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Experimental Therapeutics, Preclinical Pharmacology

Regression of U-87 MG Human Glioblastomas in Nude Mice after Treatment with a Cytotoxic Somatostatin Analog AN-238

Hippokratis Kiaris, Andrew V. Schally, Attila Nagy, Baodong Sun, Karoly Szepeshazi and Gabor Halmos
Hippokratis Kiaris
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Andrew V. Schally
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Attila Nagy
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Baodong Sun
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Karoly Szepeshazi
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Gabor Halmos
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DOI:  Published February 2000
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    Fig. 1.

    Effect of treatment with cytotoxic SST analogue AN-238 on the growth of U-87 MG human glioblastomas xenografted into nude mice. A, changes in the tumor volume in nude mice after treatment with a single i.v. injection of cytotoxic SST analogue AN-238, cytotoxic radical AN-201, unconjugated mixture of AN-201 and the carrier peptide RC-121, or the carrier peptide RC-121 at 150 nmol/kg doses. #, the sharp decrease in the average tumor volume on day 11 in the RC-121-treated group was due to an animal bearing a tumor that became necrotic and subsequently disintegrated. *, P < 0.05 versus control; **, P < 0.01 versus control †, On day 15, the tumor volume of 3 of 4 animals exceeded 3,500 mm3 and the animals were sacrificed. Thus, the tumor volume on day 15 is shown. B, changes in the tumor volume in nude mice treated with 1 or 2 i.v. injections of AN-238 or AN-201 at 150 nmol/kg. *, P < 0.05 versus control; **, P < 0.01 versus control. C, effect of pretreatment with RC-121 administered s.c. at 50 μg/day per animal for 7 days or at 500μ g/animal 4 h before the administration of AN-238 at 150 nmol/kg. Vertical bars, SEM. *, P = 0.051 versus the AN-238-treated group and not significant versus control.

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    Fig. 2.

    Changes in body weights of nude mice bearing U-87 MG human glioblastoma and treated with 1 or 2 i.v. injections of AN-238 or AN-201 at 150 nmol/kg.

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    Fig. 3.

    Changes in tumor volume in athymic nude mice bearing s.c. xenografts of U-87 MG malignant glioblastomas after treatment with 150 nmol/kg of AN-238 or 13.75 μmol/kg of AN-162. Vertical bars, SEM. *, P = 0.0281. On day 8, tumors from the AN-162-treated mice were partially removed, and when new tumors on day 20 reached a volume of approximately 500 mm3, mice were divided into two experimental groups and treated with AN-162 or AN-238.

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    Fig. 4.

    Effect of systemic treatment with cytotoxic radical AN-201 or cytotoxic SST analogue AN-238 on the survival time of nude mice inoculated orthotopically with U-87 MG glioblastoma cells.

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    Fig. 5.

    A, representative example of Scatchard plots of 125I-RC-160 binding to the membrane fraction isolated from untreated U-87 MG tumors. Specific binding was determined as described. Each point represents the mean of triplicate determinations. B, representative displacement of 125I-RC-160 binding to membrane fractions of U-87 MG tumors by increasing concentrations of RC-121 (•) and cytotoxic somatostatin analogue AN-238 (▪). 100% specific binding is defined as the difference between binding in the absence and in the presence of 10−5m RC-160. Each point represents the mean of triplicate determinations. C, polyacrylamide gel electrophoresis of reverse-transcribed and subsequently PCR-amplified mRNAs for SSTR-2 and hGAPDH in three representative xenografts of U-87 MG human glioblastomas from untreated nude mice (lanes 1–3); M, molecular weight DNA marker; N, negative control; P, positive control (NCI-H-69 human small cell lung carcinoma).

Tables

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  • Table 1

    Effect of cytotoxic SST analogue AN-238, cytotoxic radical AN-201, carrier peptide RC-121, and mixture of RC-121 and AN-201 on tumor volume, tumor weight, and animal mortality in athymic nude mice bearing U-87MG human glioblastomas

    TreatmentTumor volume (mm3)Tumor burdenaMortalityb
    InitialFinal
    Control516 ± 1724782 ± 1012117.5 ± 20.30 /5
    AN-201447 ± 2143133 ± 125694.2 ± 40.51 /6
    RC-121+ AN-201466.8 ± 1135200 ± 713148.1 ± 20.91 /5
    AN-238535.2 ± 190867.1 ± 313.323.5 ± 8.10 /6
    RC-121593.2 ± 2553769 ± 626c
    RC-121 (chronically)d+ AN-238455 ± 177.3596 ± 20620.9 ± 60 /7
    RC-121 (acute)e+ AN-238413.8 ± 1553054.9 ± 109792.6 ± 30.30 /5
    AN-238 (days 0, 11)890.7 ± 378.1637.5 ± 248.326.2 ± 10.91 /9
    AN-201 (days 0, 11)941.1 ± 304.93274.2 ± 794.9112.9 ± 25.73 /10
    • a Tumor weight (mg)/body weight (g).

    • b Number of dead animals/number of total animals.

    • c On day 15, the tumor volume of 3 of 4 animals exceeded 3500 mm3, and the animals were sacrificed. Thus, the tumor volume on day 15 is shown and no data are available on tumor burden.

    • d Mice were treated daily for 7 days with RC-121 (50 μg/day per animal s.c.) prior to the administration of AN-238 at 150 nmol/kg.

    • e Mice received RC-121 at 500 μg s.c. 4 h before the administration of AN-238 at 150 nmol/kg.

  • Table 2

    Effect of treatment with cytotoxic SST analogue AN-238a and cytotoxic radical AN-201a on the percent area of necrosis of U-87MG glioblastomas transplanted into nude mice

    Treatment% area of necrosis
    Control38 ± 13
    AN-238 (day 0)44 ± 7
    AN-201 (day 0)31 ± 10
    AN-238 (days 0 and 11)63 ± 8
    AN-201 (days 0 and 11)34 ± 8
    RC-121 (500 μg) s.c. 4 h before AN-23843 ± 4
    RC-121 (50 μg/day) s.c. for 7 days before AN-23877 ± 11b
    • a Cytotoxic SST analogue AN-238 and cytotoxic radical AN-201 were injected i.v. at 150 nmol/kg once (day 0) or twice (days 0 and 11).

    • b P = 0.041.

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February 2000
Volume 6, Issue 2
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Regression of U-87 MG Human Glioblastomas in Nude Mice after Treatment with a Cytotoxic Somatostatin Analog AN-238
Hippokratis Kiaris, Andrew V. Schally, Attila Nagy, Baodong Sun, Karoly Szepeshazi and Gabor Halmos
Clin Cancer Res February 1 2000 (6) (2) 709-717;

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Regression of U-87 MG Human Glioblastomas in Nude Mice after Treatment with a Cytotoxic Somatostatin Analog AN-238
Hippokratis Kiaris, Andrew V. Schally, Attila Nagy, Baodong Sun, Karoly Szepeshazi and Gabor Halmos
Clin Cancer Res February 1 2000 (6) (2) 709-717;
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