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Prodrug enzymes and their applications in image-guided therapy of cancer: tracking prodrug enzymes to minimize collateral damage

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Abstract

Many cytotoxic therapies are available to kill cancer cells. Unfortunately, these also inflict significant damage on normal cells. Identifying highly effective cancer treatments that have minimal or no side effects continues to be a major challenge. One of the strategies to minimize damage to normal tissue is to deliver an activating enzyme that localizes only in the tumor and converts a nontoxic prodrug to a cytotoxic agent locally in the tumor. Such strategies have been previously tested but with limited success due in large part to the uncertainty in the delivery and distribution of the enzyme. Imaging the delivery of the enzyme to optimize timing of the prodrug administration to achieve image-guided prodrug therapy would be of immense benefit for this strategy. Here, we have reviewed advances in the incorporation of image guidance in the applications of prodrug enzymes in cancer treatment. These advances demonstrate the feasibility of using clinically translatable imaging in these prodrug enzyme strategies.

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Abbreviations

bCD:

Bacterial cytosine deaminase

CD:

Cytosine deaminase

Chk:

Choline kinase

dCK:

Deoxycytidine kinase

DPD:

Dihydropyrimidine dehydrogenase

EPR:

Enhanced permeability and retention

FDG:

[18F]fluorodeoxyglucose

5-FC:

5-Fluorocytosine

FdUMP, FdUDP, and FdUTP:

2′-Deoxy-5-fluorouridine mono-, di-, and triphosphates

[18F]FHBG:

9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine

FNucs:

Fluoronucleotides

5-FU:

5-Fluorouracil

FUMP, FUDP, and FUTP:

5-Fluorouridine-5′-mono-, di-, and triphosphates

GCV:

Ganciclovir

GDEPT:

Gene encoding prodrug-activating enzyme therapy

HSV1:

Herpes simplex virus type 1

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

MRSI:

Magnetic resonance spectroscopic imaging

PET:

Positron emission tomography

PLL:

Poly-l-lysine

siRNA:

Small interfering RNA

tCho:

Total choline

TDEPT:

Targeting group-directed enzyme/prodrug therapy

TK:

Thymidine kinase

UPRT:

Uracil phosphoribosyltransferase

VDEPT:

Virus-directed enzyme prodrug therapy

VPDEPT:

Vasculature permeability-dependent enzyme/prodrug therapy

yCD:

Yeast cytosine deaminase

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Acknowledgments

Support from P50 CA103175, P30 CA006973, R01 CA73850, R01 CA82337, R01 CA136576, R01 CA138515, and R01 CA138264 is gratefully acknowledged.

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Authors and Affiliations

  1. JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Marie-France Penet, Zhihang Chen, Cong Li, Paul T. Winnard Jr. & Zaver M. Bhujwalla

  2. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Zaver M. Bhujwalla

  3. Department of Radiology, Johns Hopkins University School of Medicine, Rm 208C Traylor Bldg., 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Zaver M. Bhujwalla

Authors
  1. Marie-France Penet
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  2. Zhihang Chen
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  3. Cong Li
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  4. Paul T. Winnard Jr.
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  5. Zaver M. Bhujwalla
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Correspondence to Zaver M. Bhujwalla.

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Penet, MF., Chen, Z., Li, C. et al. Prodrug enzymes and their applications in image-guided therapy of cancer: tracking prodrug enzymes to minimize collateral damage. Drug Deliv. and Transl. Res. 2, 22–30 (2012). https://doi.org/10.1007/s13346-011-0052-0

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