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Cytotoxicity of lysomustine and its isomers, and their potential use for selection of cells

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Abstract

N ɛ-Nitroso-N ɛ-[N′-(2-chloroethyl)carbamoyl]-L-lysine (I) and N ɛ-[N′-(2-chloroethyl)-N′-nitrosocarbamoyl]-L-lysine (II), the isomers being the constituents of antitumor agent lysomustine, were isolated from the agent by reverse phase HPLC (RP-HPLC). The study of cytotoxicity of the above compounds against K562 cells showed that lesions induced by isomer (II) produce a significant cytotoxic effect, but can be efficiently repaired by the action of MGMT (O6-methylguanine-DNA methyltransferase). Under similar conditions, lesions induced by isomer (I) produce a substantially smaller effect but are weakly, if at all, repairable by MGMT. The effects of a clinically approved agent lysomustine, which is a mixture of isomers (I) and (II), are similar to those of isomer (II). The results obtained point to a different chemical nature of DNA lesions induced by two lysomustine isomers. Our data indicate that lysomustine and its isomer (II) can be used for in vitro selection of cells expressing MGMT.

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Abbreviations

ANU:

alkylnitrosourea

BG:

O6-benzylguanine

CFU:

colony-forming unit

BCNU:

1,3-bis(2-chloroethyl)-1-nitrosourea

EGFP:

enhanced green fluorescent protein

MGMT:

O6-methylguanine-DNA methyltransferase

MGMTm:

a mutant form of MGMT

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

    F. N. Rozov, T. S. Grinenko & A. V. Belyavsky

  2. Postovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, ul. S. Kovalevskoy/Akademicheskaya, 22/20, Yekaterinburg, 620990, Russia

    G. L. Levit, A. N. Grishakov & V. P. Krasnov

Authors
  1. F. N. Rozov
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  2. T. S. Grinenko
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  3. G. L. Levit
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  4. A. N. Grishakov
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  5. A. V. Belyavsky
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  6. V. P. Krasnov
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Corresponding author

Correspondence to V. P. Krasnov.

Additional information

Original Russian Text © F.N. Rozov, T.S. Grinenko, G.L. Levit, A.N. Grishakov, A.V. Belyavsky, V.P. Krasnov, 2011, published in Bioorganicheskaya Khimiya, 2011, Vol. 37, No. 6, pp. 786–792.

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Rozov, F.N., Grinenko, T.S., Levit, G.L. et al. Cytotoxicity of lysomustine and its isomers, and their potential use for selection of cells. Russ J Bioorg Chem 37, 713–718 (2011). https://doi.org/10.1134/S1068162011060112

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  • DOI: https://doi.org/10.1134/S1068162011060112

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