In vivo pro-apoptotic and antitumor efficacy of a c-Raf antisense phosphorothioate oligonucleotide: relationship to tumor size.
Previously, we have shown that a phosphorothioate antisense oligonucleotide (ODN) targeted against c-raf RNA (ISIS5132; cRaf-AS) induces apoptosis in human tumor cells. We now show that the same ODN also efficiently triggers apoptosis in human tumor xenografts in nu/nu mice. Although cRaf-AS showed a clearly inhibitory effect on the growth of established tumors (approximately 150 mm3) compared to a mismatched control ODN (MM), tumor progression was not prevented. This correlated with a partial refractoriness of the tumor to cRaf-AS-induced cell killing, which seemed to be due to an inhomogeneous and inefficient penetration of the ODN into the tumor tissue rather than cellular resistance. In agreement with this conclusion, we found that growth of small tumors (<50 mm3) was completely inhibited concomitantly with an accumulation of the ODN throughout the tumor. These data show that the cRaf-AS is a highly efficacious antitumor agent, provided accessibility into the tumor tissue is warranted, and suggest that PS-AS-ODN treatment may be particularly useful in an adjuvant setting.
Lau
Quek Choon
QC
Institute of Molecular Biology and Tumor Research, Philipps University, Marburg, Germany.
Achenbach
Tatjana V
TV
Borchers
Oliver
O
Müller
Rolf
R
Slater
Emily P
EP
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D013873:Thionucleotides / Q000737:chemistry / Q000494:pharmacology*
D016376:Oligonucleotides, Antisense; D009943:Organophosphorus Compounds; D013873:Thionucleotides; D019908:Proto-Oncogene Proteins c-raf