells harvested from cultures was 53%. Mean total number of LAK cells infused per patient was 7.6 +/- 0.4 x 10(10) (range, 2 to 15.2 x 10(10]. LAK activity was measured in vitro by lysis of 51Cr-labeled natural killer-resistant Daudi and fresh tumor targets. LAK effector cells regularly lysed these targets in vitro. Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.
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PMID:Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. 326 May 37

Liver uptake of 111In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an 111In-labeled anti-melanoma antibody 96.5 (111In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of 111In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to 111In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of 111In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to 111In-96.5 infusion demonstrated a significant drop [P less than 0.001] in the liver/heart ratio of radioactivity [2.81 +/- 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 +/- 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (Vd) and the plasma t1/2 both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration X time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P less than 0.05). Although tissue distribution of 111In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.
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PMID:Immunospecific saturable clearance mechanisms for indium-111-labeled anti-melanoma monoclonal antibody 96.5 in humans. 339 Aug 37

An experimental model of meningeal carcinomatosis has been produced by subarachnoid inoculation of B16 melanoma cells into C57BL mice. Injection of 10(3) viable cells was sufficient to cause 100% tumor incidence and death within a median survival time of 17 days. The tumor infiltrated diffusely the meninges of the brain and spinal cord and filled the ventricular system. Electron microscopic study of the leptomeningeal tumor revealed newly formed microvessels with fenestrated endothelium. The integrity of the blood-brain barrier was studied by the extravasation of the Evans blue and the Horseradish peroxidase tracers. Barrier disruption became evident from the seventh day on, using Evans blue. Electron microscopy study showed peroxidase activity in the luminal and abluminal sides of the meningeal microvessels, and within the tight junctions. Similar findings were noted in cortical capillaries adjacent to the meningeal tumor. Brain concentrations of Adriamycin (ADR) following administration of an intravenous dose of either 10 mg/kg or 50 mg/kg were measured on days 0 to 14 after tumor inoculation. A significant increase in mean +/- SEM content of whole brain ADR was observed only with the 50 mg/kg dose in days 7 to 14 (0.69 +/- 0.02 micrograms/g wet tissue weight) as compared to tumor-free controls (0.43 +/- 0.01, p less than 0.05). Our study suggests that barrier alteration in meningeal carcinomatosis allows extravasation of tracer solutes. Still, in order to achieve a significant increase in a water soluble drug penetration through the disrupted barrier, a high-dose drug regimen is required.
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PMID:Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis. A morphologic and adriamycin-penetration study. 355 64

The prevalence and treatment of 255 eyelid tumors in 200 dogs was related to breed, age, sex, location, and tumor type. Treatment methods included cryosurgery and surgical excision. The mean age of all dogs with eyelid tumors was 9.6 years (+/- 0.2 SEM). Beagles, Siberian Huskies, and English Setters had a higher risk of tumor development, whereas the mixed-breed dogs had a lower risk. Sebaceous tarsal gland adenomas, benign melanomas, and papillomas were observed most often (88%). Malignant tumors (melanoma, adenocarcinoma, basal cell carcinoma, mast cell tumor, squamous cell carcinoma, hemangiosarcoma, and myoblastoma) comprised 8.2% of the tumors. Tumor recurrence rates between dogs treated with cryosurgery and those treated surgically were not significantly different (15.1% and 10.5%, respectively). The mean recurrence time after cryosurgery was 7.4 months (+/- 1.9 SEM), whereas it was 28.3 months (+/- 7.2 SEM) after surgical excision. Using either treatment, the long-term side effects were similar. The overall cosmetic appearance was observed to be better with cryosurgery.
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PMID:Prevalence and treatment of palpebral neoplasms in the dog: 200 cases (1975-1983). 379 87


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