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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 Index¹

Program in Molecular Pharmacology and Chemistry [Y. S., F. L., J. C., F. M. S.] and Departments of Radiation Therapy [A. H-F.], Medicine [V. A. M., M. G. K.], and Surgery [V. R. R.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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 of tumor EGFR expression levels. We subsequently investigated the extent to which ZD1839 might improve radiation therapy (RT) in similar animal models of human cancer within the limits of tolerance at a relevant organ site.

Experimental Design: We carried out studies of ZD1839 in in vivo models of human non-small cell lung (A549 and SK-LC-16) and breast (MDA-MB468) cancers and human mesothelioma (JMN). The tumors were implanted s.c. over the rib cage or on the most proximate breast and RT given ventral dorsally to the chest only, with mediastinal protection. After the tumor reached a palpable size (0.4–0.6 mm), treatment was initiated with the maximum-tolerated dose (MTD) of ZD1839 (150 mg/kg once daily x 5 for 2 successive weeks), RT (a total of 40 Gy given fractionally at 4 Gy once daily x 5 for 2 successive weeks), or both ZD1839 and RT.

Results: This level of RT induced no untoward effects in the mice and was effective (18–72%) in bringing about regression of the tumors with a few complete regressions. ZD1839 alone, given p.o. on the same schedule at its MTD (150 mg/kg), was modestly inhibitory (35–40%) to tumor growth. RT and ZD1839 could be given together at the same doses on the same schedule, resulting in marked regression (50–99%) and a large number of complete regressions of each of the tumors studied. In these studies, the MTD of ZD1839 could be combined with the MTD of RT with no change in schedule or increase toxicity over ZD1839 or RT alone.

Conclusions: ZD1839 significantly enhanced the antitumor action of RT against the test tumors without significant adverse effects, increasing the therapeutic selectively of ionizing radiation in these model systems. These results predict substantial benefits for this multimodality regimen of therapy in patients.

Commentary

Molecular Targets for Radiation Therapy: Bringing Preclinical Data into Clinical Trials

Philip J. Tofilon, Scott Saxman, and C. Norman Coleman
Clin. Cancer Res. 2003 9: 3518-3520. [Full Text] [PDF]

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