Differential effects of FR900482 and FK317 on apoptosis, IL-2 gene expression, and induction of vascular leak syndrome.
Vascular leak syndrome (VLS) is a harmful side effect that resulted in withdrawal of the antitumor drug FR900482, but not FK317, from clinical trials. Here we present chromatin immunoprecipitation data showing that FK317, like FR900482, crosslinks minor-groove binding proteins to DNA in vivo. However, these drugs differ in how they induce cell death. We demonstrate that, whereas FR900482 induces necrosis, FK317 induces a necrosis-to-apoptosis switch that is drug concentration dependent. Northern blot analyses of drug-treated cells suggest that this "switch" is mediated, at least in part, by modulation of the expression levels of Bcl-2. Additionally, FR900482, in contrast to FK317, induces the expression of known elicitors of both Bcl-2 gene expression and VLS. These findings provide plausible explanations for why these structurally similar drugs have different biological effects, especially with respect to VLS.
Beckerbauer
Lois
L
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
Tepe
Jetze J
JJ
Eastman
Rebecca A
RA
Mixter
Philip F
PF
Williams
Robert M
RM
Reeves
Raymond
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019559:Capillary Leak Syndrome / Q000139:chemically induced*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells / Q000187:drug effects; D008969:Molecular Sequence Data; D009336:Necrosis; D010078:Oxazines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D007376:Interleukin-2; D010078:Oxazines; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C053335:FR 900482; C112463:FK 317 dihydrobenzoxazine; D004247:DNA