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Potent Antitumor Activity of MS-247, a Novel DNA Minor Groove Binder, Evaluated by an in Vitro and in Vivo Human Cancer Cell Line Panel¹

Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455 [T. Y., S. S., K. Y., A. K., K. I.]; Life Sciences Laboratory, Mitsui Chemical Inc., Chiba 297-0017 [A. M., H. K., Y. N., H. K.]; Institute of Biological Science, Mitsui Pharmaceuticals, Inc., Chiba 297-0017 [I. M., H. E., Y. M., K. T., O. N.]; Faculty of Engineering, Soka University, Tokyo 192-0003 [T. A.]; and Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 [T. T.], Japan

We synthesized a novel anticancer agent MS-247 (2-[[N-[1-methyl-2-[5-[N-[4-[N,N-bis(2-chloroethyl) amino] phenyl]] carbamoyl]-1H-benzimidazol-2-yl] pyrrol-4-yl] carbamoyl] ethyldimethylsulfonium di-p-toluenesulfonate) that has a netropsin-like moiety and an alkylating residue in the structure. We evaluated antitumor activity of MS-247 using a human cancer cell line panel coupled with a drug sensitivity database and subsequently using human cancer xenografts. The average MS-247 concentration required for 50% growth inhibition against a panel of 39 cell lines was 0.71 µM. The COMPARE analysis revealed that the differential growth inhibition pattern of MS-247 significantly correlated with those of camptothecin analogues and anthracyclins, indicating that MS-247 and the two drug groups might have similar modes of action. MS-247 exhibited remarkable antitumor activity against various xenografts. A single i.v. injection of MS-247 significantly inhibited the growth of all 17 xenografts tested, which included lung, colon, stomach, breast, and ovarian cancers. In many cases, MS-247 was more efficacious than cisplatin, Adriamycin, 5-fluorouracil, cyclophosphamide, VP-16, and vincristine and was almost comparable with paclitaxel and CPT-11; these are the most clinically promising drugs at present. MS-247 was noticeably more effective than paclitaxel (in HCT-15) and CPT-11 (in A549, HBC-4, and SK-OV-3). The toxicity of MS-247, indicated by body weight loss, was reversible within 10 days after administration. The MS-247 mode of action showed DNA binding activity at the site where Hoechst 33342 bound, inhibited topoisomerases I and II (as expected by the COMPARE analysis) blocked the cell cycle at the G₂-M phase, and induced apoptosis. These results indicate that MS-247 is a promising new anticancer drug candidate to be developed further toward clinical trials.

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