Modulation of tumor radiation response with G3139, a bcl-2 antisense oligonucleotide

Nicole Wiedenmann; Masashi Koto; Uma Raju; Luka Milas; Kathryn A. Mason

doi:10.1007/s10637-007-9058-3

Modulation of tumor radiation response with G3139, a bcl-2 antisense oligonucleotide

Nicole Wiedenmann, Masashi Koto, Uma Raju, Luka Milas, Kathryn A. Mason

Experimental Radiation Oncology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Overexpression of anti-apoptotic bcl-2 protein has been found in hematological and solid tumors and has been associated with increased resistance against cytotoxic therapy. While bcl-2 antisense (AS) treatment combined with chemotherapy has been successfully tested in clinical trials, trials evaluating the combination of bcl-2 AS with radiotherapy have not yet been performed. The aim of this study was to investigate in vivo anti-tumor effects of a combined modality treatment scheme consisting of radiation and the bcl-2 targeted AS oligonucleotide (ODN) G3139 (Oblimersen Sodium). Two human colon carcinoma cell lines, SW620, bcl-2 positive and HT-29, bcl-2 negative, were grown as xenografts and compared in their response to combined bcl-2 AS/radiation treatment. G3139 potentiated the radiation response of bcl-2 positive SW620 tumors, but had no significant effect on bcl-2 negative HT-29 tumors assayed by tumor growth delay. The profound enhancement of SW620 tumor growth delay by G3139 did not translate into effects on tumor cure, as no significant effect of G3139 was found on SW620 radiocurability (TCD₅₀ assay). The control ODN G3622 had no effect on SW620 radiation response, indicating an ODN sequence specific effect.

Original language	English (US)
Pages (from-to)	411-416
Number of pages	6
Journal	Investigational New Drugs
Volume	25
Issue number	5
DOIs	https://doi.org/10.1007/s10637-007-9058-3
State	Published - Oct 2007

Keywords

Antisense oligonucleotide
Bcl-2
Colon cancer
Radiation response
TCD
Tumor growth delay
Xenografts

ASJC Scopus subject areas

Oncology
Pharmacology
Pharmacology (medical)

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10.1007/s10637-007-9058-3

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title = "Modulation of tumor radiation response with G3139, a bcl-2 antisense oligonucleotide",

abstract = "Overexpression of anti-apoptotic bcl-2 protein has been found in hematological and solid tumors and has been associated with increased resistance against cytotoxic therapy. While bcl-2 antisense (AS) treatment combined with chemotherapy has been successfully tested in clinical trials, trials evaluating the combination of bcl-2 AS with radiotherapy have not yet been performed. The aim of this study was to investigate in vivo anti-tumor effects of a combined modality treatment scheme consisting of radiation and the bcl-2 targeted AS oligonucleotide (ODN) G3139 (Oblimersen Sodium). Two human colon carcinoma cell lines, SW620, bcl-2 positive and HT-29, bcl-2 negative, were grown as xenografts and compared in their response to combined bcl-2 AS/radiation treatment. G3139 potentiated the radiation response of bcl-2 positive SW620 tumors, but had no significant effect on bcl-2 negative HT-29 tumors assayed by tumor growth delay. The profound enhancement of SW620 tumor growth delay by G3139 did not translate into effects on tumor cure, as no significant effect of G3139 was found on SW620 radiocurability (TCD50 assay). The control ODN G3622 had no effect on SW620 radiation response, indicating an ODN sequence specific effect.",

keywords = "Antisense oligonucleotide, Bcl-2, Colon cancer, Radiation response, TCD, Tumor growth delay, Xenografts",

author = "Nicole Wiedenmann and Masashi Koto and Uma Raju and Luka Milas and Mason, {Kathryn A.}",

note = "Funding Information: Acknowledgements This work was supported by National Cancer Institute Cancer Center Core Grants CA-16632 and CA-06294, and by a Laboratory Study Agreement with Aventis. The expert technical assistance of Robert Neal, David Valdecanas, Nancy Hunter, and Jessica Pickett are gratefully acknowledged.",

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doi = "10.1007/s10637-007-9058-3",

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AU - Wiedenmann, Nicole

AU - Koto, Masashi

AU - Raju, Uma

AU - Milas, Luka

AU - Mason, Kathryn A.

N1 - Funding Information: Acknowledgements This work was supported by National Cancer Institute Cancer Center Core Grants CA-16632 and CA-06294, and by a Laboratory Study Agreement with Aventis. The expert technical assistance of Robert Neal, David Valdecanas, Nancy Hunter, and Jessica Pickett are gratefully acknowledged.

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N2 - Overexpression of anti-apoptotic bcl-2 protein has been found in hematological and solid tumors and has been associated with increased resistance against cytotoxic therapy. While bcl-2 antisense (AS) treatment combined with chemotherapy has been successfully tested in clinical trials, trials evaluating the combination of bcl-2 AS with radiotherapy have not yet been performed. The aim of this study was to investigate in vivo anti-tumor effects of a combined modality treatment scheme consisting of radiation and the bcl-2 targeted AS oligonucleotide (ODN) G3139 (Oblimersen Sodium). Two human colon carcinoma cell lines, SW620, bcl-2 positive and HT-29, bcl-2 negative, were grown as xenografts and compared in their response to combined bcl-2 AS/radiation treatment. G3139 potentiated the radiation response of bcl-2 positive SW620 tumors, but had no significant effect on bcl-2 negative HT-29 tumors assayed by tumor growth delay. The profound enhancement of SW620 tumor growth delay by G3139 did not translate into effects on tumor cure, as no significant effect of G3139 was found on SW620 radiocurability (TCD50 assay). The control ODN G3622 had no effect on SW620 radiation response, indicating an ODN sequence specific effect.

AB - Overexpression of anti-apoptotic bcl-2 protein has been found in hematological and solid tumors and has been associated with increased resistance against cytotoxic therapy. While bcl-2 antisense (AS) treatment combined with chemotherapy has been successfully tested in clinical trials, trials evaluating the combination of bcl-2 AS with radiotherapy have not yet been performed. The aim of this study was to investigate in vivo anti-tumor effects of a combined modality treatment scheme consisting of radiation and the bcl-2 targeted AS oligonucleotide (ODN) G3139 (Oblimersen Sodium). Two human colon carcinoma cell lines, SW620, bcl-2 positive and HT-29, bcl-2 negative, were grown as xenografts and compared in their response to combined bcl-2 AS/radiation treatment. G3139 potentiated the radiation response of bcl-2 positive SW620 tumors, but had no significant effect on bcl-2 negative HT-29 tumors assayed by tumor growth delay. The profound enhancement of SW620 tumor growth delay by G3139 did not translate into effects on tumor cure, as no significant effect of G3139 was found on SW620 radiocurability (TCD50 assay). The control ODN G3622 had no effect on SW620 radiation response, indicating an ODN sequence specific effect.

KW - Antisense oligonucleotide

KW - Bcl-2

KW - Colon cancer

KW - Radiation response

KW - TCD

KW - Tumor growth delay

KW - Xenografts

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Modulation of tumor radiation response with G3139, a bcl-2 antisense oligonucleotide

Abstract

Keywords

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