Effects of ER-37328 on primary tumor, liver metastasis, and life span in a murine colon 38 orthotopic transplantation model.
12,13-Dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c] pyrimido[5,6,1-jk] carbazole-4,6,10(5H,11H)-trione hydrochloride (ER-37328) is a novel topoisomerase II poison with potent tumoricidal activity against solid tumor cells both in vitro and in vivo. Here, we describe studies on the effects of ER-37328 on the primary tumor, liver metastasis, and survival in a murine Colon 38 orthotopic transplantation model. When ER-37328 (10 mg/kg) was administered i.v. at 11 days or 20 days after transplantation, strong regression of the primary tumor was observed on both administration schedules. On the later schedule, ER-37328 completely blocked liver metastasis, whereas the mean number of metastases in the control group was 23.9. To examine the antitumor activity against Colon 38 at the liver in more detail, ER-37328 was administered to mice that had received an inoculation of Colon 38 tumor into the liver. ER-37328 showed strong tumor-regression activity against Colon 38 growing in the liver. In addition, administration of ER-37328 on a schedule of every 7 days four times caused a significant increase of 79% in life span in the orthotopic transplantation model, calculated by using mean survival times. Pharmacokinetic study revealed that ER-37328 was highly distributed to the tumor and organs. The ratios of the area under the concentration-time curves of ER-37328 in the tumor, lung, liver, and kidney versus plasma were 81, 77, 47, and 40, respectively. This high distribution to the tumor and liver may explain the potent antitumor activity of ER-37328 against Colon 38 tumor in the liver. In conclusion, the topoisomerase II poison ER-37328 is a promising candidate for clinical application against colon cancer.
Nakamura
Katsuji
K
Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki 300-2635, Japan. k2-nakamura@hhc.eisai.co.jp
Taniguchi
Tomoyoshi
T
Funahashi
Yasuhiro
Y
Yoshimatsu
Kentaro
K
D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D014183:Transplantation, Heterologous
D002227:Carbazoles; C470233:ER37328; D011743:Pyrimidines; D005047:Etoposide