Relationship between plasnna exposure of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite and antitumor response in mice bearing human colon carcinoma xenografts

William C. Zamboni, Laura L. Jung, Merrill J. Egorin, Deborah R. Hamburger, Erin Joseph, Ruzhi Jin, Sandra Strychor, Ramesh K. Ramanathan, Julie L. Eiseman

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

9-Nitrocamptothecin has completed phase III studies in patients with newly diagnosed and refractory pancreatic cancer; however, the optimal 9-nitrocamptothecin treatment regimen is unclear. We used an intermittent schedule of 9-nitrocamptothecin to evaluate the relationship between plasma exposure of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite and antitumor response in mice bearing human colon carcinoma xenografts, 9-Nitrocamptothecin was given orally at 0.44, 0.67, or 1.0 mg/kg/d qd × 5d × 2 weeks repeated q 4 weeks for two cycles to female C. B-17 SCID mice bearing HT29 or ELC2 human colon xenografts. Pharmacokinetic studies were done after oral administration of 0.67 mg/kg × 1. Serial samples were obtained and 9-nitrocamptothecin and 9-aminocamptothecin lactone concentrations in plasma were determined by high-performance liquid chromatography analysis with fluorescence detection. The areas under plasma concentration versus time curve (AUC) from 0 to infinity for 9-nitrocamptothecin and 9-aminocamptothecin were calculated. The antitumor activity of 9-nitrocamptothecin was dose-dependent in both colon xenografts. At all doses, 9-nitrocamptothecin treatment resulted in significant antitumor activity in both xenografts compared with vehicle-treated and control groups and achieved levels of tumor regression that met criteria (minimum %T/C ≤ 40%) for antitumor activity. In mice bearing HT29 xenografts, the 9-nitrocamptothecin and 9-aminocamptothecin lactone AUCs after administration of 9-nitrocamptothecin at 0.67 mg/kg were 41.3 and 5.7 ng/mL h, respectively. The responses seen in these xenograft models occurred at systemic exposures that are tolerable in adult patients. These results suggest that the intermittent schedule of 9-nitrocamptothecin may be an active regimen in patients with colorectal carcinoma.

Original languageEnglish (US)
Pages (from-to)4867-4874
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number13
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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