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

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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.

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Acknowledgments

We are grateful to Cancer Society Auckland, the Lang Foundation and Auckland UniServices Ltd for financial support.

Conflict of interest

None.

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Authors and Affiliations

  1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Ying Yi Chen, Pradeep B. Lukka, Wayne R. Joseph, Graeme J. Finlay, Mark J. McKeage & Bruce C. Baguley

  2. Department of Pharmacology and Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Pradeep B. Lukka, James W. Paxton & Mark J. McKeage

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  1. Ying Yi Chen
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  2. Pradeep B. Lukka
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  7. Bruce C. Baguley
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Correspondence to Bruce C. Baguley.

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Chen, Y.Y., Lukka, P.B., Joseph, W.R. et al. Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent. Cancer Chemother Pharmacol 74, 25–35 (2014). https://doi.org/10.1007/s00280-014-2469-x

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  • DOI: https://doi.org/10.1007/s00280-014-2469-x

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