Val-12 E37G, an activator of RalGDS, had no survival effect on either death pathway, similar to RasS17N, the full survival antagonist. Thus, Ras provides two independent survival pathways each of which inhibits a distinct apoptotic mechanism. Our study presents one of the few clear-cut cases where only the Ras/ ERK, but not the Ras/PI3K/Akt pathway, plays a dominant survival signaling role.

Interferon-␣ (IFN-␣) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-␣ makes frequent dosing (daily or three times weekly) over an extended period (6 -12 months or more) necessary. To improve the pharmacokinetics of IFN-␣ and decrease dosing frequency, IFN-␣ was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-␣ showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-␣. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 g/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 g/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-␣ given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated doserelated antiviral activity for Ն8 days based on an in vitro bioassay, whereas antiviral activity from IFN-␣-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2Ј,5Ј-oligoadenylate synthetase mRNA relative to IFN-␣-or vehicle-treated animals were maintained for Ն10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-␣.

BR96-Dox provides a unique strategy to deliver doxorubicin to Le(Y)-expressing tumor and was well tolerated at doses of 700 mg/m(2) every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.