The recombinant anti-EGF receptor immunotoxin 425(scFv)-ETA' suppresses growth of a highly metastatic pancreatic carcinoma cell line

Bruell, Daniela; Stöcker, Michael; Hühn, Michael; Redding, Nicole; Kupper, Michaël B.; Schumacher, Petra B.; Paetz, Antje; Bruns, Christiane; Haisma, Hidde J.; Fischer, Rainer; Finnern, Ricarda; Barth, Stephanie

doi:10.3892/ijo.23.4.1179

Cited by 28 publications

(47 citation statements)

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“…Growth factor receptors like IL-2R, EGF-R, TGF-β, and c-kit are promising targets for treatment of various solid tumors (Bruell et al 2003;Schmidt-Arras et al 2004). c-kit has been implicated as the driver of cancers either due to overactivity of c-kit/SCF axis or activating c-kit mutations.…”

Section: Discussionmentioning

confidence: 98%

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Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins

Choudhary

Pardo

Rosinke

et al. 2015

Appl Microbiol Biotechnol

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Autocrine activation of c-kit (KIT receptor tyrosine kinase) has been postulated to be a potent oncogenic driver in small cell lung cancer, neuroblastoma (NB), and poorly differentiated colorectal carcinoma (CRC). Although targeted therapy involving tyrosine kinase inhibitors (TKIs) such as imatinib mesylate is highly effective for gastrointestinal stromal tumor carrying V560G c-kit mutation, it does not show much potential for targeting wild-type KIT (WT-KIT). Our study demonstrates the role of stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing malignancies such as NBs and CRCs. We constructed SCF-based recombinant bacterial toxins by genetically fusing mutated form of natural ligand SCF to receptor binding deficient forms of Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA') and evaluated their efficacy in vitro. Efficient targeting was achieved in all receptor-positive neuroblastoma (IMR-32 and SHSY5Y) and colon cancer cell lines (COLO 320DM, HCT 116, and DLD-1) but not in receptor-negative breast carcinoma cell line (MCF-7) thereby proving specificity. While dose- and time-dependent cytotoxicity was observed in both neuroblastoma cell lines, COLO 320DM and HCT 116 cells, only an anti-proliferative effect was observed in DLD-1 cells. We prove that these novel targeting agents have promising potential as KIT receptor tyrosine kinase targeting system.

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Section: Discussionmentioning

confidence: 98%

“…The amplified SCF sequence was cloned directly at the N-terminus of the ETA' sequence into pMT-425(scFv)-ETA' digested with Sfi I and Not I (Bruell et al 2003) to assemble pMT SCF-ETA'. The primer sequences used for cloning are described in Table S1 in the Electronic supplementary material (ESM).…”

Section: Construction Of Recombinant Clonesmentioning

confidence: 99%

Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins

Choudhary

Pardo

Rosinke

et al. 2015

Appl Microbiol Biotechnol

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“…Although EGFR was shown to have no independent prognostic significance in advanced cancer (Baekelandt et al, 1999), the EGFR and HER2/neu were frequently overexpressed in malignant tumours. Recent microassay analysis revealed that amplification of EGFR gene was found in many tumours including ovarian cancer (Lei et al, 1999), glioblastoma (Hui et al, 2001), pancreatic cancer (Bruell et al, 2003;Schreiner et al, 2003), gastric cancer (Garcia et al, 2003), prostate cancer (Skacel et al, 2001), and lung adenocarcinoma and head/ neck squamous cell carcinoma (Haedicke et al, 2003;Shintani et al, 2003), suggesting that overexpression of EGFR may be linked to the oncogenesis of various cancers. High level of EGFR expression also correlates with increased tumour resistance to radiation (Shintani et al, 2003), suggesting that EGFR may mediate radioresistance of cancer cells (Liang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Various strategies have been developed to target EGFR and to deter cancer cell growth (Zhang et al, 2000;Bruell et al, 2003;Heimberger et al, 2003). For example, the treatment of cancer cells with EGFR tyrosine kinase inhibitor markedly potentiates the efficacy of many cytotoxic agents against several human cancer xenografts (She et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Lack of EGF receptor contributes to drug sensitivity of human germline cells

et al. 2005

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Germline mutations have been associated with generation of various types of tumour. In this study, we investigated genetic alteration of germline tumours that affect the drug sensitivity of cells. Although all germline tumour cells we tested were hypersensitive to DNA-damaging drugs, no significant alteration was observed in their DNA repair activity or the expression of DNA repair proteins. In contrast, germline tumours expressed very low level of epidermal growth factor receptor (EGFR) compared to drug-resistant ovarian cancer cells. An immunohistochemical analysis indicated that most of the primary germline tumours we tested expressed very low level of EGFR. In accordance with this, overexpression of EGFR in germline tumour cells showed an increase in drug resistance, suggesting that a lack of EGFR, at least in part, contributes to the drug sensitivity of germline tumours.

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“…More recently, DAB 389 EGF and anti-EGFR immunotoxins have been developed for local treatment of brain and pancreatic tumors. [213][214][215] One method for improving specifi city for EGFR+ malignant cells is to target mutant versions of the EGFR with recombinant immunotoxins. 216 , 217 Another is to target the heparin binding form of the EGFR, which can be modulated by heparin.…”

Section: Immunotoxins Targeting the Epidermal Growth Factor Receptormentioning

confidence: 99%

Immunotoxins for targeted cancer therapy

Kreitman¹

Chimeric Toxins

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The recombinant anti-EGF receptor immunotoxin 425(scFv)-ETA' suppresses growth of a highly metastatic pancreatic carcinoma cell line

Cited by 28 publications

References 0 publications

Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins

Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins

Lack of EGF receptor contributes to drug sensitivity of human germline cells

Immunotoxins for targeted cancer therapy

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