Unlike the toxicity difference between (RX) 8 À and (rX) 8 ÀPMO, the L!D replacement did not change the toxicity of (RXR) 4 ÀPMO ( Figure 6 ). Substitution of either one R (rXR) or two R (rXr) from the RXR repeat neither reduced nor increased the toxicity profile of (RXR) 4 ÀPMO. At this point, we do not fully understand the mechanisms of (RXR) 4 À and (RX) 8 ÀPMO conjugate toxicity, but look forward to studying this topic further.