In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice

Jpn J Cancer Res. 1999 Oct;90(10):1163-70. doi: 10.1111/j.1349-7006.1999.tb00691.x.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Body Weight / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Carbazoles / therapeutic use*
  • Cisplatin / therapeutic use
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / pathology
  • Doxorubicin / therapeutic use
  • Drug Administration Schedule
  • Female
  • Glucosides / therapeutic use*
  • Humans
  • Indoles*
  • Leukemia P388 / drug therapy
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Paclitaxel / therapeutic use
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Time Factors

Substances

  • Antineoplastic Agents
  • Carbazoles
  • Glucosides
  • Indoles
  • edotecarin
  • Doxorubicin
  • Paclitaxel
  • Cisplatin