Table B.2.

Response–Response and temporality concordance for the tool compound etoposide

Concentration of etoposide	MIE In utero DNA topoisomerase II inhibition	KE1 In utero MLL chromosomal rearrangement	AO Infant leukaemia
0.01–0.1 μM, in vitro (TopII enzymes and cells in culture)	+++ (DNA damage response in various cells)	–
0.1–1 μM, in vitro cell cultures	+++ (haematopoietic progenitor and stem cells)	+
0.5–5 μM, ex vivo, mouse fetal liver HSC concentrationa	+++ (inference from MLL cleavage)	+ (only MLL cleavage)	– (no leukaemia development)
Max 5 μM, ex vivo, mouse fetal liver HSC concentrationa	+++ (inference from MLL cleavage)	+ MLL fusions detected only in DNA repair deficient mice	– (no leukaemia development)
Max > 150 μM, plasma concs in etoposide‐treated patientsb	+++ (inference from MLL cleavage)	++ MLL‐AF4 fusion gene and protein	+ treatment‐related acute leukaemia

^aA range of concentrations is linearly extrapolated on the basis of the concentration of 5 μM after the dose of 10 mg/kg.

^bPlasma concentration of etoposide cannot be directly extrapolated to the concentration at the active site. Probably the actual active cellular concentrations of etoposide is much lower, perhaps 10% or less of the plasma concentration.