Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts

Pieter H J Houba, Epie Boven, Ida H. Van der Meulen-Muileman, Ruben G G Leenders, Johannes W. Scheeren, Herbert M. Pinedo, Hidde J. Haisma

Research output: Contribution to journalArticle

Abstract

N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 μM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol . g-1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol . g-1 (P <0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by β-glucuronidase. In this respect, a considerably higher β-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by β-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)673-680
Number of pages8
JournalBiochemical Pharmacology
Volume57
Issue number6
DOIs
StatePublished - Mar 15 1999
Externally publishedYes

Fingerprint

Bearings (structural)
Daunorubicin
Pharmacokinetics
Prodrugs
Heterografts
Nude Mice
Ovarian Neoplasms
Tumors
Glucuronidase
Neoplasms
Tissue
Maximum Tolerated Dose
Plasmas
Chemical activation

Keywords

  • Anthracycline prodrugs
  • Daunorubicin
  • Human β-glucuronidase
  • Human ovarian cancer xenografts

ASJC Scopus subject areas

  • Pharmacology

Cite this

Houba, P. H. J., Boven, E., Van der Meulen-Muileman, I. H., Leenders, R. G. G., Scheeren, J. W., Pinedo, H. M., & Haisma, H. J. (1999). Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts. Biochemical Pharmacology, 57(6), 673-680. https://doi.org/10.1016/S0006-2952(98)00343-8

Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts. / Houba, Pieter H J; Boven, Epie; Van der Meulen-Muileman, Ida H.; Leenders, Ruben G G; Scheeren, Johannes W.; Pinedo, Herbert M.; Haisma, Hidde J.

In: Biochemical Pharmacology, Vol. 57, No. 6, 15.03.1999, p. 673-680.

Research output: Contribution to journalArticle

Houba, PHJ, Boven, E, Van der Meulen-Muileman, IH, Leenders, RGG, Scheeren, JW, Pinedo, HM & Haisma, HJ 1999, 'Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts', Biochemical Pharmacology, vol. 57, no. 6, pp. 673-680. https://doi.org/10.1016/S0006-2952(98)00343-8
Houba, Pieter H J ; Boven, Epie ; Van der Meulen-Muileman, Ida H. ; Leenders, Ruben G G ; Scheeren, Johannes W. ; Pinedo, Herbert M. ; Haisma, Hidde J. / Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts. In: Biochemical Pharmacology. 1999 ; Vol. 57, No. 6. pp. 673-680.
@article{d62f04f73f424070b00760e401ef057f,
title = "Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts",
abstract = "N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 μM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50{\%} of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol . g-1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol . g-1 (P <0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by β-glucuronidase. In this respect, a considerably higher β-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by β-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity. Copyright (C) 1999 Elsevier Science Inc.",
keywords = "Anthracycline prodrugs, Daunorubicin, Human β-glucuronidase, Human ovarian cancer xenografts",
author = "Houba, {Pieter H J} and Epie Boven and {Van der Meulen-Muileman}, {Ida H.} and Leenders, {Ruben G G} and Scheeren, {Johannes W.} and Pinedo, {Herbert M.} and Haisma, {Hidde J.}",
year = "1999",
month = "3",
day = "15",
doi = "10.1016/S0006-2952(98)00343-8",
language = "English (US)",
volume = "57",
pages = "673--680",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts

AU - Houba, Pieter H J

AU - Boven, Epie

AU - Van der Meulen-Muileman, Ida H.

AU - Leenders, Ruben G G

AU - Scheeren, Johannes W.

AU - Pinedo, Herbert M.

AU - Haisma, Hidde J.

PY - 1999/3/15

Y1 - 1999/3/15

N2 - N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 μM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol . g-1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol . g-1 (P <0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by β-glucuronidase. In this respect, a considerably higher β-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by β-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity. Copyright (C) 1999 Elsevier Science Inc.

AB - N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-β-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 μM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol . g-1 after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol . g-1 (P <0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by β-glucuronidase. In this respect, a considerably higher β-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by β-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity. Copyright (C) 1999 Elsevier Science Inc.

KW - Anthracycline prodrugs

KW - Daunorubicin

KW - Human β-glucuronidase

KW - Human ovarian cancer xenografts

UR - http://www.scopus.com/inward/record.url?scp=0033559861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033559861&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(98)00343-8

DO - 10.1016/S0006-2952(98)00343-8

M3 - Article

C2 - 10037453

AN - SCOPUS:0033559861

VL - 57

SP - 673

EP - 680

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 6

ER -