Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-alpha-Pseudomonas exotoxin-40 (TP40) is a recombinant fusion protein. TP40 consists of the entire human transforming growth factor-alpha (TGF alpha) protein fused to a 40,000 Da. segment of the Pseudomonas exotoxin A protein. TP40 is a bifunctional molecule that possesses the epidermal growth factor (EGF) receptor binding properties of TGF alpha and the cell killing properties of Pseudomonas exotoxin A. These properties make TP40 a selective cytotoxic agent that kills EGF receptor bearing cells. TP40 has been shown to effectively kill human tumor cell lines that possess EGF receptors in vitro and in nude mice. In the present study, TP40 was tested against tumors taken directly from patients and grown in a soft agar human tumor cloning system. A total of 107 patients' tumors (taken from patients with tumors refractory to chemotherapy) were tested with a continuous exposure to 0.5-50 nM concentrations of the agent. TP40 exhibited a clear dose response effect against a wide variety of human solid tumor colony-forming units with greater than or equal to 84% of evaluable tumors responding at a drug concentration greater than or equal to 24 nM. When used as a continuous exposure, concentrations of TP40 as low as 5 nM demonstrated substantial in vitro activity. This activity included cytotoxicity against breast, colorectal, endometrial, head and neck, non small-cell lung, gastric, sarcoma, and pancreatic cancer tumor colony-forming units. Additional in vivo testing of this compound is warranted.
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PMID:Activity of a recombinant transforming growth factor-alpha-Pseudomonas exotoxin hybrid protein against primary human tumor colony-forming units. 160 49

TGF-alpha-PE40 is a chimeric protein composed of transforming growth factor alpha (TGF-alpha) linked to a modified Pseudomonas toxin from which the cell recognition domain has been deleted (PE40). TGF-alpha-PE40 has been shown to have cytotoxic effects on human cancer cell lines that express the epidermal growth factor (EGF) receptor on their surface, and when given i.p., it prolongs the survival of nude mice bearing i.p. tumors. Because several normal tissues, including liver, express EGF receptors on their surfaces, it has not been clear that this agent can be used systemically to treat EGF receptor-bearing tumors. In this study, we have delivered TGF-alpha-PE40 for 7 days by continuous infusion through a miniosmotic pump placed in the peritoneal cavity of nude immunodeficient mice. Two different human cancer cell lines that express EGF receptors on their surface were implanted s.c. One was A431, an epidermoid carcinoma; the other was DU-145, a prostate carcinoma. By using this mode of continuous i.p. delivery, we were able to achieve a constant serum level of TGF-alpha-PE40 that was nontoxic to the mice and yet delayed the growth of both tumors implanted s.c. and caused partial regression of one. We conclude that it is possible to deliver TGF-alpha-PE40 systemically and achieve a therapeutic serum level in mice without major toxicity. Although side effects may be expected, this study establishes that there is a therapeutic window for this agent in the therapy of cancers with high numbers of EGF receptors.
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PMID:Antitumor activity of a transforming growth factor alpha-Pseudomonas exotoxin fusion protein (TGF-alpha-PE40). 203 21

The epidermal growth factor (EGF) receptor is overexpressed in human pancreatic cancers and cultured cell lines. TP40 is a chimeric protein composed of transforming growth factor-alpha (TGF-alpha) linked to a modified Pseudomonas exotoxin A (PE40) that exerts growth inhibitory effects on cells bearing a high number of EGF receptors. Therefore, we compared the effect of TP40 on the growth of Chinese hamster ovary (CHO), cells expressing varying levels of the EGF receptor and on the growth of two human pancreatic cancer cell lines. The growth of CHO cells devoid of endogenous EGF receptors was minimally altered by high concentrations of TP40, even following a 72-h incubation period. In contrast, in CHO cells expressing approximately 95,000 and 438,000 EGF receptors per cell, one-half maximal growth inhibition occurred at 5 and 3 ng/ml TP40, respectively. Following a 72-h incubation in T3M4 and COLO 357 human pancreatic cancer cells, one-half maximal growth inhibition occurred at 0.2 and 0.4 ng/ml TP40, respectively. This effect was significantly greater than that of native Pseudomonas exotoxin A. These findings indicate that human pancreatic cancer cells are markedly sensitive to the growth inhibitory effects of TP40 and raise the possibility that TP40 may have a therapeutic role in this disorder.
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PMID:Cytotoxic effects of TGF-alpha-Pseudomonas exotoxin A fusion protein in human pancreatic carcinoma cells. 878 29

Human pancreatic cancers overexpress the epidermal growth factor (EGF) receptor (EGFR) and all 5 ligands that bind to this receptor, including amphiregulin. It is not known, however, whether amphiregulin contributes in an autocrine manner to enhance pancreatic cancer cell growth. Therefore, we used an amphiregulin antisense oligonucleotide (AR-AS) to suppress amphiregulin expression in T3M4 human pancreatic cancer cells. These cells express high levels of EGFR and amphiregulin. AR-AS abolished amphiregulin immunoreactivity in T3M4 cells, decreased amphiregulin release into the medium and inhibited cell growth in a dose-dependent manner. Exogenous amphiregulin reversed AR-AS-mediated growth inhibition. A random oligonucleotide (AR-R) did not alter either cell growth or cellular amphiregulin immunoreactivity. AR-AS also increased cellular EGFR protein levels and enhanced the growth-inhibitory actions of TP40, a chimeric protein consisting of transforming growth factor-alpha coupled to Pseudomonas exotoxin that internalizes into cells via EGFR. These findings indicate that there is an important EGFR/ amphiregulin autocrine loop in T3M4 cells and raise the possibility that modalities aimed at abrogating amphiregulin action may prove useful in pancreatic cancer, especially when used in conjunction with EGFR-targeted therapy.
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PMID:Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy. 924 97

Pseudomonas exotoxin (PE) requires proteolytic cleavage to generate a 37-kDa C-terminal fragment that translocates to the cytosol and ADP-ribosylates elongation factor 2. Cleavage within cells is mediated by furin, occurs between arginine 279 and glycine 280, and requires an arginine at both P1 and P4 residues. To study the proteolytic processing of PE-derived chimeric toxins, TGFalpha-PE38 (transforming growth factor fused to the domains II and III of PE) and a mutant form, TGFalpha-PE38gly279, were each produced in Escherichia coli. When assessed on various epidermal growth factor (EGF) receptor-positive cell lines, TGFalpha-PE38 was 100-500-fold more toxic than TGFalpha-PE38gly279. In contrast to PE, where cleavage by furin is only evident at pH 5.5, furin cleaved TGFalpha-PE38 over a broad pH range, while TGFalpha-PE38gly279 was resistant to cleavage. TGFalpha-PE38 was poorly toxic for furin-deficient LoVo cells, unless it was first pretreated in vitro with furin. Furin treatment produced a nicked protein that was 30-fold more toxic than its unnicked counterpart. Using the single chain immunotoxin HB21scFv-PE40 as a substrate, furin-mediated processing of an antibody-based immunotoxin was also evaluated. HB21scFv-PE40, which targets cells expressing the transferrin receptor, was cleaved in a similar fashion to that of TGFalpha-PE38 and nicked HB21scFv-PE40 exhibited increased toxicity for LoVo cells. In short-term experiments, the rate of reduction in protein synthesis by furin-nicked immunotoxins was increased compared with unnicked protein, indicating that cleavage by furin can be a rate-limiting step. We conclude that furin-mediated cleavage of PE-derived immunotoxins is important for their cytotoxic activity.
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PMID:Furin-mediated cleavage of Pseudomonas exotoxin-derived chimeric toxins. 939 13

Growth factor receptors provide unique opportunities for development of targeted anticancer therapy. Members of the type I receptor tyrosine kinase family, including epidermal growth factor (EGF) receptor (EGFR) and ErbB-2/neu, are often overexpressed in various human cancer cells, including breast. Recently, it has been shown that both ErbB-3 and ErbB-4 are receptors for heregulin (HRG)/Neu differentiation factor. Eight chimeric toxins composed of the extracellular and EGF-like domains of four different HRG isoforms and truncated Pseudomonas exotoxin (PE38KDEL) were constructed. The fusion proteins exhibited activity similar to the native HRG in inducing ErbB receptors phosphorylation. The EGF-like domain of HRG13 and HRGbeta2 fused to PE38KDEL showed the highest cytotoxic activity, with a IC50 of < or = 0.001 ng/ml. The alpha isoforms that were fused to PE38KDEL were 100-fold less active than the beta isoforms. The HRG-Pseudomonas exotoxin (PE) toxins show extremely high activity against cells expressing ErbB-4 receptor, alone or together with other members of the ErbB receptor family. Cells that do not express ErbB-4 but express ErbB-3 receptor, together with the ErbB-2 or EGFR, exhibited moderate sensitivity to HRG-PE toxins. HRG-PE toxins have little or no activity against cells expressing EGFR, ErbB-2, or ErbB-3 alone. More than an 80% tumor regression was achieved by intratumor injection of 1 microg of fusion proteins per day for 5 days. Continuous i.p. administration of EGF-like domain of HRGbeta1-PE38KDEL for 7 days via a miniosmotic pump at a dose of 40 microg/kg/day inhibited the growth of ErbB-4 receptor positive but not ErbB-4 receptor negative cell lines in athymic nude mice. We conclude that there is therapeutic potential of HRG-PE toxins in the therapy of cancers overexpressing the ErbB-4 or ErbB-2 plus ErbB-3 receptors.
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PMID:Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo. 956 95

Receptor-mediated targeted tumor therapy is an important applied consequence of the studies on the genetic causes of cancer. These therapy concepts have to be evaluated in novel animal models that reflect the molecular aberrations found in human tumors. Here we introduce an animal model that allows the evaluation of drugs directed against a surface receptor that is frequently altered in primary human adenocarcinomas. Tumor toxins are polypeptides in which a tumor cell-specific recognition domain and a toxic effector domain have been joined by DNA recombination in vitro. Tumor cell recognition is contributed by a single-chain antibody domain specific for the extracellular domain of the erbB-2 receptor [scFv(FRP5)] and cytotoxicity by the enzymatically active domain of a bacterial exotoxin (exotoxin A from Pseudomonas aeruginosa). The erbB-2 receptor is overexpressed in many primary human cancer cells and is a favorable target for directed tumor therapy. The fusion protein scFv(FRP5)-exotoxin A has previously been shown to be able to efficiently and specifically kill erbB-2 receptor-expressing tumor cells. We have investigated the potential of this tumor toxin to detect and eliminate metastasizing tumor cells upon systemic administration. Murine renal carcinoma cells genetically modified with human erbB-2 receptor and bacterial beta-galactosidase genes form large pulmonary metastases when injected into the tail vein of BALB/c mice. Administration of the tumor toxin over a 10-day time period starting 1 day after tumor cell transplantation totally suppressed the formation of metastases. The treatment of animals 11 days after tumor cell transplantation, allowing the establishment of many pulmonary metastases, led to a drastic reduction in their number and size.
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PMID:Systemic treatment with a recombinant erbB-2 receptor-specific tumor toxin efficiently reduces pulmonary metastases in mice injected with genetically modified carcinoma cells. 963 94

The recombinant oncotoxin AR209 [e23(Fv)PE38KDEL; formerly OLX-209] was developed to treat neoplasia that expresses the c-erbB-2 (HER-2/neu) protein product p185(erbB-2). The AR209 compound contains a single-chain antibody domain specific for p185(erbB-2), coupled with a portion of the Pseudomonas exotoxin. The drug has been shown to be effective in inhibiting cells that overexpress erbB-2 due to gene amplification and in cells that do not contain amplified erbB-2 but express slightly higher levels of the protein than normal cells do. To test the efficacy of AR209 on human lung tumors, athymic nude mice were inoculated intrathoracically with a cell line derived from a poorly differentiated lung adenocarcinoma. This cell line, termed 201T, expresses moderately elevated levels of p185(erbB-2) 7.6-fold over normal bronchial epithelium. Mice treated with i.v. injections of AR209 for 5 weeks after orthotopic tumor implantation had smaller tumors and in 20% of cases showed no evidence of disease. The data from this study indicate that AR209 may be an effective treatment for patients with non-small cell lung cancers that express p185(erbB-2).
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PMID:Effects of anti-erbB-2 (HER-2/neu) recombinant oncotoxin AR209 on human non-small cell lung carcinoma grown orthotopically in athymic nude mice. 981 40