Enhancing Cancer Therapy with Nano-Delivery Systems
- B.S. in Chemistry, University of California, Los Angeles, 1970
- M.S. in Chemistry, University of California, Santa Barbara, 1972
- Ph.D. in Chemistry, State University of New York, Buffalo, 1976
Tumor necrosis factor, drug carriers, sphingolipids, drug copolymers
Tumor necrosis factor (TNF) has been identified as a major molecular effector of several inflammatory and immunological reactions. Furthermore, because of its antitumor effects in vivo in a number of syngeneic and xenogeneic murine tumor models, TNF has been evaluated clinically using both systemic and, more recently, locoregional administration, typically in combination with hyperthermia and chemotherapy. The results of regional administration indicate that toxic effects observed systemically can be tolerated using TNF levels sufficient to achieve a clinically positive outcome. We are studying the molecular basis for TNF / chemotherapy / hyperthermia interactions involved in tumor necrosis and apoptosis.
Mechanistic studies have revealed possible therapeutic targets by demonstrating the potency of particular sphingolipids in apoptosis induction, despite the existence of certain cellular resistance mechanisms. For example, human melanoma or soft tissue sarcoma cell lines that demonstrate complete resistance to TNF nevertheless are susceptible to exogenous ceramide- or sphingosine-mediated cytotoxicity. Furthermore, in a murine leukemia model of p170 glycoprotein-mediated multidrug resistance, these sphingolipids also induced apoptotic responses in the drug-resistant cell line even though the susceptibility to doxorubicin in this cell line was approximately two logs lower than that in the parental line.
In addition to these mechanistic studies, we are attempting to develop a strategy to induce apoptosis by targeting exogenous sphingolipids to tumors in vivo. This is a new and particularly attractive approach, in light of our observations that these sphingolipids can induce apoptosis / cytotoxicity in vitro in tumor cells that have one or more mechanisms of multidrug resistance.
We have also evaluated new paclitaxel copolymer formulations in Taxol-resistant human ovarian carcinoma nude mouse xenograft models. These formulations improved survival and even achieved some cures in these models. It is our goal to establish the mechanistic basis for the superior therapeutic profile of these paclitaxel copolymers compared to Taxol.
Another area of our research involves an international collaboration studying the mechanism of pro-TNF processing and the role of its leader sequence. We have determined that pro-TNF is present as a homotrimer in the endoplasmic reticulum immediately after synthesis and that this trimerization is required for its biological activity. Furthermore, all of the cytoplasmic domain and about half of the transmembrane domain of the pro-TNF leader sequence can be eliminated without affecting sorting to or orientation in the membrane or maturation to the secreted form. Thus, the highly conserved leader must play an as-yet-unknown role. More recently we have established that human pro-TNF is palmitoylated, despite the existence of the hydrophobic transmembrane domain. We are interested in determining if there is a role for this lipid in TNF downstream signaling.
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