Oral antisense that targets protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis, and growth factor production.
Protein kinase A type I (PKAI) transduces mitogenic signals from different growth factors and oncogenes and is overexpressed in the majority of human cancers. We and other investigators previously have reported that different PKAI inhibitors, including antisense oligonucleotides, have antitumor activity. In this study, we used a novel hybrid DNA/RNA mixed-backbone oligonucleotide (MBO) targeting the PKAI subunit RIalpha. We demonstrated that after oral administration, the MBO antisense RIalpha inhibited the growth of human colon cancer xenografts in nude mice and showed a cooperative antitumor effect with Taxol, which outlasted treatment withdrawal and significantly prolonged survival of mice compared with untreated controls or to single-agent-treated mice. Immunohistochemical analysis of tumor specimens showed inhibition of target protein RIalpha and of growth factor expression along with a marked inhibition of angiogenesis and an increase in p27 expression. In conclusion, a novel MBO that targets PKAI, administered p.o., is effective and cooperates with the anticancer drug Taxol on both tumor growth and expression of factors involved in the control of cell proliferation, cell cycle, and angiogenesis. Because the MBO described has completed a phase I trial involving i.v. injection in cancer patients, these results provide the biological rationale of its activity after oral administration and may be translated into a therapeutic strategy in a clinical setting.
Tortora
G
G
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università Federico II, Naples, Italy. gtortora@unina.it
Bianco
R
R
Damiano
V
V
Fontanini
G
G
De Placido
S
S
Bianco
A R
AR
Ciardiello
F
F
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D017239:Paclitaxel / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000972:Antineoplastic Agents, Phytogenic; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D006133:Growth Substances; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017868:Cyclic AMP-Dependent Protein Kinases; D017239:Paclitaxel