Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis, and cooperate with cytotoxic drugs in human cancer cell lines

• Published in: International journal of cancer Vol. 93; no. 2; pp. 172 - 178
• Main Authors: Ciardiello, Fortunato, Caputo, Rosa, Troiani, Teresa, Borriello, Gaetano, Kandimalla, Ekambar R., Agrawal, Sudhir, Mendelsohn, John, Bianco, A. Raffaele, Tortora, Giampaolo
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 15.07.2001; Wiley-Liss
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; antisense oligonucleotides; Apoptosis; Biological and medical sciences; Cell Division - drug effects; chemotherapy; Cisplatin - pharmacology; combination therapy; Doxorubicin - pharmacology; Drug Combinations; EGFR blockade; epidermal growth factor receptors; General aspects; growth factor receptors; Humans; Medical sciences; oligonucleotides; Oligonucleotides, Antisense - pharmacology; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Topotecan - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Cell proliferation; Targeting; Doxorubicin; Epidermal growth factor; Taxane derivatives; Established cell line; Paclitaxel; Drug interaction; Inhibition; Antimitotic; Platinum II Complexes; Biological receptor; Human; Drug combination; Cytokine; Enzyme inhibitor; Topotecan; Malignant tumor; Antisense oligonucleotide; In vitro; Biological activity; Cisplatin; Alkylating agent; Antibiotic; Growth factor receptor; Polypeptide; Cell death; Anthracyclins; Growth factor; Apoptosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.1335

We have constructed a series of 22 phosphorothioate 20‐mer antisense oligonucleotides directed against different regions of the human (EGFR) mRNA. Treatment with EGFR antisense oligonucleotides showed a dose‐dependent inhibition of human GEO colon cancer cell growth in soft agar. Western blot analysis demonstrated a significant reduction in EGFR expression after treatment with each EGFR antisense oligonucleotide. The ability to inhibit GEO anchorage‐independent growth, however, varied among the EGFR antisense sequences with an IC50 ranging between 0.5 and 3.5 μM. Two of these antisense oligonucleotides targeting the regions between 2457–2476 and 614–4633 bases of the human EGFR mRNA have been modified as hybrid DNA/RNA mixed backbone oligonucleotides (MBO) to examine their anticancer properties in vivo. The 2 EGFR antisense MBOs retained the same biological properties of the fully phosphorothioate EGFR antisense oligonucleotides targeting the same EGFR mRNA sequences, such as blocking EGFR synthesis, inhibiting cell growth and enhancing programmed cell death in human cancer cell lines that express functional EGFRs. Furthermore, a potentiation in the growth inhibitory effect on GEO cancer cells was observed after treatment with these EGFR antisense MBOs in combination with cytotoxic drugs, including cisplatin, doxorubicin, paclitaxel, or topotecan. These results show the antiproliferative activity of specific EGFR antisense oligonucleotides and allow to identify novel EGFR antisense MBOs that deserve further evaluation as potential selective anticancer agents alone or in combination with cytotoxic drugs in human carcinomas that express functional EGFRs. © 2001 Wiley‐Liss, Inc.