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Radiopharmaceuticals for the Imaging of ABC-Transporter-Mediated Multidrug Resistance in Cancer

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Resistance to Targeted ABC Transporters in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 4))

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Abstract

ATP-binding cassette (ABC) transporter proteins, the most widely studied of which is P-glycoprotein (P-gp), function to translocate a wide range of xenobiotics across biological membranes, especially those exposed to the external environment. Radiopharmaceuticals that are substrates for ABC-transporter proteins are used to image their expression. They can be divided into single photon-emitters, especially technetium-99 m, and positron emitters, e.g. carbon-11 and fluorine-18. Tc-99m-MIBI has been most frequently used to image ABC transporters. Following passive diffusion into cytoplasm, it accumulates in mitochondria at a rate dependent on tissue perfusion and cellularity. Tissue retention of Tc-99m-MIBI correlates inversely with P-gp expression and can be modified with P-gp antagonists. Inter-individual variability of P-gp expression is linked to C3435T polymorphism of the human ABCB1 gene. C/C, T/C and T/T genotypes are associated with increased, intermediate and low P-gp expression, respectively. Functional up-regulation of ABC proteins results from exposure to inhibitors, resulting in acquired multi-drug resistance (MDR). Tc-99m-MIBI has been used for imaging MDR in several cancers. Early compounds developed to reverse MDR have not shown any benefit in patient outcome due to toxicity or interactions with chemotherapeutic agents. Newer MDR modulators, however, are less toxic, more specific for P-gp and do not interact with anti-cancer drugs. Combinations of chemotherapeutics to reverse MDR with tumour targeting agents are being evaluated. In conclusion, clinical trials optimally tailored to tumour types, genetic polymorphism and adequate dosing regimens need to be conducted and based on imaging for selecting patients whose cancers express MDR primarily though ABC-mediated mechanisms.

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Abbreviations

ABC-transporters:

ATP-binding cassette transporters

MDR:

Multi drug resistance

P-gp:

P-glycoprotein

PET:

Positron emission tomography

SPECT:

Single photon emission tomography

MIBI:

Tc-99m-hexakis-methoxy-isobutyl isonitrile

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Authors and Affiliations

  1. Department of Nuclear Medicine, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK

    Sabina Dizdarevic M.D., M.Sc., F.R.C.P. & Adrien Michael Peters M.A., M.D., D. Sc., F. Med. Sci.

  2. Clinical Imaging Science Centre, Brighton and Sussex Medical School, Brighton, UK

    Sabina Dizdarevic M.D., M.Sc., F.R.C.P.

  3. Department of Nuclear Medicine, Royal Sussex County Hospital, Eastern Road, Brighton, BN2 5BE, UK

    Sabina Dizdarevic M.D., M.Sc., F.R.C.P.

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  1. Sabina Dizdarevic M.D., M.Sc., F.R.C.P.
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  2. Adrien Michael Peters M.A., M.D., D. Sc., F. Med. Sci.
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Correspondence to Sabina Dizdarevic M.D., M.Sc., F.R.C.P. .

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Editors and Affiliations

  1. Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany

    Thomas Efferth

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Dizdarevic, S., Peters, A.M. (2015). Radiopharmaceuticals for the Imaging of ABC-Transporter-Mediated Multidrug Resistance in Cancer. In: Efferth, T. (eds) Resistance to Targeted ABC Transporters in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 4. Springer, Cham. https://doi.org/10.1007/978-3-319-09801-2_6

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