Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines

William C. Zamboni, Peter J Houghton, Jeff L. Hulstein, Mark Kirstein, Jessica Walsh, Pam J. Cheshire, Suzan K. Hanna, Mary K. Danks, Clinton F. Stewart

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)269-276
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume43
Issue number4
DOIs
StatePublished - Feb 17 1999
Externally publishedYes

Fingerprint

Topotecan
Extracellular Fluid
Neuroblastoma
Heterografts
Tumors
Cells
Cell Line
Fluids
Neoplasms
Bearings (structural)
Lactones
Inhibitory Concentration 50
Plasmas
Microdialysis
Capillary Permeability
High performance liquid chromatography
Antineoplastic Agents
Area Under Curve

Keywords

  • Microdialysis
  • Neuroblastoma
  • Topotecan
  • Tumor exposure

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines. / Zamboni, William C.; Houghton, Peter J; Hulstein, Jeff L.; Kirstein, Mark; Walsh, Jessica; Cheshire, Pam J.; Hanna, Suzan K.; Danks, Mary K.; Stewart, Clinton F.

In: Cancer Chemotherapy and Pharmacology, Vol. 43, No. 4, 17.02.1999, p. 269-276.

Research output: Contribution to journalArticle

Zamboni, William C. ; Houghton, Peter J ; Hulstein, Jeff L. ; Kirstein, Mark ; Walsh, Jessica ; Cheshire, Pam J. ; Hanna, Suzan K. ; Danks, Mary K. ; Stewart, Clinton F. / Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines. In: Cancer Chemotherapy and Pharmacology. 1999 ; Vol. 43, No. 4. pp. 269-276.
@article{f7311e16a6f34933b72c77aaa9156c44,
title = "Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines",
abstract = "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.",
keywords = "Microdialysis, Neuroblastoma, Topotecan, Tumor exposure",
author = "Zamboni, {William C.} and Houghton, {Peter J} and Hulstein, {Jeff L.} and Mark Kirstein and Jessica Walsh and Cheshire, {Pam J.} and Hanna, {Suzan K.} and Danks, {Mary K.} and Stewart, {Clinton F.}",
year = "1999",
month = "2",
day = "17",
doi = "10.1007/s002800050894",
language = "English (US)",
volume = "43",
pages = "269--276",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines

AU - Zamboni, William C.

AU - Houghton, Peter J

AU - Hulstein, Jeff L.

AU - Kirstein, Mark

AU - Walsh, Jessica

AU - Cheshire, Pam J.

AU - Hanna, Suzan K.

AU - Danks, Mary K.

AU - Stewart, Clinton F.

PY - 1999/2/17

Y1 - 1999/2/17

N2 - 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.

AB - 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.

KW - Microdialysis

KW - Neuroblastoma

KW - Topotecan

KW - Tumor exposure

UR - http://www.scopus.com/inward/record.url?scp=0032979381&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032979381&partnerID=8YFLogxK

U2 - 10.1007/s002800050894

DO - 10.1007/s002800050894

M3 - Article

C2 - 10071976

AN - SCOPUS:0032979381

VL - 43

SP - 269

EP - 276

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 4

ER -