Immunomodulatory oligonucleotides as novel therapy for breast cancer: pharmacokinetics, in vitro and in vivo anticancer activity, and potentiation of antibody therapy.
Oligonucleotides containing CpG motifs and immunomodulatory oligonucleotides (IMO) containing a synthetic immunostimulatory dinucleotide and a novel DNA structure have been suggested to have potential for the treatment of various human diseases. In the present study, a newly designed IMO was evaluated in several models of human (MCF-7 and BT474 xenograft) and murine (4T1 syngeneic) breast cancer. Pharmacokinetics studies of the IMO administered by s.c., i.v., p.o., or i.p. routes were also accomplished. The IMO was widely distributed to various tissues by all four routes, with s.c. administration yielding the highest concentration in tumor tissue. The IMO inhibited the growth of tumors in all three models of breast cancer, with the lowest dose of the IMO inhibiting MCF-7 xenograft tumor growth by >40%. Combining the IMO with the anticancer antibody, Herceptin, led to potent antitumor effects, resulting in >96% inhibition of tumor growth. The IMO also exerted in vitro antitumor activity, as measured by cell growth, apoptosis, and proliferation assays in the presence of Lipofectin. This is the first report of the pharmacokinetics of this agent in normal and tumor-bearing mice. Based on the present results, we believe that the IMO is a good candidate for clinical development for breast cancer therapy used either alone or in combination with conventional cancer therapeutic agents.
Wang
Hui
H
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Boulevard, 113 Volker Hall, 35294, USA.
Rayburn
Elizabeth R
ER
Wang
Wei
W
Kandimalla
Ekambar R
ER
Agrawal
Sudhir
S
Zhang
Ruiwen
R
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009841:Oligonucleotides / Q000276:immunology* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D009841:Oligonucleotides; D000068878:Trastuzumab