In vivo Anti‐tumor Activity of a Novel Indolocarbazole Compound, J‐107088, on Murine and Human Tumors Transplanted into Mice

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Abstract
J‐107088 (6‐N‐(1‐hydroxymethyl‐2‐hydroxy)ethylamino‐12,13‐dihydro‐2,10‐dihydroxy‐13‐(β‐D‐glu‐copyranosyl)‐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 L 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‐107showed 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.

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