This laboratory investigates the pharmacology of new anticancer agents and chemopreventive agents, including: 1)mechanisms of action; 2)antitumor effects in human tumor cells in vitro and in small animal (rodent) models; 3)pharmacokinetic disposition of new agents in animals and in human clinical trials; and 4)toxicologic effects of these agents in vitro and in vivo. 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.
Mechanism of action studies performed in the laboratory include assessments of covalent and non-covalent DNA binding, inhibition of topoisomerase enzyme systems, and perturbation of cellular redox defense systems such as the glutathione-based transferase, reducatse and peroxidase enzymes. Disruption of the mitochondrial membrane potential also is investigated as a triggering event for apoptotic cell death from anticancer agents.
Clinical pharmacokinetic studies of anticancer drugs are investigated using high-performance liquid chromato-graphy and other analytical methods to quantitate anticancer drug levels in the plasma of patients treated with refractory cancers. These studies include the analysis of the impact of resistance-modulating agents of anthracycline drug disposition in patients with hema-tologic malignancies. Modulators such as cyclosporin A and its D-analog, valspodar (PSC-833), have been shown to significantly reduce the clearance of daunorubicin and iâ€™s metabolite, daunorubicinol, in patients with resistant acute myeloid leukemias. Other drugs that are assayed in clinical specimens include the alkylating agents melphalan and mitomycin C; the anthracyclines daunorubicin, doxorubicin, and mitoxantrone; and in bone marrow transplant patients, the topoisomerase II inhibitor etoposide.