UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two immunotoxins, the ricin A chain-multivalent hybrid antibody (750 kDa) and the complex A chain-staphylococcal protein A-rabbit IgG antibody (370 kDa), were prepared. A simple method was elaborated to test the immunotoxins' efficiency in selectively killing target cells in tumor-bearing mice. The target cell (murine EL4 leukemia) was coated with a xenogenic molecule by a method conserving its ability to proliferate and kill the inoculated animals. When the challenged animals were treated with these immunotoxins, which were specific for the antigenic molecule coating the tumor cells, survival time was lengthened compared with that of untreated animals, corresponding to a proportion of over 90% cells killed. This demonstrates the efficiency of the immunotoxins and the validity of the method elaborated.
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PMID:Experimental model for testing the efficiency of immunotoxins administered in vivo: evaluation of two ricin A-chain--multivalent antibody immunotoxins. 278 2

We have produced monoclonal antibodies against the epidermal growth factor (EGF) receptor which bind to the receptor with high affinity, compete with EGF for binding, block EGF-induced tyrosine kinase activity, and activate internalization and down-regulation of the receptor. These antibodies are cytostatic against cultured A431 cells at concentrations of 5-20 nM. In addition, they prevent the growth of A431 tumor xenografts in athymic mice. In the present experiments, we have attempted to improve the antitumor activity of monoclonal antibody 528 IgG2a against the EGF receptor by linking it to recombinant ricin A chain (rRA). The immunoconjugate (528 IgG-rRA) showed a potent cytotoxic effect on A431 cells in vitro. At a concentration of 10 pM, it inhibited the proliferation of cultured A431 cells by 50% and also inhibited protein synthesis in these cells by 50%. Proliferation was prevented and cell death occurred at 528 IgG-rRA concentrations of 60 pM or greater. Recombinant free ricin A chain was far less toxic. The cytotoxic effect of the immunoconjugate was neutralized by 528 IgG at concentrations 100-fold higher than 528 IgG-rRA. When the cytotoxic effect of 528 IgG-rRA was compared among several human cell lines expressing different numbers of EGF receptors, the capacity to inhibit both proliferation and protein synthesis generally correlated with the number of EGF receptors on the plasma membranes of these cells. Since 528 IgG-rRA is a very potent immunotoxin against A431 cells in culture, we designed experiments to test its in vivo antitumor activity against A431 xenografts in athymic mice. To measure the clearance of 528 IgG-rRA, 50 micrograms of immunotoxin were injected i.p. into athymic mice, blood was collected from the animals at regular intervals, and the level of immunotoxin in the serum was assayed by protein synthesis inhibition in cultured A431 cells. The blood level of active immunoconjugate reached a maximum 6 h after i.p. injection. The half-life of the absorption phase was 2.2 h, the half-life for elimination was 9.2 h, and blood levels which could be potentially cytotoxic were maintained for 48-72 h. We investigated a number of immunotoxin treatment schedules, including every other day for 4 days, based on these data. The results demonstrate that, while 528 IgG-rRA has higher in vivo antitumor activity than 528 IgG against A431 cell xenografts, this is accompanied by toxicity against the murine host.
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PMID:Cytotoxicity against human tumor cells mediated by the conjugate of anti-epidermal growth factor receptor monoclonal antibody to recombinant ricin A chain. 278 51

Monoclonal antibody 791T/36, recognizing a Mr 72,000 antigen on the surface of colon carcinoma cells, has been used to construct an immunotoxin by conjugating to it the ribosomal inhibitor protein, ricin toxin A chain. The antibody 791T/36 has been shown to bind to membranes of freshly disaggregated tumor cells from human colon tumors, and to localize in tumors in vivo. Subacute toxicology testing in rats receiving immunotoxin i.v. showed, at highest doses, weight loss, decreased serum albumin, and hepatocyte vacuolization without elevation in liver function tests. A Phase I dose escalation study was carried out in which 17 patients with metastatic colorectal cancer were treated with doses of immunotoxin ranging from 0.02 to 0.2 mg/kg/day in 1-h i.v. infusions for a 5-day course. Side-effects included a composite of signs and symptoms thought to be generic to ricin A chain immunotoxins, including decreased serum albumin, mild fever, and flu-like symptoms, all being reversible. Two additional findings, reversible proteinuria and mental status changes, were also noted which may be characteristic of this immunotoxin. By 10-20 days after therapy, most patients developed IgM and IgG antibodies against both the ricin toxin A chain and the immunoglobulin portion of the immunotoxin, which were asymptomatic. A strong anticombining site antibody response was seen. Biological activity manifest as mixed tumor regression was seen in five patients.
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PMID:Phase I study of monoclonal antibody-ricin A chain immunotoxin XomaZyme-791 in patients with metastatic colon cancer. 279 Aug 28

We have summarized what is currently known about the distribution, biological role, and the mechanism of action of the single chain ribosome-inactivating proteins and described the purification of one of them, gelonin, as an example. ITs have been made with several of these proteins and, depending upon the antibody used for conjugation, these immunoconjugates can show specific in vitro cytotoxicity which is similar to that shown by equivalent ITs prepared with ricin A chain. The most potent of these conjugates have shown antitumor efficacy in a variety of animal tumor models, including both syngeneic rodent tumors and xenografts in nude or immunosuppressed mice. An important point needs to be addressed, however, before concluding that ITs containing single chain toxins will be clinically useful. A major problem with this approach is that it is likely that both the antibody and the toxin components of these conjugates will be immunogenic. Both antitoxin and antixenogenic immunoglobulin responses have been shown to occur in animals after infusion of IT, although it has not yet been clearly demonstrated that such antibody responses adversely effect the pharmacokinetics or the efficacy of immunoconjugates. Thus, preliminary enthusiasm over the efficacy of these new reagents must be tempered with the knowledge that their use in the clinic may be limited by the host immune responses or other as yet undefined factors. The fact that there are many immunologically distinct single chain ribosome-inactivating proteins does suggest one way of evading the antitoxin response, by a sequential treatment with a panel of immunoconjugates, each containing a different single chain toxin.
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PMID:Immunotoxins containing single-chain ribosome-inactivating proteins. 290 25

With the aim of targeting toxins to selected cells in the gonad, we have prepared conjugates of ovine luteinizing hormone (oLH) with a single chain ribosome-inactivating protein called gelonin. The two proteins were thiolated by using N-succinimidyl-3-(2-pyridyldithio)propionate and subsequently reacted under appropriate conditions to form oLH-S-S-gelonin complex. A complete biochemical analysis of thiolated oLH and oLH-gelonin conjugates has been performed. The linkage of the hormone to the toxin probably occurred through a single amino group in the alpha-subunit, with the beta-subunit remaining free. Modification of a single amino group on the alpha-subunit reduced receptor binding and immunological reactivity of the thiolated oLH, but subsequent complexing with the toxin-gelonin did not seriously compromise these activities. oLH and gelonin were calculated to be present in a 1:1 ratio in the hormonotoxin preparation. The conjugate retained significant steroidogenic activity in rat granulosa cells. Upon reaction with mouse tumor Leydig cells (MA-10 cells), the toxin component of the complex became internalized to a sufficient degree to effectively inhibit protein synthesis. The studies provide a rational basis for the design and study of large hormonotoxins.
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PMID:Hormonotoxins. Preparation and characterization of ovine luteinizing hormone-gelonin conjugate. 291 44

In the present study, we established a dependable system by which human pre-B- and non-T/non-B-acute lymphoblastic leukemia (ALL) cells are efficiently transplanted into nude mice; the transplanted tumors provide a useful model for investigating the efficacy of antitumor agents in the in vivo therapy of human cancer. NALM-6 (a pre-B-ALL cell line) cells were transplanted under varying conditions as the pre-B-leukemia cells, whereas REH (a non-T/non-B-ALL cell line) cells were transplanted as the non-T/non-B-leukemia cells. Under optimal and near optimal conditions, 71 of 101 X-irradiated mice (70%) developed distinct tumors approximately 2 wk after i.d. inoculation of a mixture of NALM-6 cells and X-irradiated human fibrosarcoma cells. Under the same conditions, 9 of 11 mice (82%) developed tumors following i.d. inoculation of REH cells admixed with X-irradiated human fibrosarcoma cells. Examination of the tumor tissues demonstrated that the tumors are of leukemia origin but not of fibrosarcoma origin. To demonstrate the usefulness of the present tumors for investigating the efficacy of antitumor agents in the in vivo therapy of human cancer, immunotoxins were tested for their specific suppressive activity against growing tumors of the transplanted NALM-6 cells. To this end, monoclonal antibodies SN5 and SN6 which define a common ALL antigen, termed CALLA, and a novel leukemia-associated cell surface glycoprotein, termed gp160, respectively, were separately conjugated with the A-chain subunit of ricin, a plant toxin; CALLA and gp160 are expressed on the cell surface of various human non-T-leukemia cells including NALM-6 cells. The conjugates of SN5 and SN6 with ricin A-chain (RA) showed specific activity against the leukemia cells but not against control cells in an in vitro assay. To investigate their in vivo efficacy in suppressing tumor growth, nude mice which had been inoculated i.d. with NALM-6 cells 25 days in advance and bore distinct palpable tumors (5 to 6 mm in diameter) were divided into five groups. One group of mice was nontreated as a control. Each of the remaining four groups of mice was given an injection of one of the following agents: (a) purified control mouse IgG (IgG1); (b) purified antibodies SN5 (IgG1) and SN6 (IgG1); (c) control IgG-RA conjugate; or (d) SN5-RA and SN6-RA. Tumors in all mice of the first four groups including the untreated group grew continuously, causing the mice to die.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Efficient transplantation of human non-T-leukemia cells into nude mice and induction of complete regression of the transplanted distinct tumors by ricin A-chain conjugates of monoclonal antibodies SN5 and SN6. 296 82

Most of our current understanding of the molecular action of mitogens such as insulin, EGF and tumor promoters is derived from studies using biochemical, pharmacological and immunological methods. In the present study, however, this important problem has been approached from a genetic point of view. To facilitate genetic studies, attempts have been made to isolate variants having receptors and/or post-receptor functions which are deficient or extraordinary in their cellular responsiveness. The first selection method was to use toxic hybrid proteins such as insulin crosslinked to the A fragment of diphtheria toxin (DTa), EGF crosslinked to the A chain of toxic ricin (RICa) and monoclonal anti-EGF receptor antibody (IgG) crosslinked to the RICa. These conjugates have provided us with a variety of cell variants which are unable to either bind the ligand or take up the bound ligand and process it for mitogenic response. The second selection procedure utilized the mechanical removal of cells whose growth was stimulated by the mitogens but was arrested at mitosis by vinblastine sulphate. Variants of mouse 3T3-L1 cells which no longer responded to the indole alkaloid tumor promoter dihydroteleocidin B exhibited various characteristics in terms of the receptors for EGF, insulin and the tumor promoters. The results obtained from these cell variants are discussed in relation to the role of different receptor systems in the regulation of DNA replication, cell growth and differentiation.
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PMID:[Mitogenic responsiveness to growth factor and tumor promoters and regulation of cell growth]. 298 3

Insulin molecules were covalently attached to detergent-solubilized Sendai virus envelope glycoproteins (HN and F polypeptides) by the use of the crosslinking reagent succinimidyl 4-(p-maleimidophenyl)butyrate (SMPB). Reconstitution of modified viral glycoproteins (carrying covalently attached insulin) together with unmodified viral glycoproteins resulted in the formation of "fusogenic" viral envelopes bearing insulin molecules. Reconstitution of such fusogenic viral envelopes in the presence of ricin A or simian virus 40 (SV40) DNA resulted in the formation of viral envelopes bearing insulin molecules and loaded with ricin A or SV40 DNA. Such viral envelopes were able to bind to hepatoma tissue culture cells (HTCC) from which Sendai virus receptors were removed by treatment with neuraminidase. Incubation of viral envelopes loaded with ricin A with virus receptor-depleted HTCC resulted in fusion-mediated injection of the toxin, as inferred from inhibition of protein synthesis and decrease in cell viability of the microinjected cells. Fusion-mediated injection of SV40 DNA was inferred from the appearance of SV40 tumor antigen in microinjected cells. Binding and fusion of the loaded viral envelopes to neuraminidase-treated HTCC was mediated solely by the virus-associated insulin molecules. Addition of free insulin molecules inhibited binding of the viral envelopes and, consequently, the microinjection of ricin A and SV40 DNA.
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PMID:Targeting of loaded Sendai virus envelopes by covalently attached insulin molecules to virus receptor-depleted cells: fusion-mediated microinjection of ricin A and simian virus 40 DNA. 299 83

Breast tumor selective antibodies (MAB) conjugated to Pseudomonas exotoxin A (PE) formed immunotoxins with potent cytotoxicities for human breast tumor cell lines. The most effective of the MAB-PE conjugates were about 500-fold more toxic to the breast tumor target cell lines than to the nontarget human fibroblast cell line. Specificity of cytotoxicity by MAB-PE conjugates was demonstrated by protection of target cells in the presence of excess unconjugated homologous antibody. A MAB-PE conjugate inhibited protein synthesis more rapidly than the corresponding MAB-ricin toxin A chain (RTA) conjugate. Generally, there was a direct correlation between the cytotoxicity of RTA and PE when conjugated to the same MAB: MABs that made highly cytotoxic RTA conjugates made effective PE conjugates and MABs that made poorly cytotoxic RTA conjugates made PE conjugates of low cytotoxicity; however, one MAB-PE immunotoxin was cytotoxic to the human breast tumor cell lines, whereas the corresponding MAB-RTA immunotoxin was noncytotoxic at the highest dose tested. In contrast to MAB-RTA conjugates, which require a cleavable (disulfide) linkage for maximal in vitro cytotoxicity, MAB-PE conjugates were about equally cytotoxic when linked by either a cleavable or noncleavable (thioether) bond.
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PMID:Antibody-Pseudomonas exotoxin A conjugates cytotoxic to human breast cancer cells in vitro. 301 Dec 43

Immunotoxins are hybrid molecules which combine the exquisite selectivity of monoclonal antibodies with the potent toxicity of protein toxins. An immunotoxin was constructed by linking a murine monoclonal antibody against the human transferrin receptor (TR) to the plant toxin, ricin. The cytotoxic activity of the anti-TR-ricin immunotoxin was tested in vitro and demonstrated highly potent and cell type-specific killing of cells derived from human glioblastoma, medulloblastoma, and leukemia. The anti-TR-ricin immunotoxin killed more than 50% of "target" cells at a concentration of 5.6 X 10(-13) M after an 18-hour incubation with the ionophore, monensin. This potency exceeds that of any other anti-TR immunotoxin reported in the literature. When the activity of the anti-TR-ricin immunotoxin against "target" tumor-derived cells was compared with the immunotoxin's activity against "non-target" cells, it could be predicted that a selective toxicity of anti-TR-ricin immunotoxin between tumor cells and normal brain was more than 150- to 1380-fold. Solid-phase indirect radioimmunoassay techniques were used to demonstrate significantly higher levels of TR in the glioblastoma- and medulloblastoma-derived cell lines, as well as in surgical tissue samples of medulloblastoma and glioblastoma, as compared to normal brain. Immunotoxins targeted to the TR may possess sufficient specificity to be of therapeutic importance, particularly to treat neoplastic disease of the central nervous system involving compartments (such as intrathecal, intraventricular, or cystic) where delivery of immunotoxins to tumor would not require transvascular transport.
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PMID:Potent and specific killing of human malignant brain tumor cells by an anti-transferrin receptor antibody-ricin immunotoxin. 303 71

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