Oral administration of a novel taxane, an antisense oligonucleotide targeting protein kinase A, and the epidermal growth factor receptor inhibitor Iressa causes cooperative antitumor and antiangiogenic activity.
OBJECTIVE
Protein kinase A type I (PKAI) and the epidermal growth factor receptor (EGFR) play a role in neoplastic transformation and interact with each other in transducing mitogenic signals. We developed different PKAI and EGFR inhibitors, demonstrating their cooperation with cytotoxic drugs and the therapeutic potential of the combined blockade of PKAI and EGFR. In this study, we investigated the effect of orally active PKAI and EGFR inhibitors in combination with a novel taxane.


METHODS
We combined a hybrid PKAI antisense oligonucleotide sequence (AS-PKAI), the EGFR inhibitor ZD1839 (Iressa), and the taxane IDN5109, studying their effect on human cancer growth, apoptosis, and angiogenesis and measuring vascular endothelial growth factor (VEGF) expression and vessel formation in vitro and after oral administration in nude mice.


RESULTS
We demonstrated cooperative growth inhibitory and proapoptotic effects and inhibition of VEGF expression with any combination of two drugs and a marked synergistic effect when all three agents were combined. Oral administration of AS-PKAI, ZD1839, and IDN5109 in combination to nude mice caused a remarkable antitumor effect with no histological evidence of tumors in 50% of mice 5 weeks after treatment withdrawal, accompanied by complete suppression of vessel formation and VEGF expression.


CONCLUSIONS
This is the first demonstration of the cooperative antitumor and antiangiogenic activity of three novel agents that block multiple signaling pathways after oral administration. Because all agents are under clinical evaluation in cancer patients, our results provide a rationale to translate this feasible therapeutic strategy in a clinical setting.
Tortora
G
G
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Via S. Pansini 5, 80131 Naples, Italy. gtortora@unina.it
Caputo
R
R
Damiano
V
V
Fontanini
G
G
Melisi
D
D
Veneziani
B M
BM
Zunino
F
F
Bianco
A R
AR
Ciardiello
F
F
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D016228:Endothelial Growth Factors / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D020319:Oligodeoxyribonucleotides, Antisense; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases; D000077156:Gefitinib