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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.

Authors :
Zamboni WC
Jung LL
Egorin MJ
Hamburger DR
Joseph E
Jin R
Strychor S
Ramanathan RK
Eiseman JL
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.

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