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At least 19 recordsLinked to original sources
PubMed1990

DNA repair induced by various mutagens in rat hepatocyte primary cultures measured in the presence of hydroxyurea, guanazole or aphidicolin.

Guanazole and aphidicolin were chosen as candidates in the search for a selective, non-genotoxic inhibitor of DNA replication which could be used instead of hydroxyurea to measure DNA repair synthesis in rat hepatocyte primary cultures by liquid scintillation counting. The genotoxicity of these 3 chemicals was studied using the Salmonella/liver homogenate assay and the autoradiographic UDS test in hepatocytes. Hydroxyurea was positive in both of these assays. Guanazole and aphidicolin did not induce DNA repair in hepatocytes. Aphidicolin was not mutagenic for Salmonella typhimurium, whereas guanazole increased the revertant numbers of strain TA102 slightly. The incorporation of [3H]thymidine was measured by liquid scintillation to determine DNA repair induced by 2-acetylaminofluorene (2-AAF), aflatoxin B1, benzo[a]pyrene, cyclophosphamide, H2O2, 6-hydroxydopamine, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methylnitrosourea (MNU), 4-nitroquinoline-N-oxide and UV irradiation in the presence of either 10 mM hydroxyurea, 15 mM guanazole or 0.015 mM aphidicolin. Aphidicolin had an inhibitory effect on DNA repair. Except for the 3 chemicals mentioned below, the sensitivity of the DNA repair measurement was the same, no matter whether hydroxyurea or guanazole was used to inhibit replicative DNA synthesis. In the presence of hydroxyurea, DNA repair synthesis was found at lower concentrations in the case of aflatoxin B1, due to differences in the solvent control values, and in the case of H2O2, possibly due to a synergistic effect between hydroxyurea and H2O2. Guanazole allowed the detection of DNA repair induced by MNNG at lower concentrations, probably because of an antagonistic effect between hydroxyurea and MNNG. Based on these results, it was concluded that guanazole, but not aphidicolin, could be used instead of hydroxyurea to measure DNA repair synthesis by liquid scintillation in rat hepatocyte primary cultures. Although guanazole does not completely fulfill the criteria for an ideal DNA replication inhibitor, it has the advantage of being less genotoxic than hydroxyurea, and also appears to have a smaller potential to falsify the results by interacting with the test compounds.

Animals↗
PubMed1976

A comparative clinical trial of 5-azacytidine and guanazole in previously treated adults with acute nonlymphocytic leukemia.

Adults with previously treated acute nonlymphocytic leukemia received either 5-azacytidine or guanazole in a randomized study. Eighteen patients were treated with 5-azacytidine at a dosage of 200-250 mg/m2/day X 5 intravenously (i.v.) and six achieved a remission (five complete). The median duration of complete remission was 100 days. Among the 12 patients who received guanazole, at a dosage of 25-30 g/m2/day X 5 by continuous i.v. infusion, only one partial remission ensued. Pm 600 WBC/mm3) than nonresponders (median 1700 WBC/mm3). Both the time taken to reach the nadir white blood coung (median, 14 days) and theduration of the nadir (median, 17 days) were long after each course of 5-azacytidine, particularly for those patients who achieved a remission. Principal toxicities seen after 5-azacytidine administration were gastrointestinal tolerance, fever, and neuromuscular toxicity. Fever was the principal toxicity observed after guanazole therapy; one patient developed erythema nodosum with arthralgias and another, recurrent pulmonary infiltrates. Survival from the start of therapy was clearly longer for the patients receiving 5-azacytidine (median 140 days) because of the prolongation of survival seen in the responding patients (median 266 + days). 5-Azacytidine has significant activity as an induction agent in adults with acute nonlymphocytic leukemia, but guanazole does not appear to be of particular value for patients with this disease.

Acute Disease↗
PubMed1975

A simple method for long-term drug infusion in mice: evaluation of guanazole as a model (38488).

A simplified technique for iv infusion in unrestricted DBA/2-J inbred mice has been described. The method, which involves direct cannulation of the tail vein with polyethylene tubing, is suitable for routine use. Guanazole, an antileukemic agent with a short plasma half-life, was evaluated as a model compound. After administration for 47 hr at the rate of 0.3 ml/hr, guanazole (30 mg/ml) caused a marked inhibition of incorporation of 14 C-uridine, administered 15 min before sacrifice, primarily into DNA of spleen, thymus and bone marrow in decreasing order. Inhibition of incorporation into RNA was less marked but followed a similar pattern. The effects on the incorporation of uridine in nucleic acids of kidney, heart and brain were minimal. Increased incorporations into RNA and DNA occurred in liver. The data for the hemopoietic and lymphoid organs, namely spleen, thymus and marrow, are consistent with the reported immunosuppressive and mylelosuppressive effects of the drug and also with the inhibition of ribonucleoside diphosphate reducaste by guanazole.

Animals↗
PubMedDate not supplied

Guanazole (NSC-1895)--a phase I clinical study.

Two dose schedules of guanazole were used in this phase I clinical study: intermittent prolonged 5-day infusion and intermittent iv bolus twice weekly. Ninety-seven treatment observations were analyzed for toxic effects resulting from the prolonged infusion and 42 from the twice-weekly bolus schedule. The main toxic effect was bone marrow suppressions, the frequency and severity of which were intensified by prior chemotherapy or radiotherapy and repetition of guanazole therapy. The leukocyte count was affected more than the platelet count. Partial responses were observed in four patients: two with lung carcinoma, one with prostate carcinoma, and one with melanoma. Further phase II clinical studies of guanazole are indicated.

Clinical Trials as Topic↗
PubMed1975

Pharmacokinetics of guanazole in patients with acute myelocytic leukemia.

Levels of guanazole (GZ) in plasma and packed cells were determined after a single tracer dose of 14C-guanazole or during a 5-day continuous intravenous therapeutic infusion of unlabeled drug to 5 patients with acute myelocytic leukemia (AML). The levels of unlabeled drug were determined colorimetrically. GZ infected as a tracer dose was rapidly distributed in an apparent volume of 0.61 l/kg, which is somewhat less than that of total body water, and the drug appeared to be eliminated essentially unchanged by glomerular filtration. The mean apparent volume of distribution increased by about 15% during infusion. An increase of 60% was also noted in the half-life (t1/2) values, with a concimitant decrease in the mean value of renal clearance rate by 40%, except in 1 case. The study demonstrates that monitoring levels of guanazole is possible during infusion therapy and indicates that the data could be used to evaluate pharmacokinetic parameters predicting the time-course of such levels in patients.

Adult↗