Early clinical trials of chemopreventive and biologic agents: Designs, populations, and endpoints.

The optimal design for initial clinical trials of chemopreventive agents for cancer has not been determined. A single design is unlikely to be the model for chemoprevention of cancer, even for prevention of a single subtype of cancer, because of the heterogeneity of drugs under investigation and the variety of biologic effects being targeted. Factors that are important in designing initial clinical trials include the proposed mechanisms of drug action, the ability and types of assays available to detect that activity or pharmacodynamic effect, and the extent of prior clinical experience. In this article, we present a discussion of the factors to be considered in initial activity studies, followed by a specific example of early clinical assessment of a noncytotoxic agent (R-flurbiprofen, E-7869) as a potential chemopreventive agent for prostate cancer.

beta-D-Arabinofuran[1',2':4,5]oxazolo-1,3,5-triazine-5-N-methyl-4,6-dione and analogues, unusually specific immunosuppressive agents.

Sequential treatment of the protected beta-D-arabinofuran[1',2':4,5]-2-aminooxazoline (2) with methyl isocyanate and diimidazole carbonyl afforded the 2,2'-anhydro-beta-D-arabinofuranosyl nucleoside, 6. Deprotection and hydrolysis yielded the corresponding arabinoside. Although the anhydronucleoside exhibited in vitro antiviral activity against herpes simplex type 1, it exacerbated the infection in vivo. Further examination uncovered an in vitro inhibition of the induction of a cell-mediated immune response without cytotoxicity.