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PubMed1986

[Antitumor effect of 1,3,3,5,5-pentaziridino-1-thia-2,4,6-triaza-3,5- diphoshorine-1-oxide].

The antitumor activity of 1.3.3.5.5-pentaziridino-1-thia-2.4.6-triaza-3.5-diphospho rine-1-oxide (SOAz) was investigated in vitro and in vivo. The results obtained were as follows: SOAz showed marginal cytotoxicity against growth of L1210 cells cultured in vitro. In the cell-cycle traverse of RPMI 8402 cells, SOAz prolonged the duration of the S phase, leading to the eventual accumulation of cells at the G2 phase. At the highest concentration, SOAz stopped the cell cycle progression completely. SOAz was found to have similar activity to carbazilquinone, cyclophosphamide or mitomycin C on P388 leukemia. SOAz showed marked antitumor effect against early-stage L1210 leukemia, and was also effective against advanced-stage L1210 leukemia. The therapeutic efficacy of SOAz depends on the treatment schedule. Single injection and intermittent treatment were superior to daily treatment. Oral administration of SOAz was effective as well as i.p., i.v. and i.m. administration.

Animals↗
PubMed1987

Sister chromatid exchange induction in patients with anaplastic gliomas undergoing treatment with radiation plus diaziquone or 1,3-bis(2-chloroethyl)-1-nitrosourea.

Diaziquone (AZQ) (NSC 182986), a lipid-soluble benzoquinone derivative, is presently being tested in a Phase III clinical trial to determine its efficacy in patients with anaplastic gliomas compared to the more standard 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment following whole-brain irradiation. These patients on single-drug chemotherapy allowed us to evaluate the effects of each agent on sister chromatid exchange (SCE) induction in vivo. Eight weeks following the final radiation treatment, patients were randomly assigned to one of two groups: (a) 200 mg BCNU/m2, i.v., every 8 weeks; of (b) 15 mg AZQ/m2/day, i.v., for 3 consecutive days, every 4 weeks. Blood (5-10 ml) was drawn by venipuncture before treatment, within 10 h after treatment, and for two BCNU-treated patients at various other times. Peripheral blood lymphocytes were cultured by standard techniques for analysis of SCE. Eight weeks after irradiation but before chemotherapy, the mean SCE frequency in the patients' peripheral blood lymphocytes was 9.6 SCEs/metaphase. Following treatment with AZQ or BCNU, the baseline SCE frequency was increased more than 2-fold or 3-fold, respectively. Two months after BCNU treatment, there was less than a 25% reduction in SCE levels compared to samples taken and cultured within 10 h after treatment. These data show that lesions leading to SCE in human peripheral blood lymphocytes are relatively longlived, and that on a mg/m2 basis, AZQ is a more potent inducer of SCE in vivo than is BCNU.

Aziridines↗
PubMed1985

Regional differences in ethylcholine mustard aziridinium ion (AF64A)-induced deficits in presynaptic cholinergic markers for the rat central nervous system.

Several highly selective biochemical markers were used to assess the persistent central cholinergic dysfunction which accompanies administration of the cholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A). Rats received a single bilateral intracerebroventricular injection of AF64A (3 nmol/3 microliter/side) or vehicle and measurements were carried out in the cerebral cortices, hippocampi and corpora striata at 7 and 21 days postinjection. The drug binding sites of muscarinic cholinergic receptors, as revealed by high-affinity binding of (-)-[3H]quinuclidinyl benzilate (a classical muscarinic antagonist), [3H]pirenzepine (a selective antagonist of the putative M1 muscarinic receptor subclass) and (+)-[3H]cis-methyldioxolane (a potent muscarinic agonist), were not significantly affected by AF64A treatment. As reported previously, activity of the cholinergic synthetic enzyme choline acetyltransferase was reduced markedly (60-65%) in the hippocampi of AF64A-treated rats. A similar reduction was noted in high-affinity binding of [3H]hemicholinium-3 (a putative radioligand for sodium-dependent high-affinity choline uptake sites on cholinergic nerve terminals) in hippocampal membranes (59-65%). However, in the cerebral cortex, these presynaptic cholinergic markers were differentially altered by AF64A pretreatment (choline acetyltransferase, unchanged; [3H]hemicholinium-3 binding, reduced by 59-65%). These results indicate that a single intracerebroventricular injection of AF64A promotes biochemical and possibly functional deficits in presynaptic cholinergic nerve terminals distal from the injection site while having minimal influences upon muscarinic cholinergic receptor populations.

Animals↗
PubMed1985

Flow cytometric analysis of pentakis(aziridino)thiatriazadiphosphorine oxide (SOAz)-induced changes in cell cycle progression of HeLa and HL-60 cells.

The treatment of HeLa and HL-60 cells with various concentrations of pentakis(arizidino)thiatriazadiphosphorine oxide results in inhibition of growth and modification of cell cycle distribution. These phenomena were observed at 10(-4) M and 5 X 10(-5) M for HeLa cells and 10(-5) M and 5 X 10(-6) M for HL-60 cells. The estimation of DNA content by flow cytometry showed an important shift in the distribution of cycling cells with a striking arrest in G2 for both cell lines with a concomitant late S-phase accumulation for HeLa cells. Incubation of cells in drug-free medium 3 days after treatment did not show any change in DNA distribution, suggesting the irreversibility of drug action.

Azirines↗
PubMed1985

Phase I clinical evaluation of diaziquone in childhood cancer.

Diaziquone (AZQ), a new lipid-soluble antitumor agent, was given by 15-30-minute infusion on a daily X 5 schedule to 47 children with refractory solid tumors and leukemia. The starting daily dose of 6 mg/m2 was escalated to 10 and 35 mg/m2 in patients with solid tumors and leukemia, respectively. In patients with solid tumors, myelosuppression was dose-limiting at a daily dose of 10 mg/m2. In patients with leukemia, prolonged pancytopenia and bone marrow hypoplasia were observed at daily doses greater than or equal to 25 mg/m2. At these higher doses, significant hyperbilirubinemia associated with sepsis was also seen. Corresponding increases of transaminases or alkaline phosphatase and significant hemolysis were not noted. The maximum tolerated dose for this daily dose schedule was 9 mg/m2 in children with solid tumors and 25 mg/m2 in children with relapsed leukemia. Responses to AZQ included stabilization of disease in osteosarcoma, neurofibrosarcoma, pinealoma, and ependymoma. A patient with juvenile chronic myelocytic leukemia in blast crisis converted back to the chronic phase. A patient with acute lymphoblastic leukemia had a substantial decrease in cerebrospinal fluid blast count. Bone marrow aplasia was achieved in children with acute lymphoblastic leukemia and acute nonlymphoblastic leukemia; however, remissions were not achieved. A phase II study of AZQ in children with refractory malignancies is now being performed by the Childrens Cancer Study Group.

Adolescent↗
PubMed1985

In vivo modulation of polyclonal activation of lymphocytes by SOAz, a cyclophosphazene derived drug. Prevention of murine glomerulonephritis induced by chronic injections of lipopolysaccharide.

The effects of a cyclophosphazene derived drug (SOAz), on the polyclonal activation of B lymphocytes induced by bacterial lipopolysaccharide (LPS) have been studied in C57B1/6 mice. It has been found that this drug is able to inhibit the polyclonal stimulation of lymphocytes and a dose-dependent effect has been observed. The therapeutic effects of SOAz injected five times a week at 40 mg/kg/day have been investigated in mice chronically injected with LPS (twice a week, 2.5 mg/kg/day) which developed an immune complex type of glomerulonephritis. A marked prevention of glomerular lesions and of deposits of IgM and IgG, and of the third complement component has been found in mice treated with SOAz as compared to not treated mice.

Animals↗
PubMed1985

Phase II trial of diaziquone in patients with colon cancer.

Seventeen patients with metastatic colon cancer received diaziquone iv daily for 5 days repeated every 28 days. Based on recommended starting doses for phase II trials (6-8 mg/m2 daily X 5), the first six patients received 7 mg/m2/day X 5. Two of these patients were heavily pretreated with chemotherapy, two had received prior 5-FU alone, and two had received no prior chemotherapy. There were no responses and three septic deaths (both of the heavily pretreated patients and one 5-FU-only patient who received concurrent radiotherapy). Eleven subsequent patients received 5.5 mg/m2/day X 5. Nine had no prior therapy; two had received prior 5-FU. No antitumor responses were observed. Myelosuppression was again the major toxic effect. No further septic deaths occurred. Diaziquone in this dose and schedule had no antitumor activity in this group of patients.

Adult↗
PubMed1985

Arene imines, a new class of exceptionally potent mutagens in bacterial and mammalian cells.

K-region aziridines of polycyclic aromatic hydrocarbons reverted Salmonella typhimurium his- (TA100, TA98) and Escherichia coli trp- strains (WP2 uvrA), without requiring activation by mammalian enzymes. The number of revertants induced per nmol in S. typhimurium TA 100, the most responsive strain, variea from 6 to 10,000 for the seven monoaziridines and the two bisaziridines tested. Interestingly, the mutagenic potencies (y) of the monoaziridines were closely related (r = 0.984) with those of the corresponding epoxide analogues (x) by the equation y = 19.6 X0.97, i.e., the aziridines were about 20-fold stronger mutagens than were the epoxides. One of the aziridines, benzo(a)pyrene (BP)-4,5-imine, was investigated in several additional mutagenicity test systems: toxicity in DNA repair-deficient (rec-) and -proficient (rec+) Bacillus subtilis strains; induction of 6-thioguanine resistance in V79 Chinese hamster cells; and induction of sister chromatid exchanges in cultured human fibroblasts. In all systems, BP-4,5-imine was much more active than the epoxide analogue, BP-4,5-oxide. The difference in activity was particularly large in the two test systems with mammalian target cells in which several hundredfold higher concentrations of the epoxide had to be used in order to elicit equipotent effects. Even r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-BP, which is one of the most potent mutagens known for V79 cells, was less active in the mammalian cells than was BP-4,5-imine. One reason that arene imines are such potent mutagens may be that they are poorly detoxified. Addition of highly purified microsomal epoxide hydrolase, which strongly reduced the mutagenicity of BP-4,5-oxide and benz(a)anthracene-5,6-oxide in S. typhimurium, had no effect on the mutagenicity of the corresponding aziridines. Furthermore, while benz(a)anthracene-5,6-oxide was inactivated by highly purified cytosolic epoxide hydrolase, benz(a)anthracene-5,6-imine was not inactivated. It is noteworthy that the arene imines are isomeric with and structurally closely related to aromatic amines. Some aziridines derived from nonaromatic structures (ethylene imines) have been reported as metabolites of xenobiotics; others are used as chemotherapeutics. At present, however, the results are mainly of theoretical interest in that a new type of arene derivatives with exceptionally potent, probably ultimate, mutagenicity was discovered and may be exploited for the study of mechanisms of chemical carcinogenesis.

Animals↗
PubMed1985

[Differential cell mutability during oogenesis and exposure to ethyleneimine and ethylmethane sulfonate in different Drosophila melanogaster lines].

The rate of recessive sex-linked lethal mutations (RLM) was estimated by brood pattern method at different stages of oogenesis, initially, in the wild-type R-86 strain of Drosophila melanogaster after treatment with EI and EMS. The former which is known to induce dominant lethals in mature oocytes of the 14th stage with a high frequency was equally effective in inducing RLM in oocytes of different age and in oogonia. EMS which does not induce dominant lethals when used as vapour was shown to increase RLM frequency in mature fraction of oocytes (the 14A stage only). Similar type of different mutability was found in mutagen-sensitive strain mus-201G1 and in the control 3-4 strain having the same genetical background as mus mutation. Female germ cells of mus-201G1 strain appeared to have a higher mutability in the case of EI, though no differences in mutability between these strains after EMS treatment were registered. The data are discussed in view of the specificity of primer damages occurring as a result of comparable mutagens action and participation of different repair systems in elimination of these damages.

Animals↗
PubMed1985

Membrane topology of light-harvesting protein B870-alpha of Rhodospirillum rubrum G-9+. Amino acid residues in contact with the lipid bilayer as inferred from labeling with photogenerated carbenes.

The amino acid residues of the light-harvesting protein B870-alpha of Rhodospirillum rubrum G-9+ that in the chromatophore membranes are in contact with the lipid phase were identified by hydrophobic photolabeling. Three reagents have been used which all contained the trifluoromethyldiazirinylphenyl group as a photo-sensitive precursor of a carbene but which otherwise differed in shape, molecular structure, and in the way they interact with membranes. 3-Trifluoromethyl-3-(m-[125I]iodophenyl)diazirine is a highly lipid-soluble compound, 11-[4-[(trifluoromethyl)diazirinyl]-phenyl]-[10-3H] 9-oxaundecanoic acid is an analogue of a fatty acid, and 1-palmitoyl-2-[11-[(trifluoromethyl)diaziri-nyl] phenyl]-[10-3H]9-oxaundecanoyl]-sn-glycero-3-phosphorylcholine one of a lecithin. Following labeling of chromatophores with these reagents, B870-alpha was isolated and subjected to (solid phase) Edman degradations in order to determine individual amino acid residues labeled. The main features of these results are as follows. 1) Labeling occurred both within the N-terminal segment (residues 1-8) and within the predominantly hydrophobic transmembrane stretch (residues 14-33). 2) Label distribution patterns within segments are indicative of helical structures to which the reagents had access to one face only of the cylindrical envelopes. 3) With regard to the transmembrane segment, the label distribution patterns were similar for all reagents whereas striking differences were noticed within the N-terminal portion. The labeling patterns are consistent with previous models proposing tight association of the transmembrane helix with that of the B870-beta chain. They also suggest that the N-terminal segment forms an amphipathic helix which interacts with the water-lipid interface of the membrane.

Affinity Labels↗
PubMed1986

Diaziquone given as a continuous infusion is an active agent for relapsed adult acute nonlymphocytic leukemia.

Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of diaziquone-induced cytotoxicity for human and murine leukemia cells with increased duration of drug exposure and the relatively short terminal plasma half-life of diaziquone, 49 patients (34 acute nonlymphocytic leukemia [ANLL], six chronic myelogenous leukemia in blast crisis [CML-B], five acute lymphocytic leukemia [ALL], four 2 degrees ANLL) with leukemia were given diaziquone as a continuous infusion for seven days. The maximum tolerated dose was 28 mg/m2/d for seven days. The dose-limiting toxicity was the duration of bone marrow aplasia (median, 49 days to greater than 500 PMNs in responders; range, 28 to 101 days). Nonhematologic toxicity was minimal. Responses occurred only in patients with relapsed ANLL, of whom 26 were treated at effective doses. There were six complete responses (CR) (23%) and two partial responses (PR) (8%), although five of eight responders never achieved platelet counts greater than 100,000/microL. Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia. The median duration of CR was 195 days (range, 88 to 860+). One patient had active CNS leukemia at the start of treatment and has had a durable (28+ month) CR in both sites of disease. Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic. The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL.

Acute Disease↗
PubMed1986

[Clinical results of a randomized controlled trial on the effect of adjuvant immunochemotherapy using Esquinon and Krestin in patients with curatively resected gastric cancer. Cooperative Study Group of Cancer Immunochemotherapy, Tokai Gastrointestinal Oncology Group].

From July 1977, a controlled clinical trial in 168 patients who received curative surgery for stomach cancer and 111 similarly treated for colorectal cancer was conducted in the form of a cooperative study involving 22 institutions. One week after surgery, carboquon (CQ) was given at a dose of 2 mg/m2 once a week, followed by PSK at a dose of 2 g/m2 every day for 4 weeks. This regimen was repeated 9 times for 55 weeks. For stomach cancer, patients were divided into 3 groups; Group A: CQ intermittently, Group B: CQ PSK in alternate doses, Group C: controls. For colorectal cancer, the patients were divided into 2 groups; Group D: CQ + PSK in alternate doses, Group E: controls. Survival rate of stage III stomach cancer patients in Group B was higher than that in Group A, the difference being statistically significant between 20 and 24 months after surgery. For colorectal cancer, the survival rate of patients with Dukes C in Group D was statistically superior to that in Group E. These differences were much more apparent among patients who received more than 6 courses of the regimen.

Adjuvants, Immunologic↗