Reductive activation of diaziquone and possible involvement of free radicals and the hydroquinone dianion.

To analyze the mode of action of diaziquone [AZQ] on DNA, we examined the activity of two AZQ analogues and N,N',N"-triethylenethiophosphoramide on three forms [supercoiled (Form I), open circular (Form II), and linear (Form III)] of PM-2 DNA. The AZQ analogues contained chlorine atoms which substituted either the carbethoxyamino groups or the aziridine groups of the parent compound. N,N',N"-triethylenethiophosphoramide is a triaziridine compound containing pentavalent phosphorus instead of a quinone group. We found that only when reduced with sodium borohydride did AZQ change the topology of the three forms of PM-2 DNA by introducing mainly single strand breaks. The AZQ analogue containing only aziridines (RQ2) was active in both its oxidized and its reduced forms, while the analogue containing only the carbethoxyamino groups (RQ14) or N,N',N"-triethylenethiophosphoramide were not active in either form. Under similar experimental conditions, Adriamycin alone altered the electrophoretic mobility of PM-2 DNA, while borohydride reduced Adriamycin did not. By using electron spin resonance spectroscopy, we showed that dihydrodiaziquone (AZQH2) oxidizes to the semiquinone in the presence of oxygen. Although AZQH2 was active against DNA, it was not active against cellular DNA synthesis as measured by [3H]thymidine incorporation into exponentially growing HEp-2 cells. However, AZQ alone prevented [3H]thymidine incorporation into HEp-2 cells. We found that HEp-2 cells have the ability to reduce AZQ to its free radical anion, but AZQH2 does not autoxidize to the free radical in the presence of cells. The reductive ability of HEp-2 cells may be responsible in part for preventing the oxidation of AZQH2 to the free radical. We found that under our conditions (1-h incubations) the aziridines are essential for the activity of aziridinyl quinones against PM-2 DNA and that in the case of AZQ the hydroquinone is also required.

The chemical reduction of diaziquone: products and free radical intermediates.

Sodium borohydride reduced diaziquone (AZQ) can cause cross-links between DNA molecules, between DNA and proteins and cause single- and double-strand DNA breaks. In order to understand these effects better, we investigated the reduction of diaziquone by borohydride, and looked at reaction products. We found that a major product was formed during the oxidation of the colorless 2-electron reduced AZQ, and that this product was a monoaziridinyl quinone. We interpret this result to mean that both the leaving aziridine as well as the remaining one can alkylate. This mode of alkylation does not explain cross-links which may occur by a different mechanism requiring simultaneous opening of the aziridine rings. Most of the antitumor activity of borohydride reduced AZQ is probably exerted during the oxidation of the 2-electron reduced AZQ (AZQH2).

Overuse of acid-suppressive therapy in hospitalized patients.

OBJECTIVES: The aims of this study were 1) to determine the frequency of use and indications for prescription of acid-suppressive medications in hospitalized patients, and 2) to determine whether patients who are prescribed these medications for stress ulcer prophylaxis are prescribed them on hospital discharge. METHODS: The use of acid-suppressive medications (histamine-2 receptor antagonists, proton pump inhibitors, and barriers--specifically, famotidine, omeprazole, and sucralfate) was assessed in 226 patients admitted consecutively to a general medical nursing unit of an urban, community, teaching hospital. Chart review was undertaken to determine the type of medication used, timing of prescription, and indication for use. RESULTS: Of hospitalized patients, 54% were receiving acid-suppressive therapy. Histamine-2 receptor antagonists were used most frequently (62%). In all, 65% of prescriptions were not indicated as determined by consensus review. Among patients put on acid-suppressive therapy for ulcer prophylaxis, 55% were discharged on the therapy. CONCLUSIONS: There is significant overuse of acid-suppressive therapy in hospitalized patients. The problem of placing low-risk patients on ulcer prophylaxis unnecessarily is compounded by discharging these patients with the medication.