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Therapeutic integration of c‐myc and bcl‐2 antisense molecules with docetaxel in a preclinical model of hormone‐refractory prostate cancer
Author(s) -
Leonetti Carlo,
Biroccio Annamaria,
D'Angelo Carmen,
Semple Sean. C.,
Scarsella Marco,
Zupi Gabriella
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20636
Subject(s) - docetaxel , prostate cancer , chemotherapy , apoptosis , cancer , concomitant , cancer research , medicine , downregulation and upregulation , prostate , oncology , biology , gene , biochemistry
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. Prostate 67: 1475–1485, 2007. © 2007 Wiley‐Liss, Inc.