Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, two isotype-matching mAb, SN5d and SN5, which are directed toward two distinctively different epitopes of common acute lymphoblastic leukemia Ag (CD10) but show a very similar binding affinity to leukemia cells, were compared for their in vivo antitumor activity after conjugated to ricin A chain (RA). Our recently established nude mouse model carrying an ascitic tumor of NALM-6 human pre-B leukemia cells was used as the tumor model. A marked difference was observed in the in vivo antitumor efficacy between SN5d-RA and SN5-RA; SN5d-RA was much more effective than SN5-RA. Several experiments were carried out to gain information concerning the mechanisms involved in the different antitumor efficacy of the two immunotoxins. Although naked (unconjugated) mAb SN5d was much less effective than SN5d-RA conjugates in the in vivo tumor suppression, mAb SN5d was more effective than mAb SN5 in the in vivo tumor suppression. Additionally, marked differences were found between SN5d and SN5 in the induction of antigenic modulation and in the regulation of Ag biosynthesis and expression. Binding of SN5 to NALM-6 leukemia cells caused strong antigenic modulation (down-regulation of Ag expression) and strongly down-regulated Ag biosynthesis and cell surface expression of new Ag. In contrast, binding of SN5d to NALM-6 leukemia cells caused little modulation of overall cell surface expression of common acute lymphoblastic leukemia Ag; the decrease of old Ag by endocytosis after binding to mAb SN5d was compensated by newly exocytosed cell-surface expressed Ag. The present results appear to reveal a novel mechanism which regulates cytotoxic activities of antibodies and immunoconjugates.
 ...
PMID:Marked difference in the in vivo antitumor efficacy between two immunotoxins targeted to different epitopes of common acute lymphoblastic leukemia antigen (CD10). Mechanisms involved in the differential activities of immunotoxins. 169 14

The potentiation of monoclonal antibody/ligand toxin (immunotoxin) cytotoxicity by the ionophore monensin (Mo) or by human serum albumin-monensin (HSA-Mo) conjugates was investigated. Since disulfide cross-linked HSA-Mo (HSA-SPDP-Mo) is rapidly inactivated by human serum (M. Colombatti et al., Cancer Res., 50: 1385-1391, 1990), we synthesized thioether cross-linked HSA-Mo conjugates (HSA-SIA-Mo). HSA-SIA-Mo is resistant to treatment with reducing agents (e.g., glutathione, dithiothreitol) and shows potentiating activity identical to that of Mo or of HSA-SPDP-Mo, enhancing immunotoxin (IT) cytotoxicity 45-35,000-fold. Human leukemic and tumor cell lines are highly sensitive to treatment with IT in combination with Mo, HSA-SPDP-Mo, or HSA-SIA-Mo (concentration required to inhibit protein synthesis by 50%, 10(-10)-2.5 x 10(-13) M). IT potentiation by both types of HSA-Mo conjugates, however, is inhibited by whole human serum. In contrast, human cerebrospinal fluid has no effect on the potentiation of IT by Mo or HSA-Mo conjugates. The serum blocking factors reside mostly in a Mr 40,000-90,000 protein fraction. Serum components of low molecular weight (less than 10,000) show no detectable effect upon the stability of HSA-Mo conjugates. The toxicity of HSA-SIA-Mo in vivo was investigated by intrathecal injections in rats. Concentrations of up to 60 micrograms/kg can be injected into the brain with only transient neurological sequelae. We therefore conclude that if the systemic delivery of HSA-Mo conjugates for the potentiation of ricin A chain-IT presents some limitations due to the blocking effect of serum, the application of HSA-Mo conjugates in combination with ricin A chain-IT for regional tumor therapy in the brain appears more promising.
 ...
PMID:Blocking effect of human serum but not of cerebrospinal fluid on ricin A chain immunotoxin potentiation by monensin or carrier protein-monensin conjugates. 173 50

Monoclonal antibody 14G2a (anti-GD2) reacts with cell lines and tumor tissues of neuroectodermal origin that express disialoganglioside GD2. mAb 14G2a was coupled to the ribosome-inactivating plant toxin gelonin with the heterobifunctional cross-linking reagent N-succinimidyl-3(2-pyridyldithio)propionate. The activity of the immunotoxin was assessed by a cell-free translation assay that confirmed the presence of active gelonin coupled to 14G2a. Data from an enzyme-linked immunosorbent assay demonstrated the specificity and immunoreactivity of the 14G2a-gelonin immunotoxin, which was identical to that of native 14G2a. Assays for complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) revealed that these functional properties of the native 14G2a antibody were also preserved in the 14G2a-gelonin immunotoxin. The gelonin-14G2a immunotoxin was directly cytotoxic to human melanoma (A375-M and AAB-527) cells and was 1000-fold more active than native gelonin in inhibiting the growth of human melanoma cells in vitro. The augmentation of tumor cell killing of 14G2a-gelonin immunotoxin was examined with several lysosomotropic compounds. Chloroquine and monensin, when combined with 14G2a-gelonin immunotoxin, augmented its cytotoxicity more than 10-fold. Biological response modifiers such as tumor necrosis factor alpha and interferon alpha and chemotherapeutic agents such as cisplatinum and N,N'-bis(2-chloroethyl)-N-nitrosourea (carmustine) augmented the cytotoxicity of 14G2a-gelonin 4- to 5-fold. The results of these studies suggest that 14G2a-gelonin may operate directly by both cytotoxic efforts and indirectly by mediating both ADCC and CDC activity against tumor cells; thus it may prove useful in the future for therapy of human neuroectodermal tumors.
 ...
PMID:A potent and specific immunotoxin for tumor cells expressing disialoganglioside GD2. 175 37

A mouse monoclonal antibody (MoAb), KM231 raised against human gastric cancer was found to recognize sialyl Lea -epitope expressed on glycoprotein and glycolipid with high affinity. KM231 reacted with many human gastrointestinal cancer tissues and could detect the antigen shed in sera of cancer patients. The present study was designed to evaluate competence of KM231 for immunotherapy of cancer. We first confirmed that KM231 could probe the cancer cells in vivo by injecting biotinylated KM231 into nude mice bearing human colorectal carcinoma cell, SW1116. Light- and electron-microscopic examination showed that the MoAb was localized in the tumor tissues and bound to the plasma membrane and cytoplasmic endosomes. Imaging studies with 125I-labeled KM231 revealed specific localization of the antibody in SW1116 tumors transplanted into nude mice. From Scatchard analysis of KM231 binding, the number of KM231 molecules bound to per SW1116 cell was calculated approximately 1.9 x 10(6) and the association constant was 1.3 x 10(8) liter/mol. We made KM231-ricin A chain immunotoxin for evaluating the tumoricidal effect of KM231. The immunotoxin exerted strong cytotoxicity toward sialyl Lea-expressing tumor cells specifically in vitro, but not toward sialyl Lea non-expressing cells. The in vivo tumoricidal effect of the immunotoxin was examined on ascites and subcutaneous xenograft tumors in nude mice. Three intraperitoneal injections of the immunotoxin (1.6 x 10(-6) mol) into nude mice bearing SW1116 ascites tumor resulted in extension of survival by 204% compared with controls. Further, repeated intraperitoneal administration of the immunotoxin (1.4 - 2 x 10(-6) mol) significantly inhibited the growth of established subcutaneous tumor (ratio of tumor inhibition = 0.7 - 0.54). These results indicated that KM231 has the ability to probe sialyl Lea-expressing tumor cells in vivo with high efficiency and to become tumoricidal drug when it conjugated with cytotoxic reagents like ricin A chain.
 ...
PMID:Application of anti-sialyl Lea monoclonal antibody, KM231, for immunotherapy of cancer. 177 33

With the aim to synthesize a bioeffective hormonotoxin for selective targeting to specific cells in the gonads, a single chain RIP was conjugated to oLH with the use of SPDP which generated oLH-S-S-gelonin hormonotoxin. Extensive physico-chemical, immunochemical and biochemical characterization reveal that 1:1 oLH-gelonin was linked through the alpha-subunit of the oLH. The hormonotoxin retained substantial receptor binding and steroidogenic activity in the leydig tumor cells. The competitive displacement analysis indicate that the binding occurs via the hormone. The presently described hormonotoxin exhibited higher receptor binding and cytotoxicity to the target cells than that of others reported so far.
 ...
PMID:In-vitro selective killing of gonadal cells by a hormonotoxin composed of ovine luteinizing hormone linked by a disulfide bond to the ribosome-inactivating protein, gelonin. 179 70

Fifteen patients with refractory B-cell lymphoma were treated in a Phase I dose escalation clinical trial with a highly potent immunotoxin consisting of the Fab' fragment of a monoclonal anti-CD22 antibody (RFB4) coupled to chemically deglycosylated ricin A chain. All patients had low, intermediate, or high grade non-Hodgkin's lymphoma. The immunotoxin was administered i.v. in two to six doses at 48-h intervals. The peak serum concentration and the t1/2 were not dose dependent among patients and averaged 1.3 micrograms/ml and 86 min, respectively. Three patients made antibody against A chain, and a fourth made antibody against both A chain and mouse immunoglobulin. Antibody responses were low (less than or equal to 85 micrograms/ml) in three patients and were not detected until 1 mo after treatment. The maximum tolerated dose of the immunotoxin was 75 mg/m2. Dose-related toxicities included vascular leak syndrome, fever, anorexia, and myalgia. Dose-limiting toxicities included pulmonary edema and/or effusion, expressive aphasia, and rhabdomyolysis (resulting in reversible kidney failure). There was no evidence of liver dysfunction. Partial responses were achieved in 38% of evaluable patients, and in those patients who had greater than 50% CD22+ tumor cells, 50% of the patients achieved a partial response. Clinical responses were not related to tumor grade and were generally transient, lasting between 1 and 4 mo.
 ...
PMID:Phase I immunotoxin trial in patients with B-cell lymphoma. 185 19

The two naturally occurring forms of ricin A chain, Mr 33,000 and Mr 30,000 (RTA33 and RTA30) have been purified, and their chemical compositions, toxicities, and tissue distributions have been determined. As reported previously, the in vitro and in vivo toxicities of RTA30 and RTA33 are similar. However, RTA30, which contains less carbohydrate with a lower mannose content than RTA33, accumulated less in the liver than did RTA33. Monoconjugate immunotoxins (i.e., containing one RTA per monoclonal antibody molecule) were constructed between RTA30 or RTA33 and the antitumor monoclonal antibody 791T/36, which recognizes a Mr 72,000 antigen on osteosarcoma and colon carcinoma cells. The two immunotoxins had similar cytoxicities in vitro but differed substantially in their pharmacokinetics and tissue distributions in vivo in nude mice bearing C170 human colorectal carcinoma xenografts. The immunotoxin derived from RTA30 (IT30) accumulated less in the liver than the immunotoxin derived from RTA33 (IT33) and cleared more slowly from the blood; the alpha and beta half-lives for IT30 and IT33 were 0.50 and 20.5 versus 0.17 and 14.6 h, respectively. As a probable consequence, IT30 accumulated to approximately 3-fold higher levels in the C170 xenografts than IT33. The reduced clearance of IT30 by the reticuloendothelial system thus resulted in prolonged survival in the blood and enhanced tumor localization relative to IT33.
 ...
PMID:Improved pharmacokinetics and tumor localization of immunotoxins constructed with the Mr 30,000 form of ricin A chain. 186 42

H65-RTA is an immunoconjugate that consists of the A chain of ricin (RTA), a ribosomal-inhibiting protein, coupled to a murine monoclonal antibody (H65) directed against the pan-T-cell antigen CD5. The CD5 antigen is heterogeneously expressed on cutaneous T-cell lymphoma tumor cells, but is not expressed on normal cells except lymphocytes. A phase I trial was therefore conducted in which 14 patients with cutaneous T-cell lymphoma progressive on other therapies were treated with up to three cycles of H65-RTA. The maximal tolerated dose (MTD) of H65-RTA was 0.33 mg/kg/d administered intravenously for 10 days as defined by dyspnea at rest at higher doses. Other reversible side effects included myalgia, mild hypoalbuminemia with weight gain, pedal edema, fatigue, fevers, and chills. Six patients received more than one cycle of H65-RTA without increased side effects compared with the first cycle. Pharmacokinetic analysis showed that peak serum drug levels were dose-dependent, and ranged from 1.13 to 5.56 micrograms/mL, with a terminal half-life ranging from 1.0 to 2.9 hours. The development of antibodies against the immunoconjugate was associated with a lower peak drug level, but not with enhanced side effects. Partial responses lasting from 3 to 8 months were documented in four patients. Three of the responding patients received more than one cycle of H65-RTA in the presence of anti-immunoconjugate antibodies. The results from this phase I trial suggest that H65-RTA is an active drug in the treatment of cutaneous T-cell lymphoma. The immunoconjugate may be safely administered repeatedly, even in the presence of anti-immunoconjugate antibodies, with responses noted. Additional studies at the MTD are needed to define the response rate in this disease.
 ...
PMID:Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma. 187 84

Immunotoxins have been used both experimentally and clinically to purge bone marrow of tumor cells or T cells before transplantation. We describe the synthesis of a streptavidin-biotin-toxin conjugate using whole ricin. Streptavidin-biotin-ricin (SA-BR) conjugates were synthesized by biotinylation of whole ricin, which was then complexed with streptavidin. Hybrid molecules consisting of a single biotinylated ricin moiety linked to a streptavidin molecule were separated by gel filtration. This SA-BR conjugate was used in an indirect cytotoxicity assay. The assay involved sensitizing of target cells with biotinylated monoclonal antibody (B-MCAB) followed by treatment with dilutions of SA-BR conjugate. The assay demonstrated a specific antibody-directed cytotoxicity. The strength of this SA-BR system is that a single conjugate was able to be used in conjunction with a library of B-MCABs to selectively target phenotypically different cell types. The application of the SA-BR conjugate is thus only restricted by the availability of B-MCABs specific for the desired target cells. The high affinity of avidin for biotin (Kd approximately 10(-15)) and the ability of a single conjugate to target phenotypically different cells through utilization of a library of B-MCABs gives SA-BR conjugates great potential in the selective targeting of individual cell types.
 ...
PMID:Streptavidin-biotin immunotoxins: a new approach to purging bone marrow. 189 57

Murine monoclonal antibody ZME-018 recognizes a 240 Kda glycoprotein present on the surface of most human melanoma cells and on over 80% of human biopsy specimens tested. Gelonin is a ribosome-inactivating plant toxin similar in nature and rivaling the activity of ricin A chain. ZME-018 was coupled to purified gelonin using the reagents SPDP and 2-iminothiolane. The ZME-gelonin conjugate was purified by S-300 Sephacryl and Blue Sepharose chromatography, removing unreacted gelonin and antibody, respectively. PAGE analysis showed that ZME was coupled to 1, 2, or 3 gelonin molecules. The ZME-gelonin conjugate was 10(6)-fold more active than gelonin itself in inhibiting the growth of log-phase human melanoma cells in culture. The immunoconjugate was not cytotoxic to antigen negative T-24 (human bladder carcinoma) cells. Treatment of melanoma cells with recombinant IFN-alpha or TNF substantially augmented the cytotoxicity of the immunoconjugate while treatment with IFN-gamma had a minor effect. Using the human tumor colony assay of melanoma cells obtained from fresh biopsy specimens, greater than 90% growth suppression was observed in 2 of 4 samples tested at a concentration of 250 ng/ml. In addition, 25% growth suppression was observed with a third sample tested, and no growth suppression was observed in 1 sample. Thus, clonogenic melanoma cells are sensitive in vitro to the cytotoxic activity of this immunotoxin at concentrations which we presume are pharmacologically relevant.
 ...
PMID:A specific and potent immunotoxin composed of antibody ZME-018 and the plant toxin gelonin. 190 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>