OtherBasic Science Investigations

Assessment of Treatment Response by Autoradiography with 14C-Aminocyclopentane Carboxylic Acid, 67Ga-DTPA, and 18F-FDG in a Herpes Simplex Virus Thymidine Kinase/Ganciclovir Brain Tumor Model

Tadashi Miyagawa, Takamitsu Oku, Toshio Sasajima, Rovathi Dasai, Bradley Beattie, Ronald Finn, Juri Gelovani Tjuvajev and Ronald Blasberg
Journal of Nuclear Medicine November 2003, 44 (11) 1845-1854;

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Corresponding images from 2 intracerebral RG2TK+ xenografts: one treated with gancyclovir (A–D) and the other treated with normal saline (control; E–H). From left to right are toluidine blue-stained histology (A and E) and parametric images of R measured with 18F-FDG (B and F), K1 of 14C-ACPC (C and G), and K1 of 67Ga-DTPA (D and H). Histology and parametric images for each animal were obtained from same tissue section. Parametric images are color coded to a range of values. Tumor outline (in red) was drawn on histologic image and electronically transferred to previously registered autoradiographic images.

  • FIGURE 2.
    FIGURE 2.

    (A and B) Photomicrographs of RG2TK+ xenografts after 3 d of GCV treatment (A) and normal saline treatment (B). (toluidine blue, ×200) (C–F) TdT-mediated dUTP-X nick-end labeling (TUNEL) staining of RG2TK+ tumor treated with GCV (C) and normal saline (D) and normal brain in treated animal (E) and nontreated animal (F). (×200)

  • FIGURE 3.
    FIGURE 3.

    Microphotographs of immunostaining for CD34, LAT1, and 4F2hc. CD34-positive endothelial cells also express LAT1 and 4F2hc in normal brain (A) and some intratumoral vessels in CGV-treated tumor (B) and in nontreated tumor (C). However, some microvessels in GCV-treated tumor expressing CD34 were stained weakly or marginally by LAT1, whereas CD98 staining intensity was relatively retained (arrows) despite microvessel in normal brain around tumor that remained LAT1 positive (asterisks).

  • FIGURE 4.
    FIGURE 4.

    Microphotographs of immunostaining for LAT1 and 4F2hc in nontreated tumor and in GCV-treated tumor. (Top, ×100; bottom, ×200)

  • FIGURE 5.
    FIGURE 5.

    Survival of animals bearing intracerebral RG2TK+ xenografts after 3 d of treatment with GCV (○) or normal saline (□). Three GCV-treated long-term survivors are not included in plot.

Tables

  • TABLE 1

    Comparison of Uptake in HSV-tk Transduced Tumor

    TissueUntreated (saline)Treated (GCV)
    14C-ACPC K1 (μL/min/g)14C-ACPC ∂K1 (μL/min/g)67Ga-DTPA K1 (μL/min/g)18F-FDG R (μmol/hg/min)14C-ACPC K1 (μL/min/g)14C-ACPC ∂K1 (μL/min/g)67Ga-DTPA K1 (μL/min/g)18F-FDG R (μmol/hg/min)
    Tumor
     Whole tumor34.5 ± 9.4 (5)*†33.8 ± 8.9 (5)*†0.182 ± 0.099 (5)†25.4 ± 7.3 (5)9.8 ± 2.7 (6)‡9.5 ± 2.7 (6)‡0.115 ± 0.051 (6)12.3 ± 3.8 (5)*†‡
     Viable tumor35.2 ± 9.6 (5)*†34.9 ± 9.7 (5)*†0.168 ± 0.014 (5)*†26.1 ± 7.5 (5)9.7 ± 2.8 (6)‡9.5 ± 2.8 (6)‡0.096 ± 0.019 (6)†‡13.1 ± 3.8 (5)*†‡
     Impending necrosis50.4 ± 18.9 (4)44.5 ± 20.1 (4)0.87 ± 0.19 (4)37.3 ± 10.6 (4)13.7 ± 7.4 (4)11.6 ± 5.1 (4)1.12 ± 1.43 (4)18.1 ± 9.0 (4)
     Necrotic tumor————1.0 ± 1.3 (5)§1.3 ± 1.2 (5)§−0.16 ± 0.61 (5)4.5 ± 1.5 (5)*†‡§
    Contralateral brain
     Frontal cortex18.9 ± 4.2 (5)18.8 ± 4.2 (5)0.081 ± 0.019 (5)42.1 ± 15.1 (5)10.9 ± 3.0 (6)‡10.7 ± 3.0 (6)‡0.092 ± 0.004 (6)30.0 ± 12.4 (5)
     Corpus callosum14.9 ± 4.1 (5)14.8 ± 4.1 (5)0.054 ± 0.011 (5)22.9 ± 7.5 (5)8.2 ± 3.2 (6)‡8.2 ± 3.2 (6)‡0.059 ± 0.018 (6)18.9 ± 7.7 (5)

    • ↵* Statistically significant value compared with corresponding contralateral frontal cortex (P < 0.05, paired t test).

    • ↵† Statistically significant value compared with corresponding contralateral corpus callosum (P < 0.05, paired t test).

    • ↵‡ Statistically significant value compared with untreated rats (P < 0.05).

    • ↵§ Significantly different from whole-tumor and viable tumor values (P < 0.05, paired t test).

    • Initial transport (clearance) constant, K1, was calculated from 10-min 14C-ACPC and 10-min 67Ga-DTPA experiments (Eq. 1); ∂K1 of ACPC was calculated (Eq. 2), and relative glucose utilization (R) was calculated from 60-min 18F-FDG data (Eq. 3; hg = 100 g). Data are shown for untreated (saline) control animals and for animals treated with GCV. Values are the mean ± SD; number of animals is given in parenthesis. One saline-treated animal died during study, and 1 GCV-treated animal did not receive 18F-FDG because radiopharmaceutical was not available.

  • TABLE 2

    Plasma Amino Acid Concentrations

    Amino acidAmino acid classUntreated (saline) Average ± SD (pmol/μL)Treated (GCV) Average ± SD (pmol/μL)
    GlyA411 ± 216308 ± 243
    AlaA650 ± 388412 ± 277
    SerA+318 ± 167267 ± 198
     Total A1,380 ± 745987 ± 713
    ValA-L273 ± 146255 ± 173
    MetA-L77 ± 3144 ± 24
    ProA-L248 ± 137180 ± 116
     Total A-L579 ± 279464 ± 305
    PheL118 ± 54104 ± 77
    IleL122 ± 54131 ± 100
    LeuL288 ± 162314 ± 221
    TyrL95 ± 4576 ± 47
    ThrL+211 ± 121130 ± 72
     Total L834 ± 340755 ± 492
    LysB423 ± 262328 ± 232
    ArgB360 ± 207343 ± 238
    HisB79 ± 4074 ± 28
     Total B861 ± 446720 ± 468
    AspAc105 ± 87105 ± 78
    GluAc361 ± 229341 ± 273
     Total Ac466 ± 271447 ± 340
    Total amino acids (mean ± SD)4,131 ± 1,9433,373 ± 2,302

    • Values are means ± SD for individual animals.

  • TABLE 3

    Comparison of 14C-ACPC, 18F-FDG, and 67Ga-DTPA Uptake in Morphologically Distinct Intratumoral Regions

    TissueUntreated (saline)Treated (GCV)
    14C-ACPC67Ga-DTPA18F-FDG14C-ACPC67Ga-DTPA18F-FDG
    Viable tumor
     High cell density1.28 ± 0.32 (5)1.28 ± 0.19 (5)*1.23 ± 0.17 (5)*1.04 ± 0.13 (6)1.01 ± 0.26 (6)1.20 ± 0.13 (5)*
     Low cell density0.89 ± 0.12 (5)0.99 ± 0.24 (5)0.96 ± 0.07 (5)0.98 ± 0.07 (6)0.87 ± 0.14 (6)*0.86 ± 0.10 (5)
     Impending necrosis1.43 ± 0.22 (4)*1.71 ± 0.81 (4)1.44 ± 0.07 (4)*1.97 ± 0.28 (4)2.22 ± 0.99 (4)1.35 ± 0.35 (4)
    Necrotic tumor
     Necrosis———0.29 ± 0.27 (5)†0.62 ± 0.45 (5)†0.38 ± 0.10 (4)†

    • ↵* Statistically significant values, paired t test (P < 0.05).

    • ↵† Statistically significant values, paired t test (P < 0.01).

    • Tumor region-to-mean tumor ratio was calculated; values are mean ± SD; number of animals is given in parenthesis.

  • TABLE 4

    Tissue Uptake (% dose/g) of 14C-ACPC, 18F-FDG, and 67Ga-DTPA Uptake in RG2-tk Gliomas

    TissueUntreated (saline)Treated (GCV)
    14C-ACPC67Ga-DTPA18F-FDG14C-ACPC67Ga-DTPA18F-FDG
    Tumor0.28 ± 0.09 (5)*0.054 ± 0.013 (5)†0.70 ± 0.21 (5)†0.11 ± 0.04 (6)‡0.057 ± 0.028 (6)0.63 ± 0.15 (5)†
    Frontal cortex0.16 ± 0.04 (5)0.024 ± 0.006 (5)1.12 ± 0.27 (5)0.12 ± 0.05 (6)0.036 ± 0.011 (6)1.51 ± 0.54 (5)
    Final plasma0.43 ± 0.18 (5)2.3 ± 0.9 (5)0.40 ± 0.09 (5)0.65 ± 0.26 (6)3.7 ± 1.5 (6)0.38 ± 0.09 (6)

    • ↵* Statistically significant values compared with frontal cortex, paired t test (P < 0.01).

    • ↵† Statistically significant values compared with frontal cortex, paired t test (P < 0.05).

    • ↵‡ Statistically significant value compared with untreated rats, unpaired t test (P < 0.01).

    • % injected dose/g tissue weight; values are mean ± SD; number of animals is given in parenthesis.

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