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Research ArticleMetabolism, Transport, and Pharmacogenomics

Cellular Influx, Efflux, and Anabolism of 3-Carboranyl Thymidine Analogs: Potential Boron Delivery Agents for Neutron Capture Therapy

Elena Sjuvarsson, Vijaya L. Damaraju, Delores Mowles, Michael B. Sawyer, Rohit Tiwari, Hitesh K. Agarwal, Ahmed Khalil, Sherifa Hasabelnaby, Ayman Goudah, Robin J. Nakkula, Rolf F. Barth, Carol E. Cass, Staffan Eriksson and Werner Tjarks
Journal of Pharmacology and Experimental Therapeutics November 2013, 347 (2) 388-397; DOI: https://doi.org/10.1124/jpet.113.207464
Elena Sjuvarsson
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Vijaya L. Damaraju
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Delores Mowles
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Michael B. Sawyer
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Rohit Tiwari
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Hitesh K. Agarwal
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Ahmed Khalil
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Sherifa Hasabelnaby
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Ayman Goudah
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Robin J. Nakkula
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Rolf F. Barth
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Carol E. Cass
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Staffan Eriksson
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Werner Tjarks
Department of Anatomy, Physiology, and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden (E.S., S.E.); Department of Oncology, University of Alberta, Edmonton, Alberta, Canada (V.L.D., D.M., M.B.S., C.E.C); Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio (R.T., H.K.A., A.K., S.H., A.G., W.T.); Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt (A.K.); Division of Pharmaceutical Organic Chemistry, College of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt (S.H.); Division of Pharmacology, College of Veterinary Medicine, Cairo University, Giza, Egypt (A.G.); and Department of Pathology, The Ohio State University, Columbus, Ohio (R.J.N., R.F.B.)
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Abstract

3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 (10B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level. N5-2OH entered cultured human CCRF-CEM cells via passive diffusion, whereas the multidrug resistance-associated protein 4 appeared to be a major mediator of N5-2OH monophosphate efflux. N5-2OH was effectively monophosphorylated in cultured murine L929 [thymidine kinase 1 (TK1+)] cells whereas formation of N5-2OH monophosphate was markedly lower in L929 (TK1–) cell variants. Further metabolism to the di- and triphosphate forms was not observed in any of the cell lines. Regardless of monophosphorylation, parental N5-2OH was the major intracellular component in both TK1+ and TK1– cells. Phosphate transfer experiments with enzyme preparations showed that N5-2OH monophosphate, as well as the monophosphate of a second 3-carboranyl thymidine analog [3-[5-(o-carboran-1-yl)pentan-1-yl]thymidine (N5)], were not substrates of thymidine monophosphate kinase. Surprisingly, N5-diphosphate was phosphorylated by nucleoside diphosphate kinase although N5-triphosphate apparently was not a substrate of DNA polymerase. Our results provide valuable information on the cellular metabolism and pharmacokinetic profile of 3-carboranyl thymidine analogs.

Footnotes

    • Received June 24, 2013.
    • Accepted September 4, 2013.
  • E.S. and V.L.D. contributed equally to this work.

  • This study was supported in part by the National Institutes of Health National Cancer Institute [Grant 5R01 CA127935]; The Ohio State University College of Pharmacy; the Swedish Research Council; and the Canadian Cancer Society Research Institute.

  • The content is solely the responsibility of the authors and does not necessarily represent the official views of the mentioned organizations/institutions.

  • dx.doi.org/10.1124/jpet.113.207464.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 2
1 Nov 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Cellular Influx, Efflux, and Anabolism of 3CTAs

Elena Sjuvarsson, Vijaya L. Damaraju, Delores Mowles, Michael B. Sawyer, Rohit Tiwari, Hitesh K. Agarwal, Ahmed Khalil, Sherifa Hasabelnaby, Ayman Goudah, Robin J. Nakkula, Rolf F. Barth, Carol E. Cass, Staffan Eriksson and Werner Tjarks
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 388-397; DOI: https://doi.org/10.1124/jpet.113.207464

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Cellular Influx, Efflux, and Anabolism of 3CTAs

Elena Sjuvarsson, Vijaya L. Damaraju, Delores Mowles, Michael B. Sawyer, Rohit Tiwari, Hitesh K. Agarwal, Ahmed Khalil, Sherifa Hasabelnaby, Ayman Goudah, Robin J. Nakkula, Rolf F. Barth, Carol E. Cass, Staffan Eriksson and Werner Tjarks
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 388-397; DOI: https://doi.org/10.1124/jpet.113.207464
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