Assessment of the genotoxic potential of ISIS 2302: a phosphorothioate oligodeoxynucleotide.
ISIS 2302, a phosphorothioate oligodeoxynucleotide with antisense activity against human ICAM-1 mRNA, was evaluated in a battery of tests to assess genotoxic potential. There was no evidence of genotoxicity in three in vitro studies performed: (i) a bacterial reverse mutation test; (ii) a chromosomal aberration test in Chinese hamster ovary cells; (iii) a mammalian cell gene mutation assay in L5187Y cells. Additionally, there was no in vivo evidence of genetic toxicity in a bone marrow micronucleus study in male and female mice. For all tests, top concentrations or doses assessed met harmonized regulatory guidelines. The cellular uptake of ISIS 2302 into target cells was confirmed using capillary gel electrophoresis and immunohistochemistry. Intracellular uptake into CHO cells, L5187Y cells, Salmonella typhimurium TA98 and bone marrow was concentration- and time-dependent. Consistent with what is known about the physical and chemical properties of phosphorothioate oligodeoxynucleotides, there was no evidence of genotoxicity in any of the assessed end-points. Furthermore, the absence of genotoxicity could not be ascribed to test system insensitivity or to an absence of exposure of the test system to ISIS 2302.
Henry
Scott P
SP
ISIS Pharmaceuticals, Carlsbad Research Center, 2292 Faraday Avenue, Carlsbad, CA 92008, USA. shenry@isisph.com
Monteith
D K
DK
Matson
J E
JE
Mathison
B H
BH
Loveday
K S
KS
Winegar
R A
RA
Matson
J E
JE
Lee
P S
PS
Riccio
E S
ES
Bakke
J P
JP
Levin
A A
AA
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D016466:CHO Cells; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019075:Electrophoresis, Capillary; D005260:Female; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D008956:Models, Chemical; D009154:Mutation; D020319:Oligodeoxyribonucleotides, Antisense / Q000633:toxicity*; D009841:Oligonucleotides / Q000633:toxicity*; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger / Q000378:metabolism; D012486:Salmonella typhimurium / Q000378:metabolism; D013873:Thionucleotides / Q000633:toxicity*; D013997:Time Factors
D007166:Immunosuppressive Agents; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger; D013873:Thionucleotides; D004247:DNA; C089753:alicaforsen