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C K Osborne

Publications and source records attributed to C K Osborne.

202 records · Page 12Linked to original sources
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Adjuvant chemotherapy.

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Antineoplastic Combined Chemotherapy Protocols↗
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Targeting the epidermal growth factor receptor in breast cancer cell lines with a recombinant ligand fusion toxin (DAB389EGF).

PURPOSE: The epidermal growth factor receptor (EGF-R) is overexpressed frequently in breast cancer and other solid tumors. Targeting this receptor with an EGF ligand fusion toxin might selectively intoxicate cancer cells while minimizing toxicity to normal cells. DAB389EGF is a recombinant fusion toxin containing the enzymatically active and membrane translocation domains of diphtheria toxin and sequences for human EGF. After binding to EGF-R, the drug is internalized, the toxin is released, and inhibition of protein synthesis and cell death ensue. We examined the cytotoxic effects of DAB389EGF on a panel of breast cancer cell lines. MATERIALS AND METHODS: Protein synthesis, monolayer growth, and anchorage-independent growth were studied in human breast cancer cell lines expressing low, intermediate, or high EGF-R concentrations. DAB389EGF concentrations and duration of exposure required for maximal effects were determined. Specificity of cellular cytotoxicity was assessed by reversing the effects with excess native EGF and by investigating the activity of two mutant analogs of DAB389EGF that either lack diphtheria toxin enzymatic activity or EGF-R binding activity. RESULTS: DAB389EGF inhibited protein synthesis in the cell line panel to a variable degree. Cell lines with low EGF-R levels were relatively resistant to the drug, while lines with intermediate to high receptor levels were very sensitive. Cell lines with intermediate or high EGF-R levels were exquisitely sensitive to DAB389EGF in monolayer and anchorage-independent growth assays with IC50 ranging from 3 to 50 pM with a continuous drug exposure. Cell lines with low receptor levels were only moderately inhibited at a 1 nM drug concentration. Cytotoxicity was reversed by the addition of native EGF. Mutant analogs that were devoid of enzymatic or receptor binding activity were inactive. Cytotoxicity was dependent on both the drug concentration andduration of exposure; at a concentration of 1 nM, a 60-minute exposure caused substantial cytotoxicity only for cells with very high EGF-R concentrations. Longer treatment durations were required with cell lines expressing intermediate or low receptor concentrations. DISCUSSION: Breast cancer cell lines expressing intermediate to high levels of EGF-R are sensitive to low concentrations of DAB389EGF. This activity requires intact receptor binding and diphtheria toxin domains. DAB389EGF offers promise as a new therapeutic strategy for solid tumors such as breast cancer that overexpress EGF-R.

Breast Neoplasms↗