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.
Imexon Enhances Gemcitabine Cytotoxicity By Inhibition Of Ribonucleotide Reductase. Source: Cancer Chemotherapy And Pharmacology
PURPOSE:<br>Gemcitabine (GEM) is currently the standard first line treatment for pancreatic cancer; however, the overall survival of patients with this disease remains poor. Imexon is a pro-oxidant small molecule which produced a high response rate in combination with GEM in a phase I trial in pancreatic cancer. In this study, we investigate the combination of GEM with a novel redox-active agent, imexon, in vitro and in vivo.<br><br>METHODS:<br>Median effect analysis was used for in vitro combination cytotoxicity. The effect of imexon on GEM metabolism and uptake into cells and into DNA and effects on ribonucleotide reductase (RNR) were examined in vitro. The pharmacokinetics and antitumor efficacy of the imexon/GEM combination was evaluated in mouse models.<br><br>RESULTS:<br>In three human pancreatic cancer lines, there was additivity for the imexon/GEM combination. There was significantly greater efficacy for the drug combination in Panc-1 xenograft tumors. A pharmacokinetic study in mice showed a near doubling in the AUC of imexon when GEM was co-administered, with no effect of imexon on GEM's pharmacokinetic disposition. In vitro, imexon did not alter GEM's metabolism or uptake into DNA, but significantly inhibited RNR, and this effect was greater when combined with GEM.<br><br>CONCLUSIONS:<br>These results suggest that the interaction between imexon and GEM may be due to complimentary inhibition of RNR plus an enhanced exposure to imexon when the GEM is administered in vivo. This combination is currently being tested in a randomized phase II trial in pancreatic cancer.<br><br>
A Phase I Study Of Imexon Plus Gemcitabine As First Line Therapy For Advanced Pancreatic Cancer. Source: Cancer Chemotherapy And Pharmacology
PURPOSE:<br>Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer.<br><br>METHODS:<br>Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) IV over 30 min on days 1, 8, and 15 every 28 days).<br><br>RESULTS:<br>One hundred five patients received 340 treatment cycles (median 2, range 1-16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics.<br><br>CONCLUSIONS:<br>The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.<br><br>