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.
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.
Yamori
T
T
Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Matsunaga
A
A
Sato
S
S
Yamazaki
K
K
Komi
A
A
Ishizu
K
K
Mita
I
I
Edatsugi
H
H
Matsuba
Y
Y
Takezawa
K
K
Nakanishi
O
O
Kohno
H
H
Nakajima
Y
Y
Komatsu
H
H
Andoh
T
T
Tsuruo
T
T
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C121173:MS 247; D011758:Pyrroles