In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice.
J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.
Arakawa
H
H
Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories. arakwahh@banyu.co.jp
Morita
M
M
Kodera
T
T
Okura
A
A
Ohkubo
M
M
Morishima
H
H
Nishimura
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002227:Carbazoles / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004317:Doxorubicin / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors
D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; D007211:Indoles; C121395:edotecarin; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin