4-imino-1-3-diazabicyclo(3.1.0)hexan-2-one and Neoplasms

Redox regulation has been shown to be an important component of malignant cell survival. Tipping the cellular redox balance through pharmacologic regulation in favor of increasing intracellular reactive oxygen species (ROS) and/or depleting protective reducing metabolites (such as glutathione and nicotinamide adenine dinucleotide phosphate) may lead to oxidative stress and resultant induction of apoptosis for the treatment of cancer. We review the biology and importance of ROS with regard to malignant and normal cells. Moreover, we discuss pre-clinical and clinical data regarding novel therapeutic agents that modulate the cellular redox system including buthionine sulfoximine, ascorbic acid, arsenic trioxide, imexon, and motexafin gadolinium as single-agents and in combination. Continued research is needed to better understand the mechanisms and specific apoptotic pathways involved in ROS-induced cell death, as well as, to determine the most rationale and effective combination of redox-active agents.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Buthionine Sulfoximine; Cell Death; Dose-Response Relationship, Drug; Glutathione; Hexanones; Humans; Metalloporphyrins; Models, Biological; Models, Chemical; Neoplasms; Oxidation-Reduction; Oxidative Stress; Oxides; Reactive Oxygen Species

Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers.. Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays.. There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at 750 mg/m2/d.. The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Female; Half-Life; Hexanones; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms

Topics: Antineoplastic Agents; Hexanones; Humans; Immunologic Factors; Neoplasms; Treatment Outcome

Following the demonstration that addition of a 2-cyano group to aziridines prevented DNA alkylation and thus reduced toxicity, many novel 2-cyanoaziridines were synthesized and evaluated as immunomodulating and antitumor agents. They typically reacted with thiols such as cysteine, depleting them and allowing the accumulation of reactive oxygen species. Two of these compounds, azimexon and ciamexon, showed activity against tumors in clinical trials. Imexon was produced by cyclization of 2-cyanoaziridine-1- carboxamide in the presence of hydroxide ions. The two enantiomers were prepared by a process involving chiral chromatography. They were equipotent against cultured tumor cells. Imexon also reacts with thiols and it is especially potent against multiple myeloma in cell cultures. An efficient chemical synthesis and a lyophilization formulation of imexon as a water soluble, injectible drug, were developed. In Phase I and I/II clinical trials imexon showed hints of activity against a variety of tumors, but a randomized double-blind Phase II trial of imexon plus gemcitabine versus gemcitabine alone in pancreatic cancer showed no enhancement of activity above that of gemcitabine alone. This result was disappointing because in cell culture and mice the two compounds were synergistic. Based on a complete response in a Phase I trial, a new Phase II clinical trial of imexon is underway in non-Hodgkins lymphoma.

Topics: Animals; Antineoplastic Agents; Aziridines; Clinical Trials as Topic; Hexanones; Humans; Immunomodulation; Mice; Neoplasms

Topics: Antineoplastic Agents; Chemistry, Pharmaceutical; Deoxycytidine; Doxycycline; Drug Industry; Drug Synergism; Gemcitabine; Hexanones; Humans; Neoplasms; Tetracyclines

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cytochromes c; Drugs, Investigational; Glycolysis; Hexanones; Humans; Mitochondria; Mitochondrial Proton-Translocating ATPases; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides