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Departments of ¹ Surgery and ² Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois and ³ Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Ralph R. Weichselbaum, Department of Radiation and Cellular Oncology, University of Chicago Hospitals, Center for Advanced Medicine, Room 1329, Mail Code 9006, 5758 South Maryland Avenue, Chicago, IL 60637. Phone: 773-702-0817; Fax: 773-834-7233. E-mail: rrw{at}rover.uchicago.edu

A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)₆GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor- by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C.A. Lopez and E.T. Kimchi contributed equally to this article. D.W. Kufe and R.R. Weichselbaum have an equity interest in and are consultants to GenVec, Inc.

⁴ Mundt et al., Clinical Cancer Research. In press.

⁵ See http://dtp.nci.nih.gov/branches/btb/ivclsp.html.

Received 11/ 6/03; revised 5/21/04; accepted 6/30/04.