Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred <i>in vitro</i>, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα <i>in vivo</i> In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized.
TNF-related apoptosis-inducing ligand receptor 2 [TRAIL-R2 or death receptor 5 (DR5)] is expressed at elevated levels in a broad range of solid tumors to mediate apoptotic signals from TRAIL or agonist antibodies.
TRAIL delivery by E. coli DH5alpha did not cause any detectable toxicity to any organs, suggesting that E. coli DH5alpha-delivered sTRAIL protein therapy may provide a feasible and effective form of treatment for solid tumors.
Hypoxia is an important feature of solid tumors that renders tumor cells resistant to some chemotherapeutic agents, including TRAIL, and we therefore investigated the role of hypoxia in TRAIL receptor expression in human colon cancer cells.
Preclinical studies in mice and nonhuman primates showed no systemic cytotoxicity upon injection of recombinant TNF-related apoptosis-inducing ligand (TRAIL) at doses that effectively suppressed solid tumors such as colon and mammary carcinomas.
These results further define Ad5-TRAIL as a novel anti-tumor therapeutic and demonstrate its potential use as a means for treating prostate tumors, as well as other solid tumors, in vivo.