Biol. Pharm. Bull. 28(7) 1259—1264 (2005)

anticancer drug that acts via inhibiting protein kinase C (PKC) and cyclin-dependent kinase 2 (CDK2). In pre-clinical studies, the compound exhibited potent anti-tumor effects both in vitro and in vivo. During clinical evaluation, the plasma concentrations of UCN-01 were much higher than predicted from non-clinical studies in experimental animals. The unexpectedly high plasma concentrations of UCN-01 in humans were explained by specific, high affinity binding of the compound to human a1-acid glycoprotein (hAGP); UCN-01 did not bind significantly to rat AGP, dog AGP or human serum albumin. In general, only unbound drug can traverse biological membranes and produce a pharmacological effect and, therefore, the therapeutic activities of drugs usually correlate with the concentration of unbound drug in blood. Thus, high affinity binding to hAGP may prevent UCN-01 being delivered to the cytoplasm of the tumor and interacting with the target molecules, PKC and CDK2. When the plasma molar concentrations of UCN-01 are less than those of hAGP, all the administered UCN-01 would be present in the hAGPbound form. Free UCN-01 would appear in blood only when the plasma molar concentrations of UCN-01 are above the hAGP levels. Consequently, administration of high doses of UCN-01 to patients would be required to provide free UCN-01 in plasma and to exhibit antitumor activity. However, high doses of UCN-01 must be administered with caution because interpatient variation in AGP levels is relatively large; therefore, some patients are likely to exhibit rapid increases in the concentration of free UCN-01 in blood and consequently be at risk from severe side effects. Additionally, the problem of inconsistent levels of AGP may be compounded by the possibility of intrapatient variation that can occur in several disease states, including cancer, depression, rheumatoid arthritis and severe burns. Therefore, in order to avoid side effects, hAGP should be measured in each patient prior to administration of high doses of UCN-01 and the concentration of free UCN-01 should be monitored after administration of the drug. It may also be necessary to administer the drug using a dose escalation protocol to ensure that the total plasma concentration of UCN-01 is comparable or exceeds hAGP levels in each patient thereby providing concentrations of free drug in plasma that can produce therapeutic benefit but are not sufficiently high to cause side effects. Thus, although UCN-01 is a promising drug, the high affinity binding to hAGP may compromise straightforward therapeutic application of the drug to provide safe and effective treatment. Therefore, we considered approaches that might negate the effect of high affinity binding of UCN-01 to hAGP. Encapsulation of UCN-01 in liposomes was proposed as a possible method of avoiding the therapeutic impact of the high affinity binding of UCN-01 to hAGP. Liposomes, especially polyethylene glycol (PEG) liposomes, are widely used as carriers for many anticancer drugs such as doxorubicin and cisplatin. In general, encapsulation into PEG liposomes increases the efficacy and decreases the side effects of anticancer drugs because the drugs are delivered preferentially to tumor tissue due to the enhanced permeability and retention effect. In addition, encapsulation in liposomes can prevent drugs interacting directly with blood components; for example, topotecan and antisense oligonucleotides are unstable in blood but degradation is reduced July 2005 Biol. Pharm. Bull. 28(7) 1259—1264 (2005) 1259