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Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.

Publication ,  Journal Article
Shankar, S; Zalutsky, MR; Friedman, H; Vaidyanathan, G
Published in: Nucl Med Biol
April 2006

PURPOSE: An inverse correlation has been established between tumor levels of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) and a positive outcome after alkylator chemotherapy. Quantitative imaging of AGT could provide important information for patient-specific cancer treatment. Several radiolabeled analogues of O6-benzylguanine (BG), a potent AGT inactivator, have been developed and shown to be capable of labeling pure AGT protein. Herein, two of these analogues--O6-3-[*I]iodobenzylguanine ([*I]IBG) and O6-3-[*I]iodobenzyl-2'-deoxyguanosine ([*I]IBdG)--were further evaluated in two murine xenograft models. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, also was investigated as an alternative agent. METHODS: Several biodistribution studies of radioiodinated IBG and IBdG were performed in TE-671 human rhabdomyosarcoma and DAOY human medulloblastoma murine xenograft models. Mice were treated with BG or its nucleoside analogue dBG to deplete the tumor AGT content. The effect of unlabeled IBG and that of 7,8-benzoflavone (BF), an inhibitor of the cytochrome P-450 isozyme CYP1A2, on the tumor uptake of the tracers was determined. The uptake of (AcO)2-[131I]IBdG along with that of [125I]IBdG in DAOY cells in vitro was determined in the presence and absence of a nucleoside transporter inhibitor, dipyridamole. RESULTS: Pretreatment of mice either with BG or dBG failed to reduce tumor levels of [*I]IBG or [*I]IBdG even though such treatments completely depleted tumor AGT content. Treatment of mice with BF increased tumor uptake of [125I]IBG by 56%; however, differentiation of tumors with and without AGT still was not possible. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, had a higher uptake in vitro in DAOY tumor cells. However, its uptake, like that of [125I]IBdG, was blocked by dipyridamole. CONCLUSIONS: Taken together, these results suggest that labeled agents that are more specific for cellular AGT and that are more metabolically stable are needed.

Duke Scholars

Published In

Nucl Med Biol

DOI

ISSN

0969-8051

Publication Date

April 2006

Volume

33

Issue

3

Start / End Page

399 / 407

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Rhabdomyosarcoma
  • Radionuclide Imaging
  • O(6)-Methylguanine-DNA Methyltransferase
  • Nuclear Medicine & Medical Imaging
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Medulloblastoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Shankar, S., Zalutsky, M. R., Friedman, H., & Vaidyanathan, G. (2006). Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine. Nucl Med Biol, 33(3), 399–407. https://doi.org/10.1016/j.nucmedbio.2005.12.015
Shankar, Sriram, Michael R. Zalutsky, Henry Friedman, and Ganesan Vaidyanathan. “Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.Nucl Med Biol 33, no. 3 (April 2006): 399–407. https://doi.org/10.1016/j.nucmedbio.2005.12.015.
Shankar S, Zalutsky MR, Friedman H, Vaidyanathan G. Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine. Nucl Med Biol. 2006 Apr;33(3):399–407.
Shankar, Sriram, et al. “Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.Nucl Med Biol, vol. 33, no. 3, Apr. 2006, pp. 399–407. Pubmed, doi:10.1016/j.nucmedbio.2005.12.015.
Shankar S, Zalutsky MR, Friedman H, Vaidyanathan G. Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine. Nucl Med Biol. 2006 Apr;33(3):399–407.
Journal cover image

Published In

Nucl Med Biol

DOI

ISSN

0969-8051

Publication Date

April 2006

Volume

33

Issue

3

Start / End Page

399 / 407

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Rhabdomyosarcoma
  • Radionuclide Imaging
  • O(6)-Methylguanine-DNA Methyltransferase
  • Nuclear Medicine & Medical Imaging
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Medulloblastoma