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Relationship between plasma exposure of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite and antitumor response in mice bearing human colon carcinoma xenografts.
Relationship between plasma exposure of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite and antitumor response in mice bearing human colon carcinoma xenografts.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2005 Jul 01; Vol. 11 (13), pp. 4867-74. - Publication Year :
- 2005
-
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 x 5d x 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 x 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 < or = 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.
- Subjects :
- Animals
Antineoplastic Agents blood
Antineoplastic Agents therapeutic use
Area Under Curve
Camptothecin blood
Camptothecin pharmacokinetics
Camptothecin therapeutic use
Cell Line, Tumor
Chromatography, High Pressure Liquid
Colonic Neoplasms metabolism
Colonic Neoplasms pathology
Female
HT29 Cells
Humans
Mice
Mice, SCID
Treatment Outcome
Antineoplastic Agents pharmacokinetics
Camptothecin analogs & derivatives
Colonic Neoplasms drug therapy
Xenograft Model Antitumor Assays methods
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 11
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 16000585
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-05-0144