Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent

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

Research output: Contribution to journalArticle

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Abstract

Purpose: SN 28049 is a new DNA-binding topoisomerase II poison identified by its curative activity against the murine colon 38 carcinoma. Previous studies showed activity to be associated with selective drug accumulation and retention in tumour tissue. Retention varied widely among different tumours and was related to antitumour activity. We determined whether differences in the uptake and retention of SN 28049 could be observed in vitro. Methods: The Co38P and LLTC lines were derived from the murine colon 38 carcinoma and Lewis lung carcinoma (3LL), respectively. The NZM4, NZM10 and NZM52 human melanoma lines, as well as the CCRF/CEM, CEM/VLB100 and CEM/E1000 human leukaemia lines were also utilised. Cell-associated drug was measured by liquid chromatography-mass spectrometry, laser-scanning confocal microscopy and fluorescence microscopy. Data for SN 28049 were compared for four SN 28049 analogues, for the structurally related drug N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) and for doxorubicin. Results: Cellular uptake of SN 28049 was rapid and associated with increased fluorescence in cytoplasmic vesicles or bodies. SN 28049 uptake after an incubation time of 1 h varied widely with different cell lines (2-98 pmol/106 cells) and did not correlate with growth inhibitory concentrations (IC50 values), which also varied widely (1.2-19 nM). Changes in the length of the N-linked side chain of SN 28049 had large effects on drug uptake by Co38P cells. SN 28049 uptake by CCRF/CEM cells was only slightly affected by the expression of P-glycoprotein (CEM/VLB100) or MRP1 protein (CEM/E1000). As measured by cytoplasmic fluorescence, SN 28049 was taken up rapidly and retained strongly by Co38P cells, DACA was taken up rapidly and retained poorly, and doxorubicin was taken up slowly and retained moderately. Conclusions: The results suggest that SN 28049 is actively transported into cytoplasmic vesicles. While vesicle-associated drug is not important for intrinsic cytotoxicity, it may play a key role as a "slow release" form that modifies pharmacokinetics in multicellular structures such as tumours.

Original languageEnglish (US)
Pages (from-to)25-35
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume74
Issue number1
DOIs
StatePublished - Jan 1 2014

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Type II DNA Topoisomerase
Antineoplastic Agents
DNA
Cytoplasmic Vesicles
Tumors
Pharmaceutical Preparations
N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide
Doxorubicin
Colon
Fluorescence
N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide
Acridines
Lewis Lung Carcinoma
Carcinoma
Neoplasms
Pharmacokinetics
Confocal microscopy
Poisons
Fluorescence microscopy
Liquid chromatography

All Science Journal Classification (ASJC) codes

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

Cite this

Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent. / Chen, Ying Yi; Lukka, Bhanu Pradeep; Joseph, Wayne R.; Finlay, Graeme J.; Paxton, James W.; McKeage, Mark J.; Baguley, Bruce C.

In: Cancer Chemotherapy and Pharmacology, Vol. 74, No. 1, 01.01.2014, p. 25-35.

Research output: Contribution to journalArticle

Chen, Ying Yi ; Lukka, Bhanu Pradeep ; Joseph, Wayne R. ; Finlay, Graeme J. ; Paxton, James W. ; McKeage, Mark J. ; Baguley, Bruce C. / Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 74, No. 1. pp. 25-35.
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abstract = "Purpose: SN 28049 is a new DNA-binding topoisomerase II poison identified by its curative activity against the murine colon 38 carcinoma. Previous studies showed activity to be associated with selective drug accumulation and retention in tumour tissue. Retention varied widely among different tumours and was related to antitumour activity. We determined whether differences in the uptake and retention of SN 28049 could be observed in vitro. Methods: The Co38P and LLTC lines were derived from the murine colon 38 carcinoma and Lewis lung carcinoma (3LL), respectively. The NZM4, NZM10 and NZM52 human melanoma lines, as well as the CCRF/CEM, CEM/VLB100 and CEM/E1000 human leukaemia lines were also utilised. Cell-associated drug was measured by liquid chromatography-mass spectrometry, laser-scanning confocal microscopy and fluorescence microscopy. Data for SN 28049 were compared for four SN 28049 analogues, for the structurally related drug N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) and for doxorubicin. Results: Cellular uptake of SN 28049 was rapid and associated with increased fluorescence in cytoplasmic vesicles or bodies. SN 28049 uptake after an incubation time of 1 h varied widely with different cell lines (2-98 pmol/106 cells) and did not correlate with growth inhibitory concentrations (IC50 values), which also varied widely (1.2-19 nM). Changes in the length of the N-linked side chain of SN 28049 had large effects on drug uptake by Co38P cells. SN 28049 uptake by CCRF/CEM cells was only slightly affected by the expression of P-glycoprotein (CEM/VLB100) or MRP1 protein (CEM/E1000). As measured by cytoplasmic fluorescence, SN 28049 was taken up rapidly and retained strongly by Co38P cells, DACA was taken up rapidly and retained poorly, and doxorubicin was taken up slowly and retained moderately. Conclusions: The results suggest that SN 28049 is actively transported into cytoplasmic vesicles. While vesicle-associated drug is not important for intrinsic cytotoxicity, it may play a key role as a {"}slow release{"} form that modifies pharmacokinetics in multicellular structures such as tumours.",
author = "Chen, {Ying Yi} and Lukka, {Bhanu Pradeep} and Joseph, {Wayne R.} and Finlay, {Graeme J.} and Paxton, {James W.} and McKeage, {Mark J.} and Baguley, {Bruce C.}",
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T1 - Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent

AU - Chen, Ying Yi

AU - Lukka, Bhanu Pradeep

AU - Joseph, Wayne R.

AU - Finlay, Graeme J.

AU - Paxton, James W.

AU - McKeage, Mark J.

AU - Baguley, Bruce C.

PY - 2014/1/1

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N2 - Purpose: SN 28049 is a new DNA-binding topoisomerase II poison identified by its curative activity against the murine colon 38 carcinoma. Previous studies showed activity to be associated with selective drug accumulation and retention in tumour tissue. Retention varied widely among different tumours and was related to antitumour activity. We determined whether differences in the uptake and retention of SN 28049 could be observed in vitro. Methods: The Co38P and LLTC lines were derived from the murine colon 38 carcinoma and Lewis lung carcinoma (3LL), respectively. The NZM4, NZM10 and NZM52 human melanoma lines, as well as the CCRF/CEM, CEM/VLB100 and CEM/E1000 human leukaemia lines were also utilised. Cell-associated drug was measured by liquid chromatography-mass spectrometry, laser-scanning confocal microscopy and fluorescence microscopy. Data for SN 28049 were compared for four SN 28049 analogues, for the structurally related drug N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) and for doxorubicin. Results: Cellular uptake of SN 28049 was rapid and associated with increased fluorescence in cytoplasmic vesicles or bodies. SN 28049 uptake after an incubation time of 1 h varied widely with different cell lines (2-98 pmol/106 cells) and did not correlate with growth inhibitory concentrations (IC50 values), which also varied widely (1.2-19 nM). Changes in the length of the N-linked side chain of SN 28049 had large effects on drug uptake by Co38P cells. SN 28049 uptake by CCRF/CEM cells was only slightly affected by the expression of P-glycoprotein (CEM/VLB100) or MRP1 protein (CEM/E1000). As measured by cytoplasmic fluorescence, SN 28049 was taken up rapidly and retained strongly by Co38P cells, DACA was taken up rapidly and retained poorly, and doxorubicin was taken up slowly and retained moderately. Conclusions: The results suggest that SN 28049 is actively transported into cytoplasmic vesicles. While vesicle-associated drug is not important for intrinsic cytotoxicity, it may play a key role as a "slow release" form that modifies pharmacokinetics in multicellular structures such as tumours.

AB - Purpose: SN 28049 is a new DNA-binding topoisomerase II poison identified by its curative activity against the murine colon 38 carcinoma. Previous studies showed activity to be associated with selective drug accumulation and retention in tumour tissue. Retention varied widely among different tumours and was related to antitumour activity. We determined whether differences in the uptake and retention of SN 28049 could be observed in vitro. Methods: The Co38P and LLTC lines were derived from the murine colon 38 carcinoma and Lewis lung carcinoma (3LL), respectively. The NZM4, NZM10 and NZM52 human melanoma lines, as well as the CCRF/CEM, CEM/VLB100 and CEM/E1000 human leukaemia lines were also utilised. Cell-associated drug was measured by liquid chromatography-mass spectrometry, laser-scanning confocal microscopy and fluorescence microscopy. Data for SN 28049 were compared for four SN 28049 analogues, for the structurally related drug N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) and for doxorubicin. Results: Cellular uptake of SN 28049 was rapid and associated with increased fluorescence in cytoplasmic vesicles or bodies. SN 28049 uptake after an incubation time of 1 h varied widely with different cell lines (2-98 pmol/106 cells) and did not correlate with growth inhibitory concentrations (IC50 values), which also varied widely (1.2-19 nM). Changes in the length of the N-linked side chain of SN 28049 had large effects on drug uptake by Co38P cells. SN 28049 uptake by CCRF/CEM cells was only slightly affected by the expression of P-glycoprotein (CEM/VLB100) or MRP1 protein (CEM/E1000). As measured by cytoplasmic fluorescence, SN 28049 was taken up rapidly and retained strongly by Co38P cells, DACA was taken up rapidly and retained poorly, and doxorubicin was taken up slowly and retained moderately. Conclusions: The results suggest that SN 28049 is actively transported into cytoplasmic vesicles. While vesicle-associated drug is not important for intrinsic cytotoxicity, it may play a key role as a "slow release" form that modifies pharmacokinetics in multicellular structures such as tumours.

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