Department of Pharmacology Faculty
Trevor W. Sweatman, Ph.D.
Room 421 Crowe Research Building
- Hatfield Polytechnic, Hertfordshire, England B.Sc.(Hons) 1976 Applied Biology
- Southampton University Medical School, Hampshire, England
Ph.D. 1981 Pharmacology
Despite the promise that gene therapy holds for certain human conditions, drug therapy will continue to provide the most significant patient benefit for the foreseeable future. Doubtless, human genomic research will prove an invaluable tool in identifying genetic variability in drug receptor number and function, thereby providing the means to a more individualized approach to drug therapy. Nevertheless, there will remain a strong impetus for 1, new delivery techniques for the existing chemotherapeutics, and 2, the development of new mechanistically novel drug therapies.
These two aspects are the focus of my research endeavours here at UTHSC, which are directed primarily at developmental chemotherapeutics belonging to the class of agents known as anthracyclines.
Whether employed alone or in combinatorial treatment regimens, anthracycline antitumor agents such as doxorubicin (Adriamycin®), the prototypical agent, remain amongst the most effective drugs for certain malignancies. Unfortunately, the original anthracycline antitumor agents suffer from a number of well known and significant drawbacks including their being substrates for the p-glycoprotein (P-gp) drug efflux mechanism associated with cellular drug resistance and the unfortunate ability to produce dose-dependent cumulative cardiotoxicity. Thus, considerations of toxicity and efficacy have, over the past 3-decades, driven the worldwide efforts at the development of new anthracycline antitumor agents.
The failure of antitumor agents to eradicate disease can be attributed to many variables including pharmacologic drug sanctuary and drug resistance. Total drug administration is usually limited by considerations of drug toxicity, e.g. myelosuppression which can be both debilitating and life-threatening. For these several reasons, the option of localized drug-delivery, either via arterial access or by drug placement is particularly appealing as, theoretically, it maximizes tumor drug exposure while minimizing both total drug dose and subsequent systemic toxicity. With regard to direct drug placement, my laboratory has a longstanding interest in intraglandular and intralesional drug administration. This work which involves proof of concept in appropriate models as well as pre-clinical and clinical pharmacology studies was recently used to good effect as part of the FDA approval process for valrubicin (Valstar®). This clinical agent is used to treat superficial carcinoma of the bladder, by direct intravesical instillation. Further developmental work is now underway with this novel anthracycline for direct intratumoral injection vs. prostatic tumors and unresectable tumors of the head and neck. Recent work has shown a good synergistic effect of valrubicin with irradiation, the latter being a common treatment modality for both of these tumor types. Presently we believe this synergism is related to one of the mechanisms of action of valrubicin, as outlined below. Further proof of concept studies with intratumoral valrubicin continue presently.
Mechanistically novel drug therapies
Most traditional antitumor agents produce cell death via cellular targets located within the nucleus. This is certainly true for classical anthracyclines like doxorubicin which intercalate with DNA and produce DNA topoisomerase inhibition. However, our studies have shown that structural modifications to the anthracycline structure can profoundly impact upon the mechanism(s) of cytotoxicity that these novel congeners produce. Thus, defined structural components of valrubicin and AD 198 (N-benzyladriamycin-14-valerate) have recently been shown to directly modulate the action of protein kinase C (PKC) through an interaction with the C1 regulatory domain. This interaction can result in rapid apoptotic cell death, an event unaffected by over expression of the anti-apoptotic protein, BCl-2, or significant synergism with tumor or cell low dose irradiation. Structure-activity studies are now underway in my laboratory to establish those features of the drug congeners which are responsible for these PKC effects. This work is multidisciplinary and involves biochemical and cellular studies of drug action, molecular studies of downstream cellular events arising from drug exposure, PKC-ligand molecular modeling and metabolic studies of drug accumulation and persistence. The long-term goal is to develop a new class of antitumor agents that incorporate PKC modulation as a part of their overall cytotoxic mechanism(s). These studies are being conducted in close collaboration with my longstanding colleagues, Dr. Mervyn Israel and Dr. Leonard Lothstein here at UT-Memphis and, for molecular modeling, with Dr. Abby Parrill at the University of Memphis.