Induction of CYP1A1 in tumor cells by the antitumor agent 2-[4-amino-3-methylphenyl]-5-fluoro-benzothiazole: a potential surrogate marker for patient sensitivity.
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 micro M resveratrol, an inhibitor of CYP1A1 induction, in combination with either 1 or 10 micro M 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 micro M 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.
Hose
Curtis D
CD
SAIC-Frederick, National Cancer Institute-Frederick, Developmental Therapeutics Program, STB-Functional Genomics Laboratory, Frederick, MD 21702, USA.
Hollingshead
Melinda
M
Sausville
Edward A
EA
Monks
Anne
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers; D004790:Enzyme Induction; D006801:Humans; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*
C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D017931:DNA Primers; D012333:RNA, Messenger; D013844:Thiazoles; D019363:Cytochrome P-450 CYP1A1