Abstract
Purpose: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. Experimental design: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. Results: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. Conclusions: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 629-636 |
| Number of pages | 8 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 56 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2005 |
| Externally published | Yes |
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Keywords
- carboxylesterase
- CPT-11
- Es1 mice
- SN-38
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)
Cite this
Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. / Morton, Christopher L.; Iacono, Lisa; Hyatt, Janice L.; Taylor, Kody R.; Cheshire, Pamela J.; Houghton, Peter J; Danks, Mary K.; Stewart, Clinton F.; Potter, Philip M.
In: Cancer Chemotherapy and Pharmacology, Vol. 56, No. 6, 01.12.2005, p. 629-636.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice
AU - Morton, Christopher L.
AU - Iacono, Lisa
AU - Hyatt, Janice L.
AU - Taylor, Kody R.
AU - Cheshire, Pamela J.
AU - Houghton, Peter J
AU - Danks, Mary K.
AU - Stewart, Clinton F.
AU - Potter, Philip M.
PY - 2005/12/1
Y1 - 2005/12/1
N2 - Purpose: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. Experimental design: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. Results: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. Conclusions: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.
AB - Purpose: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. Experimental design: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. Results: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. Conclusions: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.
KW - carboxylesterase
KW - CPT-11
KW - Es1 mice
KW - SN-38
UR - http://www.scopus.com/inward/record.url?scp=26444585076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=26444585076&partnerID=8YFLogxK
U2 - 10.1007/s00280-005-1027-y
DO - 10.1007/s00280-005-1027-y
M3 - Article
C2 - 15918039
AN - SCOPUS:26444585076
VL - 56
SP - 629
EP - 636
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 6
ER -