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¹ SAIC-Frederick, National Cancer Institute-Frederick, Developmental Therapeutics Program, STB-Functional Genomics Laboratory, Frederick, MD, and ² Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD

Requests for Reprints: Anne Monks, STB Laboratory of Functional Genomics, SAIC-Frederick Inc., Building 432/230, P. O. Box B, Frederick, MD 21702.

A candidate antitumor agent, 2-(4-amino-3-methylphenyl)-5-fluoro-benzothiazole (5F-203), like its non-fluorinated parent compound (DF-203), has a unique cytotoxicity pattern in the National Cancer Institute in vitro anticancer drug screen. These compounds show selective toxicity for a subset of cell types including estrogen receptor positive breast cancer and certain renal and ovarian cancer cell lines. Metabolic activation of these benzothiazoles seems to be mediated through the CYP1 family of cytochrome P450s. In an effort to characterize the involvement of CYP1A1 and CYP1B1 in the unique toxicity response of 5F-203, constitutive and 5F-203-induced gene expression patterns were measured in 60 cell lines of the National Cancer Institute drug screen using TaqMan real-time PCR. The patterns of CYP1A1 and CYP1B1 gene expression in the 60 cell lines were correlated with the toxicity pattern of 5F-203 and DF-203. There was significant correlation between drug sensitivity and induced CYP1A1 (R = 0.752, P < 0.001), but not constitutive CYP1A1 mRNA expression. CYP1A1 protein expression was found to mirror the corresponding gene expression, indicating that gene expression changes were concordant with function. Treatment of sensitive cell lines with 10 µM resveratrol, an inhibitor of CYP1A1 induction, in combination with either 1 or 10 µM 5F-203 showed an ablation of the observed CYP1A1, but not CYP1B1 mRNA induction in parallel with a decreased sensitivity to 5F-203. Fine needle aspirates were obtained from a variety of human tumor xenografts, and treated ex vivo with 1 µM 5F-203 for 24 h. In these samples, induction of CYP1A1 by 5F-203 correlated with in vitro sensitivity (R = 0.711, P < 0.05), and corresponded to in vivo sensitivity in human tumor xenografts. These data are concordant with the idea that toxicity of 5F-203 requires activation by CYP1A1, and therefore induction of CYP1A1 mRNA in response to 5F-203 treatments ex vivo may provide a possible surrogate marker for determination of drug-sensitive tumors in patients.

Key Words: CYP1A1 • CYP1B1 • Surrogate markers • 2-[4-Amino-3-methylphenyl]-5-fluoro-benzothiazole

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.

Grant support: This project has been funded, in whole or in part, with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. Note: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.

² Tracy D. Bradshaw, University of Nottingham, United Kingdom, personal communication.

Received 7/ 1/03; revised 9/ 3/03; accepted 9/10/03.

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