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 | Timothy Madden, PharmD
Research Interests:
Animal models, phase I clinical trials, drug combinations, drug approval |
The future of anticancer therapy will include the incorporation of cytostatic therapy into cytotoxic therapy. While the use of these relatively nontoxic compounds (e.g., antiangiogenic compounds, epidermal growth factor receptor antagonists) may greatly enhance the effects of cytotoxic agents, the sequence in which they are used may substantially affect their respective toxicities and efficacy. In collaboration with Dr. Francis Ali-Osman (Department of Neurosurgery), I have investigated the mechanisms of drug combination sequence synergy. We published a report on the clinical effects of paclitaxel on doxorubicin toxicity and efficacy and performed laboratory investigations of the mechanism by which taxanes potentiate drugs that target topoisomerases I and II. We are now collaborating with Dr. Roy Herbst (Department of Thoracic/Head and Neck Medical Oncology) to investigate the consequences of using drug combinations that include antiangiogenic agents and cytotoxic drugs. Earlier this year, we published the results of a clinical trial demonstrating that TNP-470, a fumagillin analogue, reduced the rate of paclitaxel metabolism when these agents were used in combination. We are currently conducting similar clinical and preclinical studies with C225, IL-1alpha, IFN, and IL-11 in combination with such cytotoxic agents as carboplatin, etoposide, 5-fluorouracil, mitoxantrone, dolastation 10, taxanes, and camptothecin analogues. These studies focus on the effects these monoclonal antibodies have on cell-cycle regulation, alterations in p21 expression, and synergy with the commonly used cytotoxic anticancer agents mentioned here. The results of these trials will be used to develop additional clinical trials to optimize the use of such hybrid approaches to combined therapy.
We continue to develop new strategies to optimize existing therapies as well. Over the past 4 years, we have aided Dr. Borje Andersson (Department of Blood and Marrow Transplantion) in the development of a new busulfan formulation, which can be administered intravenously at high doses as a conditioning regimen for stem cell transplantation. Studies using this formulation have proved the hypothesis that the heterogeneity in drug exposure associated with oral administration of this water-insoluble compound could be abolished with intravenous administration. Comparison of the pharmacokinetics of busulfan when administered in an intravenous formulation versus an oral one demonstrates a consistent fourfold reduction in interpatient variability in busulfan's area under the concentration-versus-time curve. These data have demonstrated for the first time a clear pharmacodynamic relationship between systemic busulfan exposure and the likelihood of graft-versus-host disease, hepatotoxicity, and overall survival.
Selected Publications
Madden T, Tran HT, Beck D, Newman RA, Abbruzzese JL. Novel marine-derived anti-cancer agents: A phase I clinical, pharmacologic and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors. Clin Cancer Res 6:1293-1301, 2000
Shaikenov TE, Adekenov SM, Baker FL, Prashad N, Williams RM, Madden T, Newman RA. Arglabin-DMA, a plant derived sesquiterpine, inhibits farnesyltransferase. Oncol Rep 12:643-650, 2000
Smith JA, Madden TL, Vijjeswarapu M, Newman RA. Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem Pharmacol 62:469-472, 2001
Soefje S, Johansen M, Herzog C, Jaffe N, Gano JB, Kleinerman ES, Madden T. The effect of IL-1alpha on etoposide pharmacokinetics in patients with relapsed metastatic osteocarcoma. Pharmacotherapy, in press
Tran HT, Madden T, Petropoulos D, Worth LL, Felix EA, Sprigg-Sanez HA, Choroszy M, Danielson M, Przepiorka D, Chan KW. Individualizing high-dose oral busulfan: Prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematological malignancies. Bone Marrow Transplant 26:463-470, 2000
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