Brantley Eileen, Trapani Valentina, Alley Michael C, Hose Curtis D, Bradshaw Tracey D, Stevens Malcolm F G, Sausville Edward A, Stinson Sherman F
Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21701, USA.
Drug Metab Dispos. 2004 Dec;32(12):1392-401. doi: 10.1124/dmd.104.001057. Epub 2004 Sep 8.
Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In "sensitive" cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabolism appears to be essential for its antiproliferative activity through DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive cancer cells. One fluorinated benzothiazole, 2-(4-amino-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiproliferative activity without a biphasic dose-response. The fluorinated benzothiazoles were also metabolized only in cells, which subsequently showed evidence of cell death. We used microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochromes P450 (CYP1A1, CYP1A2, or CYP1B1) to clarify the basis for fluorinated benzothiazole metabolism. 5F 203 induced CYP1A1 and CYP1B1 mRNA expression in sensitive breast and renal cancer cells, whereas 5F 203 induced CYP1A1 mRNA but not CYP1B1 mRNA expression in sensitive ovarian cancer cells. 5F 203 did not induce CYP1A1 or CYP1B1 mRNA expression in any "resistant" cancer cells. The fluorinated benzothiazoles induced CYP1A1 protein expression exclusively in sensitive cells. [14C]5F 203 bound substantially to subcellular fractions in sensitive cells but only minimally in resistant cells. These data are concordant with the antiproliferative activity of fluorinated benzothiazoles deriving from their ability to become metabolized and bind to macromolecules within sensitive cells.
氟化的2-(4-氨基-3-甲基苯基)苯并噻唑对某些癌细胞具有强大的抗增殖活性，这与未氟化的2-(4-氨基-3-甲基苯基)苯并噻唑（DF 203，NSC 674495）相似。在“敏感”癌细胞中，DF 203可被CYP1A1代谢、诱导其表达并与之共价结合。代谢似乎通过形成DNA加合物对其抗增殖活性至关重要。然而，双相剂量反应关系阻碍了它作为化疗药物的直接开发。我们研究了氟化苯并噻唑是否能在没有双相剂量反应的情况下抑制癌细胞生长，以及氟化苯并噻唑是否也会代谢为活性物质，并与敏感癌细胞中的大分子结合。一种氟化苯并噻唑，2-(4-氨基甲基苯基)-5-氟苯并噻唑（5F 203，NSC 703786）确实表现出强大的抗增殖活性，且没有双相剂量反应。氟化苯并噻唑也仅在细胞中代谢，随后显示出细胞死亡的迹象。我们使用来自表达细胞色素P450（CYP1A1、CYP1A2或CYP1B1）的基因工程人B淋巴细胞系的微粒体来阐明氟化苯并噻唑代谢的基础。5F 203在敏感的乳腺癌和肾癌细胞中诱导CYP1A1和CYP1B1 mRNA表达，而5F 203在敏感的卵巢癌细胞中诱导CYP1A1 mRNA表达，但不诱导CYP1B1 mRNA表达。5F 203在任何“耐药”癌细胞中均未诱导CYP1A1或CYP1B1 mRNA表达。氟化苯并噻唑仅在敏感细胞中诱导CYP1A1蛋白表达。[14C]5F 203在敏感细胞中与亚细胞组分大量结合，但在耐药细胞中仅少量结合。这些数据与氟化苯并噻唑的抗增殖活性源于其在敏感细胞中代谢并与大分子结合的能力相一致。
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