Robert T. Dorr

Professor of Pharmacology and
Director, Pharmacology Research Program, Arizona Cancer Center
Ph.D., University of Arizona, 1984

Arizona Cancer Center 4963C
(520) 626-7892
bdorr@azcc.arizona.edu

Research Interests

We investigate the pharmacology of new anticancer agents and chemopreventive agents, including

• mechanisms of action
  
• antitumor effects in human tumor cells in vitro and in small animal (rodent) models
  
• pharmacokinetic disposition of new agents in animals and in human clinical trials
  
• toxicologic effects of these agents in vitro and in vivo.
  

Research Activities

New antitumor agents under study include a series of redox-active derivatives of 2-cyanoaziridine that were derived from an original imminopyrolidone compound called imexon. Imexon has been shown to have unique activity in the B-cell bone marrow disease, multiple myeloma. Unique features of imexon include the lack of myelosuppression and a novel mechanism of action involving binding to thiols and perturbation of redox systems in the cell leading to apoptosis. Mitochondrial thiols appear to be selectively targeted by the agents in this series, many of which have broader antitumor activity than the parent compound, imexon.

A second group of compounds are DNA-binding drugs derived from anthracenes (more than 100 synthesized) or from mitomycin C. The anthracenes, which intercalate into DNA and impair topoisomerase II enzymes, have shown activity in breast cancer. The mitosene derivatives, which cross-link DNA, have activity in melanomas and other solid tumors. Molecular structure-activity relationships have been developed for each series of agents, which are targeted to tumors refractory to existing classes of antitumor agents.

Chemopreventive drugs under development include the green tea derivative, EGCG, which is a potent antioxidant polyphenolic agent found in green tea. This agent was shown to be well tolerated when applied topically to mice receiving simulated solar exposure. It also has favorable topical pharmacokinetics: stable in a cream base and able to penetrate into skin but not be absorbed through the skin, thereby preventing systemic toxicity to the liver seen with an injectable drug. Another topical antioxidant under development to prevent skin cancer is the creosote bush derivative NDGA, which has been shown to prevent DNA synthesis in tumor cells by a mechanism currently being investigated.

Selected Publications

Chow H-H S, Cai Y, Alberts DS, Hakim I, Dorr RT, Shahi F, Crowell JA, Yang CS, Hara Y. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E1. Cancer Epidemiology, Biomarkers & Prevention 10: 53-58, 2001.

Taylor CT, Dorr RT, Fanta P, Hersh EM, Salmon SE: A phase I and pharmacodynamic evaluation of polyethylene glycol-cojugated L-asparaginase in patients with advanced solid tumors. Cancer Chemother Pharmacol 47: 83-88, 2001.

Dorr RT, Karanes C, Spier C, Grogan T, Greer J, Moore J, Weinberger J, Schiller G, Pearce T, Litchman M, Dalton W, Roe D, List AF: Phase I/II Study of the P-Glycoprotein Modulator PSC 833 (Valspodar) in Patients with Acute Myeloid Leukemia. J Clin Onc 19(6): 1589-1599, 2001.

Xing C, Wu P, Skibo EB, Dorr RT. Design of cancer-specific antitumor agents based on aziridinylcyclopent [b]indoloquinolones. J Med Chem 43(3):457-466, 2000.