The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 selectively potentiates radiation response of human tumors in nude mice, with a marked improvement in therapeutic index.

摘要: Purpose: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) markedly potentiates the efficacy of many cytotoxic agents against several human cancer xenografts, irrespective tumor EGFR expression levels. We subsequently investigated extent to which might improve radiation therapy (RT) in similar animal models within limits tolerance at a relevant organ site. Experimental Design: carried out studies vivo non-small cell lung (A549 and SK-LC-16) breast (MDA-MB468) cancers mesothelioma (JMN). tumors were implanted s.c. over rib cage or on most proximate RT given ventral dorsally chest only, with mediastinal protection. After reached palpable size (0.4–0.6 mm), treatment was initiated maximum-tolerated dose (MTD) (150 mg/kg once daily × 5 for 2 successive weeks), (a total 40 Gy fractionally 4 both RT. Results: This level induced no untoward effects mice effective (18–72%) bringing about regression few complete regressions. alone, p.o. same schedule its MTD mg/kg), modestly inhibitory (35–40%) growth. could be together doses schedule, resulting marked (50–99%) large number regressions each studied. In these studies, combined change increase toxicity alone. Conclusions: significantly enhanced antitumor action test without significant adverse effects, increasing therapeutic selectively ionizing model systems. These results predict substantial benefits this multimodality regimen patients.