Liposome-incorporated Grb2 antisense oligodeoxynucleotide increases the survival of mice bearing bcr-abl-positive leukemia xenografts.
We previously demonstrated that liposome-incorporated antisense oligodeoxynucleotide specific for the grb2 mRNA (L-Grb2) inhibited Grb2 protein expression and the proliferation of bcr-abl-positive leukemia cell lines. To determine whether L-Grb2 has the potential of being a therapeutic modality against bcr-abl-positive leukemia, we studied the tissue distribution of L-Grb2 in normal mice before studying its effects in mice bearing bcr-abl-positive leukemia xenografts. L-Grb2 was widely distributed in the body. The highest tissue concentrations of L-Grb2 were found in the spleen and liver, which are the organs where the tumor mass of bcr-abl-positive leukemia is mainly found. At 4 h post-injection, the amount of L-Grb2 detected per g of tissue was 64 microg in spleen and 50 microg in liver. Intravenous injection of bcr-abl-positive 32D mouse leukemia cells into radiated NOD/scid mice caused a lethal leukemia syndrome; we determined whether L-Grb2 could prolong the survival of mice bearing such xenografts. One day after leukemia cell inoculation, mice received twice weekly intravenous injections of L-Grb2. At an injection dose of 15 mg of L-Grb2 per kg of mouse body weight, 80% of mice treated with L-Grb2 survived to 48 days (end of study) whereas 0% of mice treated with the same dose of liposomal control oligonucleotide survived; the mean survival duration of these groups was 44 and 20 days, respectively. Our data indicate that L-Grb2 prolonged the survival of mice bearing bcr-abl-positive leukemia xenografts. L-Grb2 may be used as a novel cancer therapeutic modality.
Tari
Ana M
AM
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. atari@mdanderson.org
Gutiérrez-Puente
Yolanda
Y
Monaco
Giuseppe
G
Stephens
Clifton
C
Sun
Tong
T
Rosenblum
Michael
M
Belmont
John
J
Arlinghaus
Ralph
R
Lopez-Berestein
Gabriel
G
D000818:Animals; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D007942:Leukemia, Experimental / Q000401:mortality / Q000628:therapy*; D007958:Leukocyte Count; D008081:Liposomes; D051379:Mice; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D008081:Liposomes; D020319:Oligodeoxyribonucleotides, Antisense; D016044:Fusion Proteins, bcr-abl