CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity

Y. Chen, Theodore DeWeese, J. Dilley, Y. Zhang, Y. Li, N. Ramesh, J. Lee, R. Pennathur-Das, J. Radzyminski, J. Wypych, D. Brignetti, S. Scott, J. Stephens, D. B. Karpf, D. R. Henderson, D. C. Yu

Research output: Contribution to journalArticle

Abstract

Radiation is an effective means of treating localized prostate cancer. However, up to 40% of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 × 108 particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostatespecific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 × 107 particles/mm3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97% or 120% of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropped to 4% of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180% and 690%, apoptosis by 330% and 880%, and decreased blood vessel number by 1290% and 600%, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.

Original languageEnglish (US)
Pages (from-to)5453-5460
Number of pages8
JournalCancer Research
Volume61
Issue number14
StatePublished - Jul 15 2001

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Adenoviridae
Prostatic Neoplasms
Radiotherapy
Radiation
Neoplasms
Tumor Burden
Heterografts
Prostate
Radiation Effects
Nude Mice
Blood Vessels
Necrosis
Therapeutics
Clinical Trials
Apoptosis
Viruses
Antigens
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. / Chen, Y.; DeWeese, Theodore; Dilley, J.; Zhang, Y.; Li, Y.; Ramesh, N.; Lee, J.; Pennathur-Das, R.; Radzyminski, J.; Wypych, J.; Brignetti, D.; Scott, S.; Stephens, J.; Karpf, D. B.; Henderson, D. R.; Yu, D. C.

In: Cancer Research, Vol. 61, No. 14, 15.07.2001, p. 5453-5460.

Research output: Contribution to journalArticle

Chen, Y, DeWeese, T, Dilley, J, Zhang, Y, Li, Y, Ramesh, N, Lee, J, Pennathur-Das, R, Radzyminski, J, Wypych, J, Brignetti, D, Scott, S, Stephens, J, Karpf, DB, Henderson, DR & Yu, DC 2001, 'CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity', Cancer Research, vol. 61, no. 14, pp. 5453-5460.
Chen, Y. ; DeWeese, Theodore ; Dilley, J. ; Zhang, Y. ; Li, Y. ; Ramesh, N. ; Lee, J. ; Pennathur-Das, R. ; Radzyminski, J. ; Wypych, J. ; Brignetti, D. ; Scott, S. ; Stephens, J. ; Karpf, D. B. ; Henderson, D. R. ; Yu, D. C. / CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. In: Cancer Research. 2001 ; Vol. 61, No. 14. pp. 5453-5460.
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title = "CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity",
abstract = "Radiation is an effective means of treating localized prostate cancer. However, up to 40{\%} of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 × 108 particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostatespecific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 × 107 particles/mm3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97{\%} or 120{\%} of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropped to 4{\%} of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180{\%} and 690{\%}, apoptosis by 330{\%} and 880{\%}, and decreased blood vessel number by 1290{\%} and 600{\%}, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.",
author = "Y. Chen and Theodore DeWeese and J. Dilley and Y. Zhang and Y. Li and N. Ramesh and J. Lee and R. Pennathur-Das and J. Radzyminski and J. Wypych and D. Brignetti and S. Scott and J. Stephens and Karpf, {D. B.} and Henderson, {D. R.} and Yu, {D. C.}",
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T1 - CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity

AU - Chen, Y.

AU - DeWeese, Theodore

AU - Dilley, J.

AU - Zhang, Y.

AU - Li, Y.

AU - Ramesh, N.

AU - Lee, J.

AU - Pennathur-Das, R.

AU - Radzyminski, J.

AU - Wypych, J.

AU - Brignetti, D.

AU - Scott, S.

AU - Stephens, J.

AU - Karpf, D. B.

AU - Henderson, D. R.

AU - Yu, D. C.

PY - 2001/7/15

Y1 - 2001/7/15

N2 - Radiation is an effective means of treating localized prostate cancer. However, up to 40% of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 × 108 particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostatespecific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 × 107 particles/mm3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97% or 120% of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropped to 4% of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180% and 690%, apoptosis by 330% and 880%, and decreased blood vessel number by 1290% and 600%, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.

AB - Radiation is an effective means of treating localized prostate cancer. However, up to 40% of men with certain risk factors will develop biochemical failure 5 years after radiotherapy. CV706, a prostate cell-specific adenovirus variant, is currently in clinical trials for the treatment of recurrent organ-confined prostate cancer. We demonstrated previously that a single administration of CV706 at 5 × 108 particles/mm3 of tumor eliminated established tumors within 6 weeks in nude mouse xenografts (Rodriguez et al., Cancer Res. 57: 2559-2563, 1997). We now demonstrate that CV706-mediated cytotoxicity is synergistic with radiation. In vitro, addition of radiation to CV706 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP and a significant increase of virus burst size, with no reduction in specificity of CV706-based cytopathogenicity for prostate cancer cells. In vivo, prostatespecific antigen (+) LNCaP xenografts of human prostate cancer were treated with CV706 (1 × 107 particles/mm3 of tumor), 10 Gy of single fraction local tumor radiation, or both. Tumor volumes of the group treated with CV706 or radiation was 97% or 120% of baseline 6 weeks after treatment. However, when the same dose of CV706 was followed 24 h later with the same dose of radiation, the tumor volume dropped to 4% of baseline at this time point and produced antitumor activity that was 6.7-fold greater than a predicted additive effect of CV706 and radiation. Histological analyses of tumors revealed that, compared with CV706 or radiation alone, combination treatment with two agents increased necrosis by 180% and 690%, apoptosis by 330% and 880%, and decreased blood vessel number by 1290% and 600%, respectively. Importantly, no increase in toxicity was observed after combined treatment when compared with CV706 or radiation alone. These data demonstrate that CV706 enhances the in vivo radioresponse of prostate tumors and support the clinical development of CV706 as a neoadjuvant agent with radiation for localized prostate cancer.

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