Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor

Transforming growth factor alpha (TGF-alpha) is an autocrine growth factor for human cancer, Overespression of TGF-alpha and its specific receptor, th e epidermal growth factor receptor (EGFR), is associated with aggressive di sease and poor prognosis, The EGFR has been proposed as a target for antica ncer therapy, Compounds that block ligand-induced EGPR activation have been developed. ZD-1839 (Iressa) is a p.o.-active, quinazoline derivative that selectively inhibits the EGFR tyrosine kinase and is under clinical develop ment in cancer patients, The antiproliferative activity of ZD-1839 alone or in combination with cytotoxic drugs differing in mechanism(s) of action, s uch as cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, doxorubi cin, etoposide, topotecan, and raltitrexed, was evaluated in human ovarian (OVCAR-3), breast (ZR-75-1, MCF-10A ras), and colon cancer (GEO) cells that coexpress EGFR and TGF-alpha. ZD-1839 inhibited colony formation in soft a gar in a dose-dependent manner in all cancer cell lines. The antiproliferat ive effect was mainly cytostatic, However, treatment with higher doses resu lted in a 2-4-fold increase in apoptosis, A dose-dependent supra-additive i ncrease in growth inhibition was observed when cancer cells were treated wi th each cytotoxic drug and ZD-1839, The combined treatment markedly enhance d apoptotic cell death induced by single-agent treatment, ZD-1839 treatment of nude mice bearing established human GEO colon cancer xenografts reveale d a reversible dose-dependent inhibition of tumor growth because GEO tumors resumed the growth rate of controls at the end of the treatment. In contra st, the combined treatment with a cytotoxic agent, such as topotecan, ralti trexed, or paclitaxel, and ZD-1839 produced tumor growth arrest in all mice . Tumors grew slowly for approximately 4-8 weeks after the end of treatment , when they finally resumed a growth rate similar to controls. GEO tumors r eached a size not compatible with normal life in all control mice within 4- 6 weeks and in all single agent-treated mice within 6-8 weeks after GEO cel l injection, In contrast, 50% of mice treated with ZD-1839 plus topotecan, raltitrexed, or paclitaxel were still alive 10, 12, and 15 weeks after canc er cell injection, respectively, These results demonstrate the antitumor ef fect of this EGFR-selective tyrosine kinase inhibitor and provide a rationa le for its clinical evaluation in combination with cytotoxic drugs.