Potent antitumor activity of MS-247, a novel DNA minor groove binder, evaluated by an in vitro and in vivo human cancer cell line panel.

Abstract

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 microM. 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.

• Authors: T Yamori, A Matsunaga, S Sato, K Yamazaki, A Komi, K Ishizu, I Mita, H Edatsugi, Y Matsuba, K Takezawa, O Nakanishi, H Kohno, Y Nakajima, H Komatsu, T Andoh, T Tsuruo
• Journal: Cancer research (Cancer Res) Vol. 59 Issue 16 Pg. 4042-9 (Aug 15 1999) ISSN: 0008-5472 [Print] United States
• PMID: 10463605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Benzimidazoles
• DNA, Neoplasm
• DNA-Binding Proteins
• MS 247
• Pyrroles

Topics

• Animals
• Antineoplastic Agents, Alkylating (chemistry, pharmacology, therapeutic use)
• Benzimidazoles (chemistry, pharmacology, therapeutic use)
• DNA, Neoplasm (drug effects)
• DNA-Binding Proteins (chemistry, pharmacology, therapeutic use)
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy, genetics)
• Pyrroles (chemistry, pharmacology, therapeutic use)
• Transplantation, Heterologous
• Tumor Cells, Cultured