Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma

Yukihiko Kato, Kiyoshi Yoshimura, Tahiro Shin, Henk Verheul, Hans Hammers, Tolib B. Sanni, Brenda C. Salumbides, Karen Van Erp, Richard Schulick, Roberto Pili

Research output: Contribution to journalArticle

Abstract

Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration-approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase-expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (∼40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4 +CD25+ T cells and Foxp3+ T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8+ T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.

Original languageEnglish (US)
Pages (from-to)4538-4546
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number15
DOIs
StatePublished - Aug 1 2007

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Histone Deacetylase Inhibitors
Renal Cell Carcinoma
Interleukin-2
Therapeutics
Regulatory T-Lymphocytes
Luciferases
T-Lymphocytes
Neoplasms
Inbred BALB C Mouse
entinostat
Injections
Kaplan-Meier Estimate
United States Food and Drug Administration
Tumor Burden
Cell Survival
Research Design
Lymph Nodes
Neoplasm Metastasis
Kidney
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma. / Kato, Yukihiko; Yoshimura, Kiyoshi; Shin, Tahiro; Verheul, Henk; Hammers, Hans; Sanni, Tolib B.; Salumbides, Brenda C.; Van Erp, Karen; Schulick, Richard; Pili, Roberto.

In: Clinical Cancer Research, Vol. 13, No. 15, 01.08.2007, p. 4538-4546.

Research output: Contribution to journalArticle

Kato, Y, Yoshimura, K, Shin, T, Verheul, H, Hammers, H, Sanni, TB, Salumbides, BC, Van Erp, K, Schulick, R & Pili, R 2007, 'Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma', Clinical Cancer Research, vol. 13, no. 15, pp. 4538-4546. https://doi.org/10.1158/1078-0432.CCR-07-0014
Kato, Yukihiko ; Yoshimura, Kiyoshi ; Shin, Tahiro ; Verheul, Henk ; Hammers, Hans ; Sanni, Tolib B. ; Salumbides, Brenda C. ; Van Erp, Karen ; Schulick, Richard ; Pili, Roberto. / Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 15. pp. 4538-4546.
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abstract = "Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration-approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase-expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80{\%}) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (∼40{\%} inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90{\%} inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4 +CD25+ T cells and Foxp3+ T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8+ T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.",
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T1 - Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma

AU - Kato, Yukihiko

AU - Yoshimura, Kiyoshi

AU - Shin, Tahiro

AU - Verheul, Henk

AU - Hammers, Hans

AU - Sanni, Tolib B.

AU - Salumbides, Brenda C.

AU - Van Erp, Karen

AU - Schulick, Richard

AU - Pili, Roberto

PY - 2007/8/1

Y1 - 2007/8/1

N2 - Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration-approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase-expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (∼40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4 +CD25+ T cells and Foxp3+ T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8+ T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.

AB - Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration-approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase-expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination. Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (∼40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4 +CD25+ T cells and Foxp3+ T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8+ T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.

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