Purpose: We have reported a 6-fold difference in the topotecan (TPT) lactone systemic exposure achieving a complete response in the human neuroblastoma xenografts NB-1691 and NB-1643. However, the relationship between tumor extracellular fluid (ECF) exposure to TPT and the antitumor activity in xenograft and in vitro models has not been established. Methods: TPT was given i.v. to mice bearing NB-1691 and NB-1643 tumors. Prior to dosing, microdialysis probes were placed in tumors of mice bearing NB-1691 and NB-1643 tumors. Plasma and tumor ECF concentrations of TPT lactone were assayed by high performance liquid chromatography. The inhibitory concentration (IC50) was determined for NB-1691 and NB-1643 cell lines in vitro. Results: The TPT AUC(ECF) values determined for NB-1691 (n = 10) and NB-1643 (n = 11) were 7.3 ± 0.84 and 25.6 ± 0.76 ng h ml-1, respectively (P < 0.05). TPT tumor ECF penetration in NB-1691 and NB-1643 was 0.04 ± 0.04 and 0.15 ± 0.11 (P < 0.05), respectively. The IC50 values recorded after 6 h of TPT exposure daily for 5 consecutive days for NB-1691 and NB-1643 were 2.7 ± 1.1 and 0.53 ± 0.19 ng/ml, respectively (P < 0.05). Conclusions: NB- 1643 was more sensitive in vitro than NB-1691, and at similar plasma TPT exposures, NB-1643 had a greater degree of TPT tumor ECF exposure and penetration as compared with NB-1691. Potential factors affecting tumor TPT ECF disposition include tumor vascularity, capillary permeability, and interstitial pressure. The clinical importance of this study is underscored by the need to select anticancer agents with a high capacity for tumor penetration and to optimize drug administration to increase tumor penetration.
Bibliographical noteFunding Information:
This work was supported in part by USPHS awards CA23099, CA32613, and CA21675 (Cancer Center Support Grant) from the National Cancer Institute and by American, Lebanese, Syrian Associated Charities (ALSAC) W.C. Zamboni á J.L. Hulstein á M. Kirstein J. Walsh á C.F. Stewart (&) Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA e-mail: email@example.com, Tel.: +1-901-495-3665; Fax: +1-901-525-6869 P.J. Houghton á P.J. Cheshire á M.K. Danks Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
- Tumor exposure