A novel MDM2 anti-sense oligonucleotide has anti-tumor activity and potentiates cytotoxic drugs acting by different mechanisms in human colon cancer.
MDM2 is over-expressed in several human tumors. Its product is a negative-feedback regulator of p53, which interferes with the control of cell proliferation and apoptosis, interacting not only with p53 but also with retinoblastoma (Rb) and E2F. Moreover, mutations in the ARF-Ink4a locus may also allow MDM2 to override p53 functions. In this study, we have used a novel oligonucleotide anti-sense MDM2, with mixed-backbone structure and demonstrate that it causes inhibition of MDM2 expression, induction of both p53 and p21/WAF1 expression and a dose-dependent, growth-inhibitory effect in human GEO colon-cancer cells. We also show that anti-sense MDM2 has a co-operative growth-inhibitory effect with different classes of cytotoxic drugs acting by different mechanisms. Moreover, anti-sense MDM2 induces apoptosis and markedly enhances the apoptotic activity of different cytotoxic drugs. Finally, we show that anti-sense MDM2 has anti-tumor activity in vivo in nude mice bearing GEO xenografts and potentiates the anti-tumor effect of cytotoxic drugs. Indeed, despite the short treatment period, the combination of anti-sense MDM2 and cytotoxic drugs causes a marked delay in tumor growth and prolongation of mice survival, lasting several months after treatment cessation. The anti-tumor effect is associated with inhibition of MDM2 expression in tumor specimens of animals treated with anti-sense MDM2, alone or in combination with a cytotoxic drug. Our results provide the rationale for development of a novel mixed-backbone anti-sense MDM2 into a clinical setting in therapeutic combination strategies with conventional cytotoxic drugs.
Tortora
G
G
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università Federico II, Naples, Italy. gtortora@unina.it
Caputo
R
R
Damiano
V
V
Bianco
R
R
Chen
J
J
Agrawal
S
S
Bianco
A R
AR
Ciardiello
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2