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

Citation
T. Yamori et al., 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, CANCER RES, 59(16), 1999, pp. 4042-4049
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
59
Issue
16
Year of publication
1999
Pages
4042 - 4049
Database
ISI
SICI code
0008-5472(19990815)59:16<4042:PAAOMA>2.0.ZU;2-5
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] py rrol-4-yl] carbamoyl] ethyldimethylsulfonium di-p-toluenesulfonate) that ha s a netropsin-like moiety and an alkylating residue in the structure. We ev aluated antitumor activity of MS-247 using a human cancer cell line panel c oupled with a drug sensitivity database and subsequently using human cancer xenografts. The average MS-247 concentration required for 50% growth inhib ition against a panel of 39 cell lines was 0.71 mu M, The COMPARE analysis revealed that the differential growth inhibition pattern of MS-247 signific antly correlated with those of camptothecin analogues and anthracyclins, in dicating that MS-247 and the two drug Groups might have similar modes of ac tion. MS-247 exhibited remarkable antitumor activity against various xenogr afts. A single i.v. injection of MS-247 significantly inhibited the growth of all 17 xenografts tested, which included lung, colon, stomach, breast, a nd ovarian cancers. In many cases, MS-247 was more efficacious than cisplat in, Adriamycin, 5-fluorouracil, cyclophosphamide, VP-16, and vincristine an d was almost comparable with paclitaxel and CPT-11; these are the must clin ically promising drugs at present. MS-247 was noticeably more effective tha n paclitaxel (in HCT-15) and CPT-11 (in A549, HBC-4, and SK-OV-3). The toxi city of MS-247, indicated by body weight loss, was reversible within 10 day s after administration. The MS-247 mode of action showed DNA binding activi ty at the site where Hoechst 33342 bound, inhibited topoisomerases I and II (as expected by the COMPARE analysis) blocked the cell cycle at the G(2)-M phase, and induced apoptosis. These results indicate that MS-247 is a prom ising new anticancer drug candidate to be developed further toward clinical trials.