Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer

Carlo Leonetti, Annamaria Biroccio, Carmen D'Angelo, Sean C. Semple, Marco Scarsella, Gabriella Zupi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

BACKGROUND. The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new forms of treatment to improve the prognosis. Since an increased expression of oncogenes, including c-myc and bcl-2, accompanies the transition to HRPC, we evaluated whether the concomitant downregulation of these oncogenes by antisense strategy sensitized HRPC to chemotherapy. METHODS. PC-3 prostate cancer cells were exposed in vitro to c-myc (INX-6295) and bcl-2 (G3139) antisense oligodeoxynucleotides (ODNs) and docetaxel given alone or in combination. Therapeutic efficacy of the different treatments was also evaluated in xenografts. RESULTS. We show that the triple combination of drugs given in the sequence G3139/docetaxel/INX-6295 was the most active in reducing the survival of PC-3. Likewise, the combination triggered apoptosis in more than 80% of cells. A marked tumor weight inhibition was observed in PC-3 xenografts after G3139/docetaxel/INX-6295 treatment, with a complete tumor regression being noted in half the mice. A 111% overall increase in life survival and a complete cure in two out of eight mice was also reported. This treatment remained effective even when started at a very late stage of tumor growth producing about 80% tumor weight inhibition (TWI), with tumor regression being maintained for 1 month. Finally, the antitumor effect resulted in a significant increase (70%) in mice survival. CONCLUSIONS. These data indicate that the combined targeting of genes involved in uncontrolled proliferation and evasion of apoptosis renders HRPC responsive to chemotherapy making this treatment a promising antineoplastic strategy.

Original languageEnglish
Pages (from-to)1475-1485
Number of pages11
JournalProstate
Volume67
Issue number13
DOIs
Publication statusPublished - Sep 15 2007

Fingerprint

docetaxel
Prostatic Neoplasms
Hormones
Tumor Burden
Oncogenes
Heterografts
Drug Therapy
Apoptosis
Therapeutics
Neoplasms
Gene Targeting
Drug Combinations
Antineoplastic Agents
Down-Regulation
oblimersen

Keywords

  • Chemotherapy
  • Combination
  • Oligodeoxynucleotides
  • Prostate cells
  • Xenografts

ASJC Scopus subject areas

  • Urology

Cite this

Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer. / Leonetti, Carlo; Biroccio, Annamaria; D'Angelo, Carmen; Semple, Sean C.; Scarsella, Marco; Zupi, Gabriella.

In: Prostate, Vol. 67, No. 13, 15.09.2007, p. 1475-1485.

Research output: Contribution to journalArticle

Leonetti, Carlo ; Biroccio, Annamaria ; D'Angelo, Carmen ; Semple, Sean C. ; Scarsella, Marco ; Zupi, Gabriella. / Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer. In: Prostate. 2007 ; Vol. 67, No. 13. pp. 1475-1485.
@article{745faa95ed344154b258da8c8dd2082f,
title = "Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer",
abstract = "BACKGROUND. The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new forms of treatment to improve the prognosis. Since an increased expression of oncogenes, including c-myc and bcl-2, accompanies the transition to HRPC, we evaluated whether the concomitant downregulation of these oncogenes by antisense strategy sensitized HRPC to chemotherapy. METHODS. PC-3 prostate cancer cells were exposed in vitro to c-myc (INX-6295) and bcl-2 (G3139) antisense oligodeoxynucleotides (ODNs) and docetaxel given alone or in combination. Therapeutic efficacy of the different treatments was also evaluated in xenografts. RESULTS. We show that the triple combination of drugs given in the sequence G3139/docetaxel/INX-6295 was the most active in reducing the survival of PC-3. Likewise, the combination triggered apoptosis in more than 80{\%} of cells. A marked tumor weight inhibition was observed in PC-3 xenografts after G3139/docetaxel/INX-6295 treatment, with a complete tumor regression being noted in half the mice. A 111{\%} overall increase in life survival and a complete cure in two out of eight mice was also reported. This treatment remained effective even when started at a very late stage of tumor growth producing about 80{\%} tumor weight inhibition (TWI), with tumor regression being maintained for 1 month. Finally, the antitumor effect resulted in a significant increase (70{\%}) in mice survival. CONCLUSIONS. These data indicate that the combined targeting of genes involved in uncontrolled proliferation and evasion of apoptosis renders HRPC responsive to chemotherapy making this treatment a promising antineoplastic strategy.",
keywords = "Chemotherapy, Combination, Oligodeoxynucleotides, Prostate cells, Xenografts",
author = "Carlo Leonetti and Annamaria Biroccio and Carmen D'Angelo and Semple, {Sean C.} and Marco Scarsella and Gabriella Zupi",
year = "2007",
month = "9",
day = "15",
doi = "10.1002/pros.20636",
language = "English",
volume = "67",
pages = "1475--1485",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "13",

}

TY - JOUR

T1 - Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer

AU - Leonetti, Carlo

AU - Biroccio, Annamaria

AU - D'Angelo, Carmen

AU - Semple, Sean C.

AU - Scarsella, Marco

AU - Zupi, Gabriella

PY - 2007/9/15

Y1 - 2007/9/15

N2 - BACKGROUND. The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new forms of treatment to improve the prognosis. Since an increased expression of oncogenes, including c-myc and bcl-2, accompanies the transition to HRPC, we evaluated whether the concomitant downregulation of these oncogenes by antisense strategy sensitized HRPC to chemotherapy. METHODS. PC-3 prostate cancer cells were exposed in vitro to c-myc (INX-6295) and bcl-2 (G3139) antisense oligodeoxynucleotides (ODNs) and docetaxel given alone or in combination. Therapeutic efficacy of the different treatments was also evaluated in xenografts. RESULTS. We show that the triple combination of drugs given in the sequence G3139/docetaxel/INX-6295 was the most active in reducing the survival of PC-3. Likewise, the combination triggered apoptosis in more than 80% of cells. A marked tumor weight inhibition was observed in PC-3 xenografts after G3139/docetaxel/INX-6295 treatment, with a complete tumor regression being noted in half the mice. A 111% overall increase in life survival and a complete cure in two out of eight mice was also reported. This treatment remained effective even when started at a very late stage of tumor growth producing about 80% tumor weight inhibition (TWI), with tumor regression being maintained for 1 month. Finally, the antitumor effect resulted in a significant increase (70%) in mice survival. CONCLUSIONS. These data indicate that the combined targeting of genes involved in uncontrolled proliferation and evasion of apoptosis renders HRPC responsive to chemotherapy making this treatment a promising antineoplastic strategy.

AB - BACKGROUND. The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new forms of treatment to improve the prognosis. Since an increased expression of oncogenes, including c-myc and bcl-2, accompanies the transition to HRPC, we evaluated whether the concomitant downregulation of these oncogenes by antisense strategy sensitized HRPC to chemotherapy. METHODS. PC-3 prostate cancer cells were exposed in vitro to c-myc (INX-6295) and bcl-2 (G3139) antisense oligodeoxynucleotides (ODNs) and docetaxel given alone or in combination. Therapeutic efficacy of the different treatments was also evaluated in xenografts. RESULTS. We show that the triple combination of drugs given in the sequence G3139/docetaxel/INX-6295 was the most active in reducing the survival of PC-3. Likewise, the combination triggered apoptosis in more than 80% of cells. A marked tumor weight inhibition was observed in PC-3 xenografts after G3139/docetaxel/INX-6295 treatment, with a complete tumor regression being noted in half the mice. A 111% overall increase in life survival and a complete cure in two out of eight mice was also reported. This treatment remained effective even when started at a very late stage of tumor growth producing about 80% tumor weight inhibition (TWI), with tumor regression being maintained for 1 month. Finally, the antitumor effect resulted in a significant increase (70%) in mice survival. CONCLUSIONS. These data indicate that the combined targeting of genes involved in uncontrolled proliferation and evasion of apoptosis renders HRPC responsive to chemotherapy making this treatment a promising antineoplastic strategy.

KW - Chemotherapy

KW - Combination

KW - Oligodeoxynucleotides

KW - Prostate cells

KW - Xenografts

UR - http://www.scopus.com/inward/record.url?scp=34548736559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548736559&partnerID=8YFLogxK

U2 - 10.1002/pros.20636

DO - 10.1002/pros.20636

M3 - Article

VL - 67

SP - 1475

EP - 1485

JO - Prostate

JF - Prostate

SN - 0270-4137

IS - 13

ER -