Tumour tissue selectivity in the uptake and retention of SN 28049, a new topoisomerase II-directed anticancer agent

Bhanu Pradeep Lukka, Ying Yi Chen, Graeme J. Finlay, Wayne R. Joseph, Emma Richardson, James W. Paxton, Bruce C. Baguley

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: A variety of anticancer drugs, including doxorubicin and mitoxantrone, have structures in which a DNA-intercalating chromophore is linked to a positively charged side chain. These drugs generally inhibit tumour growth and survival by poisoning the enzyme DNA topoisomerase II. SN 28049, a benzonaphthyridine derivative with these properties, has curative activity against the Colon 38 tumour in mice. Previous pharmacokinetic studies have demonstrated tumour-selective retention with approximately 20-fold higher area under the concentration-time curve (AUC) for tumour tissue as compared to normal tissues. We have investigated here whether such retention is tumour specific. Methods: Plasma and tissue pharmacokinetics were assessed in the murine Lewis lung (LL3) tumour in C57 BL/6 mice and in xenografts of the NZM4, NZM10 and NZM52 human melanoma lines in Balb/c Rag-1 immunodeficient mice. The in vitro cellular localisation of SN 28049 in murine and human cell lines was studied by confocal fluorescence microscopy. Results: A 260-fold variation, from 8.9 μM h (NZM4) to 2,334 μM h (Colon 38), was found among the different tumours. Only small variations were observed in the corresponding plasma AUC (2.9-5 μM h). Moreover, in vivo activity, as measured by tumour growth delay, varied from 1 day (NZM4) to curative (Colon 38), consistent with the tumour pharmacokinetic data. In cultured cell lines, SN 28049 was found in cytoplasmic bodies, suggesting that drug sequestration could contribute to tumour pharmacokinetics. Conclusion: SN 28049 shows dramatic differences in both tumour AUC and antitumour activity against different tumours. These differences point to the presence of a tumour-specific uptake and retention mechanism.

Original languageEnglish (US)
Pages (from-to)1013-1022
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume72
Issue number5
DOIs
StatePublished - Nov 1 2013

Fingerprint

Type II DNA Topoisomerase
Antineoplastic Agents
Tumors
Tissue
Neoplasms
Pharmacokinetics
Colon
N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide
Cells
Pharmaceutical Preparations
Plasmas
Cell Line
Mitoxantrone
Confocal microscopy
Fluorescence microscopy
Chromophores
Growth
Fluorescence Microscopy
Heterografts
Confocal Microscopy

All Science Journal Classification (ASJC) codes

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

Cite this

Tumour tissue selectivity in the uptake and retention of SN 28049, a new topoisomerase II-directed anticancer agent. / Lukka, Bhanu Pradeep; Chen, Ying Yi; Finlay, Graeme J.; Joseph, Wayne R.; Richardson, Emma; Paxton, James W.; Baguley, Bruce C.

In: Cancer Chemotherapy and Pharmacology, Vol. 72, No. 5, 01.11.2013, p. 1013-1022.

Research output: Contribution to journalArticle

Lukka, Bhanu Pradeep ; Chen, Ying Yi ; Finlay, Graeme J. ; Joseph, Wayne R. ; Richardson, Emma ; Paxton, James W. ; Baguley, Bruce C. / Tumour tissue selectivity in the uptake and retention of SN 28049, a new topoisomerase II-directed anticancer agent. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 72, No. 5. pp. 1013-1022.
@article{913a5e3243aa489bbb72faca284e3fb1,
title = "Tumour tissue selectivity in the uptake and retention of SN 28049, a new topoisomerase II-directed anticancer agent",
abstract = "Purpose: A variety of anticancer drugs, including doxorubicin and mitoxantrone, have structures in which a DNA-intercalating chromophore is linked to a positively charged side chain. These drugs generally inhibit tumour growth and survival by poisoning the enzyme DNA topoisomerase II. SN 28049, a benzonaphthyridine derivative with these properties, has curative activity against the Colon 38 tumour in mice. Previous pharmacokinetic studies have demonstrated tumour-selective retention with approximately 20-fold higher area under the concentration-time curve (AUC) for tumour tissue as compared to normal tissues. We have investigated here whether such retention is tumour specific. Methods: Plasma and tissue pharmacokinetics were assessed in the murine Lewis lung (LL3) tumour in C57 BL/6 mice and in xenografts of the NZM4, NZM10 and NZM52 human melanoma lines in Balb/c Rag-1 immunodeficient mice. The in vitro cellular localisation of SN 28049 in murine and human cell lines was studied by confocal fluorescence microscopy. Results: A 260-fold variation, from 8.9 μM h (NZM4) to 2,334 μM h (Colon 38), was found among the different tumours. Only small variations were observed in the corresponding plasma AUC (2.9-5 μM h). Moreover, in vivo activity, as measured by tumour growth delay, varied from 1 day (NZM4) to curative (Colon 38), consistent with the tumour pharmacokinetic data. In cultured cell lines, SN 28049 was found in cytoplasmic bodies, suggesting that drug sequestration could contribute to tumour pharmacokinetics. Conclusion: SN 28049 shows dramatic differences in both tumour AUC and antitumour activity against different tumours. These differences point to the presence of a tumour-specific uptake and retention mechanism.",
author = "Lukka, {Bhanu Pradeep} and Chen, {Ying Yi} and Finlay, {Graeme J.} and Joseph, {Wayne R.} and Emma Richardson and Paxton, {James W.} and Baguley, {Bruce C.}",
year = "2013",
month = "11",
day = "1",
doi = "10.1007/s00280-013-2280-0",
language = "English (US)",
volume = "72",
pages = "1013--1022",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Tumour tissue selectivity in the uptake and retention of SN 28049, a new topoisomerase II-directed anticancer agent

AU - Lukka, Bhanu Pradeep

AU - Chen, Ying Yi

AU - Finlay, Graeme J.

AU - Joseph, Wayne R.

AU - Richardson, Emma

AU - Paxton, James W.

AU - Baguley, Bruce C.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Purpose: A variety of anticancer drugs, including doxorubicin and mitoxantrone, have structures in which a DNA-intercalating chromophore is linked to a positively charged side chain. These drugs generally inhibit tumour growth and survival by poisoning the enzyme DNA topoisomerase II. SN 28049, a benzonaphthyridine derivative with these properties, has curative activity against the Colon 38 tumour in mice. Previous pharmacokinetic studies have demonstrated tumour-selective retention with approximately 20-fold higher area under the concentration-time curve (AUC) for tumour tissue as compared to normal tissues. We have investigated here whether such retention is tumour specific. Methods: Plasma and tissue pharmacokinetics were assessed in the murine Lewis lung (LL3) tumour in C57 BL/6 mice and in xenografts of the NZM4, NZM10 and NZM52 human melanoma lines in Balb/c Rag-1 immunodeficient mice. The in vitro cellular localisation of SN 28049 in murine and human cell lines was studied by confocal fluorescence microscopy. Results: A 260-fold variation, from 8.9 μM h (NZM4) to 2,334 μM h (Colon 38), was found among the different tumours. Only small variations were observed in the corresponding plasma AUC (2.9-5 μM h). Moreover, in vivo activity, as measured by tumour growth delay, varied from 1 day (NZM4) to curative (Colon 38), consistent with the tumour pharmacokinetic data. In cultured cell lines, SN 28049 was found in cytoplasmic bodies, suggesting that drug sequestration could contribute to tumour pharmacokinetics. Conclusion: SN 28049 shows dramatic differences in both tumour AUC and antitumour activity against different tumours. These differences point to the presence of a tumour-specific uptake and retention mechanism.

AB - Purpose: A variety of anticancer drugs, including doxorubicin and mitoxantrone, have structures in which a DNA-intercalating chromophore is linked to a positively charged side chain. These drugs generally inhibit tumour growth and survival by poisoning the enzyme DNA topoisomerase II. SN 28049, a benzonaphthyridine derivative with these properties, has curative activity against the Colon 38 tumour in mice. Previous pharmacokinetic studies have demonstrated tumour-selective retention with approximately 20-fold higher area under the concentration-time curve (AUC) for tumour tissue as compared to normal tissues. We have investigated here whether such retention is tumour specific. Methods: Plasma and tissue pharmacokinetics were assessed in the murine Lewis lung (LL3) tumour in C57 BL/6 mice and in xenografts of the NZM4, NZM10 and NZM52 human melanoma lines in Balb/c Rag-1 immunodeficient mice. The in vitro cellular localisation of SN 28049 in murine and human cell lines was studied by confocal fluorescence microscopy. Results: A 260-fold variation, from 8.9 μM h (NZM4) to 2,334 μM h (Colon 38), was found among the different tumours. Only small variations were observed in the corresponding plasma AUC (2.9-5 μM h). Moreover, in vivo activity, as measured by tumour growth delay, varied from 1 day (NZM4) to curative (Colon 38), consistent with the tumour pharmacokinetic data. In cultured cell lines, SN 28049 was found in cytoplasmic bodies, suggesting that drug sequestration could contribute to tumour pharmacokinetics. Conclusion: SN 28049 shows dramatic differences in both tumour AUC and antitumour activity against different tumours. These differences point to the presence of a tumour-specific uptake and retention mechanism.

UR - http://www.scopus.com/inward/record.url?scp=84887161779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887161779&partnerID=8YFLogxK

U2 - 10.1007/s00280-013-2280-0

DO - 10.1007/s00280-013-2280-0

M3 - Article

VL - 72

SP - 1013

EP - 1022

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 5

ER -