Monogene and polygene therapy for the treatment of experimental prostate cancers by use of apoptotic genes bax and bad driven by the prostate-specific promoter ARR2PB

Ye Zhang, Jiang Yu, Emmanual Unni, Tsang C. Shao, Bicheng Nan, Thiti Snabboon, Susan Kasper, Francesca Andriani, Larry Denner, Marco Marcelli

Research output: Contribution to journalArticle

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Abstract

We have shown that adenovirus-mediated manipulation of apoptotic genes such as bax could be a therapeutic option for prostate cancer. Unfortunately, the response of experimental prostate tumors to a single therapeutic gene of the apoptotic pathway is short-lived, and most of these tumors relapse after a short period of time. In this investigation we present data generated with adenovirus AvARR2PB-Bad, in which the apoptotic gene bad was placed under the control of the dihydrotestosterone (DHT)-inducible third-generation probasin-derived promoter ARR2PB. This therapeutic virus was given alone or in combination with other therapeutic viruses to a variety of in vitro and in vivo experimental models of prostate cancer. On infection with AvARR2PB-Bad, DHT-induced Bad overexpression occurred specifically in androgen receptor-positive (AR+) cells of prostatic derivation. The apoptotic effect of AvARR2PB-Bad (group 1) was compared with that of AvARR2PB-Bax (which overexpresses the apoptotic protein Bax) (group 2), with that of the combination AvARR2PB-Bad plus AvARR2PB-Bax (group 3), and with that of the control virus AvARR2PB-CAT (group 4) in the cell line LNCaP. In addition to identifying the modality of apoptosis induction by overexpressed Bad, the results suggested that group 3 contained more apoptotic cells than any other group. In additional studies, AR+ androgen-dependent LNCaP cells or AR+ and androgen-independent C4-2 cells were injected subcutaneously into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4. There was a better response in group 3 compared with group 2, and in group 2 compared with group 1. A better response in group 3 was confirmed during a 8-week follow-up period, in which no treatment was administered. Two LNCaP and C4-2 tumors of group 3 disappeared at the end of treatment and did not recur after an 8-week follow-up period. The data suggest that polygene therapy with apoptotic molecules is more effective in experimental models of androgen-dependent or -independent prostate cancer than monogene therapy.

Original languageEnglish (US)
Pages (from-to)2051-2064
Number of pages14
JournalHuman Gene Therapy
Volume13
Issue number17
DOIs
StatePublished - 2002
Externally publishedYes

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Investigational Therapies
Prostate
Prostatic Neoplasms
Androgens
Genes
Viruses
Dihydrotestosterone
Neoplasms
Adenoviridae
Theoretical Models
Therapeutics
bcl-2-Associated X Protein
Androgen Receptors
Nude Mice
Apoptosis
Recurrence
Cell Line
Infection

ASJC Scopus subject areas

  • Genetics

Cite this

Monogene and polygene therapy for the treatment of experimental prostate cancers by use of apoptotic genes bax and bad driven by the prostate-specific promoter ARR2PB. / Zhang, Ye; Yu, Jiang; Unni, Emmanual; Shao, Tsang C.; Nan, Bicheng; Snabboon, Thiti; Kasper, Susan; Andriani, Francesca; Denner, Larry; Marcelli, Marco.

In: Human Gene Therapy, Vol. 13, No. 17, 2002, p. 2051-2064.

Research output: Contribution to journalArticle

Zhang, Ye ; Yu, Jiang ; Unni, Emmanual ; Shao, Tsang C. ; Nan, Bicheng ; Snabboon, Thiti ; Kasper, Susan ; Andriani, Francesca ; Denner, Larry ; Marcelli, Marco. / Monogene and polygene therapy for the treatment of experimental prostate cancers by use of apoptotic genes bax and bad driven by the prostate-specific promoter ARR2PB. In: Human Gene Therapy. 2002 ; Vol. 13, No. 17. pp. 2051-2064.
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abstract = "We have shown that adenovirus-mediated manipulation of apoptotic genes such as bax could be a therapeutic option for prostate cancer. Unfortunately, the response of experimental prostate tumors to a single therapeutic gene of the apoptotic pathway is short-lived, and most of these tumors relapse after a short period of time. In this investigation we present data generated with adenovirus AvARR2PB-Bad, in which the apoptotic gene bad was placed under the control of the dihydrotestosterone (DHT)-inducible third-generation probasin-derived promoter ARR2PB. This therapeutic virus was given alone or in combination with other therapeutic viruses to a variety of in vitro and in vivo experimental models of prostate cancer. On infection with AvARR2PB-Bad, DHT-induced Bad overexpression occurred specifically in androgen receptor-positive (AR+) cells of prostatic derivation. The apoptotic effect of AvARR2PB-Bad (group 1) was compared with that of AvARR2PB-Bax (which overexpresses the apoptotic protein Bax) (group 2), with that of the combination AvARR2PB-Bad plus AvARR2PB-Bax (group 3), and with that of the control virus AvARR2PB-CAT (group 4) in the cell line LNCaP. In addition to identifying the modality of apoptosis induction by overexpressed Bad, the results suggested that group 3 contained more apoptotic cells than any other group. In additional studies, AR+ androgen-dependent LNCaP cells or AR+ and androgen-independent C4-2 cells were injected subcutaneously into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4. There was a better response in group 3 compared with group 2, and in group 2 compared with group 1. A better response in group 3 was confirmed during a 8-week follow-up period, in which no treatment was administered. Two LNCaP and C4-2 tumors of group 3 disappeared at the end of treatment and did not recur after an 8-week follow-up period. The data suggest that polygene therapy with apoptotic molecules is more effective in experimental models of androgen-dependent or -independent prostate cancer than monogene therapy.",
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AU - Shao, Tsang C.

AU - Nan, Bicheng

AU - Snabboon, Thiti

AU - Kasper, Susan

AU - Andriani, Francesca

AU - Denner, Larry

AU - Marcelli, Marco

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N2 - We have shown that adenovirus-mediated manipulation of apoptotic genes such as bax could be a therapeutic option for prostate cancer. Unfortunately, the response of experimental prostate tumors to a single therapeutic gene of the apoptotic pathway is short-lived, and most of these tumors relapse after a short period of time. In this investigation we present data generated with adenovirus AvARR2PB-Bad, in which the apoptotic gene bad was placed under the control of the dihydrotestosterone (DHT)-inducible third-generation probasin-derived promoter ARR2PB. This therapeutic virus was given alone or in combination with other therapeutic viruses to a variety of in vitro and in vivo experimental models of prostate cancer. On infection with AvARR2PB-Bad, DHT-induced Bad overexpression occurred specifically in androgen receptor-positive (AR+) cells of prostatic derivation. The apoptotic effect of AvARR2PB-Bad (group 1) was compared with that of AvARR2PB-Bax (which overexpresses the apoptotic protein Bax) (group 2), with that of the combination AvARR2PB-Bad plus AvARR2PB-Bax (group 3), and with that of the control virus AvARR2PB-CAT (group 4) in the cell line LNCaP. In addition to identifying the modality of apoptosis induction by overexpressed Bad, the results suggested that group 3 contained more apoptotic cells than any other group. In additional studies, AR+ androgen-dependent LNCaP cells or AR+ and androgen-independent C4-2 cells were injected subcutaneously into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4. There was a better response in group 3 compared with group 2, and in group 2 compared with group 1. A better response in group 3 was confirmed during a 8-week follow-up period, in which no treatment was administered. Two LNCaP and C4-2 tumors of group 3 disappeared at the end of treatment and did not recur after an 8-week follow-up period. The data suggest that polygene therapy with apoptotic molecules is more effective in experimental models of androgen-dependent or -independent prostate cancer than monogene therapy.

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