Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Aziridines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 955 records · Page 53Linked to original sources
PubMedDate not supplied

Degradable starch microspheres in cytostatic treatment of a liver carcinoma; experimental studies in rats with 5-fluorouracil, tauromustine, carmustine, doxorubicin and RSU-1069.

The degradable starch microspheres (DSM) used have a size of 45 microns and are dissolved by amylase in blood. After intraarterial administration of a mixture of DSM and cytostatic drugs the coinjected drugs remain for a longer time in the target tissue/tumor. A transient hypoxia occurs. Systemic exposure of drugs is decreased. Rats with a carcinoma implanted into the liver were given DSM and drugs via the hepatic artery. DSM did not significantly increase the incorporation of 5-fluorouracil (5-FU) into liver tumor RNA. The incorporation of 5-FU into intestinal and bone marrow RNA increased. DSM increased the antitumor effect of doxorubicin, tauromustine, carmustine and RSU-1069 (aziridine 2-nitroimidazole). Side effects, such as liver and gastric necroses and body weight loss, appeared in some rats. The toxic overspill to the stomach seemed to be reduced by giving the DSM in two parts, with all the cytotoxic drug in the first part. The effect on liver and tumor was not decreased by this procedure. DSM alone had no anti-tumor effect. DSM alone decreased liver UDP-glucuronic acid in tumor-free rats, given either by the hepatic artery or, in the double dose, by the portal vein. DSM alone did not increase liver NADPH-cytochrome c reductase activity or serum ASAT (aspartate-aminotransferase) or ALAT (alanine-aminotransferase), indicating that the DSM are inert to the liver, when infused into the tributary vessels.

Adenosine Triphosphate↗
PubMed1993

Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin.

Toxicity from drugs activated by bioreductive metabolism has been suggested as a means to eliminate the treatment resistance caused by hypoxic tumor cells. In general, drugs have been selected to maximize the hypoxic cytotoxicity ratio [exposure (drug concentration x time) in air:exposure in nitrogen] to cause equal toxicity. On this basis, two recently developed drugs have very similar characteristics; an aziridine derivative of misonidazole (RSU1069) and a benzotriazine di-N-oxide (SR4233). The oxygen dependence of the toxic response has not previously been characterized. This report shows that the toxicity from SR4233 extends over a much greater range of oxygen concentrations than does that of RSU1069. Furthermore, unlike all previous drugs studied, the toxicity of SR4233 does not level off at high oxygen concentrations, but continues to decrease as the oxygen concentration increases. For 1 mM oxygen (the solubility of oxygen in medium at 37 degrees C equilibrated with 100% oxygen and water vapor) the toxicity from SR4233 is at least 2000-fold less than that for hypoxia. Modeling the effect of oxygen on combined radiation and toxicity shows that radiation plus SR4233 should be much more effective in eliminating hypoxic cells than radiation plus RSU1069. The unusual oxygen dependence of toxicity by SR4233 may indicate a unique biochemical activation process.

Animals↗
PubMed1995

Major molecular weight heterogeneity of estrogen receptor from breast cancer is not related to neoplasia.

Recent investigation from our laboratory revealed that the estrogen receptor (ER) from breast cancer is characterized by a high molecular weight polymorphism: SDS-polyacrylamide gel electrophoresis of [3H]-tamoxifen aziridine ([3H]-TAZ) labeled cytosols usually display several bands corresponding to the native receptor (67 KDa) and lower molecular cleavage products. High frequency of such altered receptors was confirmed here by size exclusion FPLC of [125I]-E2 labeled cytosols from a series of 98 breast cancers: on the average, 60% of the ER molecules were strongly degraded (Mr < or = 37 KDa). The absence of transcriptional activating domains (ABC domains) in such receptors was further demonstrated by assessing their ability to bind to hydroxylapatite (HAP). Thus, in presence of 500 mM KCI, 55% of ERs from another series of 54 cytosols failed to strongly adsorb to this phosphocalcic matrix, a characteristic property of receptors without exposed ABC domains. Finally, [3H]-TAZ labeled cytosols from normal uterine tissue and MCF-7 human breast cancer cells growing in nude mice displayed identical multibands electrophoretic patterns revealing in both cases native and cleaved receptors. Since latter receptor forms were never detected in MCF-7 cells growing in monolayer culture, we put forward the hypothesis that they were produced under the action of proteolytic enzymes acting at the time of tissue processing. Hence, most of the truncated receptors detected in human breast cancer cytosols should not be markers of malignancy.

Animals↗
PubMed1996

Increased resistance to N,N',N"-triethylenethiophosphoramide (thiotepa) in cells expressing the Escherichia coli formamidopyrimidine-DNA glycosylase.

Thiotepa (N,N',N'-triethylenethiophosphoramide) is an alkylating agent used in cancer chemotherapy. A reaction pathway by which thiotepa alkylates purified DNA involves hydrolysis to aziridine, which forms N7-aminoethyl guanine and aminoethyl adenine. These lesions are repaired in Escherichia coli by the formamidopyrimidine-DNA glycosylase (Fpg) protein. To determine whether such lesions are formed by thiotepa in mammalian cells, we have overexpressed the E. coli Fpg protein in Chinese hamster ovary cells. The transfected cells were more resistant to the lethal and mutagenic effects of thiotepa than the parental cells. The number of replication-blocking lesions formed by thiotepa, measured by quantitative PCR analysis, was lower in the transfected cells. These results show that expression of the Fpg protein increases the cell resistance to thiotepa and suggest that this compound produces ring-opened guanines, which are involved in its cytotoxic action.

Animals↗
PubMed1996

Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation.

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.

Amino Acid Sequence↗
PubMed1995

Structural and function modification of DNA by mitomycin C. Mechanism of the DNA sequence specificity of mitomycins.

Mitomycin C (MC) is a clinically used antitumor agent, which upon reductive activation activates and cross-links DNA. The covalent products of alkylation and cross-linking by the unnatural synthetic enantiomer of MC (ent-MC) were isolated as drug-deoxyguanosine monoadducts and drug-deoxyguanosine bisadducts and were fully characterized structurally. Specificity of alkylation and cross-linking of guanines in the CpG.CpG sequence was observed by ent-MC, similarly to that observed previously by MC. These findings define the mechanism of recognition of the CpG.CpG sequence of DNA by the mitomycins in the minor groove. In contrast, the natural MC metabolite, 2,7-diaminomitosene (2,7-DAM) which lacks the aziridine alkylator function is shown to recognize and alkylate guanines only the GpG.CpC sequence in the major groove, by a different mechanism. Thoughts on the molecular evolution of the basic mitomycin structure as a very efficient lethal DNA cross-linker are discussed.

Antibiotics, Antineoplastic↗
PubMed1997

Comparative molecular field analysis-based predictive model of structure-function relationships of polyamine transport inhibitors in L1210 cells.

Maintenance of intracellular polyamine concentrations necessary for cell growth and proliferation is regulated in part by an energy-dependent polyamine uptake system. To obtain information on the characteristics of the polyamine uptake system in L1210 leukemia cells, we have applied computational chemistry techniques to the study of relationships between structure and function of 57 polyamine analogues. Ki values of polyamine analogues, derived from competitive inhibition of [3H]spermidine transport into L1210 cells, were chosen as the measure of biological activity. Using comparative molecular field analysis (CoMFA), a model was constructed to relate molecular structure with biological activity. The model was based on 4 monocationic, 8 dicationic, 14 tricationic, and 20 tetracationic polyamine analogues with a range of Ki values for the inhibition of [3H]spermidine uptake of 0.97-521 microM. The CoMFA model successfully predicted the inhibitory potency of 11 polyamines that had not previously been tested for polyamine uptake inhibitory activity. The 11 values predicted were within 33 +/- 62% of the actual Ki values. The test group included aziridinyl diamines, acetylated spermidines, two new oxazolidinonyl spermidines, monoaziridinyl spermidines, and a diaziridinyl spermine. Several of the compounds from this test group have been shown to have anticancer activity in mice. Consistent with the CoMFA model, certain basic functional groups, such as aziridines that have pKa values in the range of 6-7, seem to interact with the polyamine transporter in a cationic form. The results suggest that the CoMFA model is useful in drug design strategies as a predictive tool for the discovery of new anticancer agents that utilize a polyamine transporter for cellular uptake.

Animals↗
PubMed1998

Problems with BHK 21 cells.

The properties of baby hamster kidney (BHK 21) cells are modified by passage in suspension culture. The suspended cells differ from monolayer cells in the surface expression of some integrin chains involved in attachment of foot-and-mouth disease virus (FMDV), in particular the progressive down-regulation of both alpha5 and alphaV integrin chains. This down-regulation is correlated with the loss of actin stress fibres. FMDV particles from these cells are unstable towards the aziridine used in inactivating the virus for vaccine production. Moreover, growth of virus in suspended cells can lead to the selection of antigenic variants which differ from those produced in monolayer cells.

Animals↗
PubMed1977

Pharmacological prophylaxis in the kindling model of epilepsy.

Review of antiepileptic drug assessment to date by means of the kindling model of epilepsy suggests that it fills a gap that is evident in standard screening methods such as maximum electroshock or pentylenetetrazol screening tests. However, in order to obtain a comprehensive profile of antiepileptic drugs regarding prophylaxis of developing seizures and treatment of well-established seizures through the kindling preparation, it is desirable to have the following: (1) standardization of kindling techniques, (2) examination of drug effects on developing as opposed to developed seizures, (3) use of a variety of animal species, involving different functional brain sites, and (4) monitoring of plasma levels of the drug administered. It is envisaged that judicious use of the kindling preparation might also enable us to gain some insight into the mechanisms by which drugs produce their prophylactic or therapeutic effect.

Amygdala↗
PubMed1999

Septohippocampal adaptive GABAergic responses by AF64A treatment.

A cholinergically disrupted laboratory animal has been produced by administration of the cholinotoxin ethylcholine aziridinium mustard (AF64A), which produced a dysfunction in the cholinergic forebrain system. After AF64A treatment, a reduction of choline acetyl transferase (ChAT) activity was measured in the hippocampal regions. ChAT activity was preferentially reduced in tissue samples of the dorsal with respect to the ventral hippocampus, and concomitantly with this reduction, a compensatory increase in ChAT activity in the medial septum was found. Tissue gamma-aminobutyric acid (GABA) content in the hippocampal and septal brain areas was not affected by AF64A, indicating a specific effect on the cholinergic septohippocampal projection. The rate of GABA accumulation induced by aminooxyacetic acid administration was higher in the dorsal hippocampus and medial septum of AF64A-treated animals, but not in their ventral hippocampus and lateral septum, where significant changes occurred in ChAT activity. Concomitantly with the changes in GABA metabolism, a significant Bmax increase and Kd reduction of 3H-flunitrazepam binding in the hippocampus of AF64A-treated animals were associated with changes in the ChAT activity. This finding suggests an increase of GABA input on the cholinergic somas of the medial septum and an uncompensated GABAergic interneuron activity in the hippocampus. In this study, we present an adaptive mechanism of homotypic compensatory metabolism by cholinergic somas, and a heterotypic response of the GABAergic septohippocampal projection system, which was elicited by AF64A administration.

4-Aminobutyrate Transaminase↗
PubMed1997

The response of germ cells to ethylene oxide, propylene oxide, propylene imine and methyl methanesulfonate is a matter of cell stage-related DNA repair.

We describe the consequences of a defect for nucleotide excision repair (NER) in oocytes for alkylation-induced mutagenesis in different germ-cell stages of Drosophila males. Mutant frequencies induced in NER+ condition (cross NER+female female x NER+male) were compared with those fixed in a NER- background (cross NER-female female x NER+male), using the X-linked recessive lethal assay (SLRL) for the measurement of forward mutations in 700 loci. In successive male germ-cell stages exposed to a low dose of 2.4 mM x h methyl methanesulfonate, efficient repair of premutational damage in spermatogonia and by the maternal repair system after fertilization was observed. Ethylene oxide (EO) and propylene oxide (PO) did not induce high mutant frequencies in postmeiotic germ cells when mutagenized males were mated with NER+ females: a 32-fold increase in dose from 750 ppm x h to 24,000 ppm x h EO (approximately LD50) led to no more than a 3-fold enhancement in mutant frequency. However, up to a 17-fold increase in mutant frequencies were obtained with NER- females. In matings with NER+ females, PO was about 10 times less mutagenic than EO. Suppression of the maternal NER system caused a hypermutability, which, on the average, was 2.4-fold lower than for EO. This indicates that the 2-hydroxyethyl adduct generated by EO is more efficiently repaired than the 2-hydroxypropyl adduct caused by PO. The low SLRL frequencies (0.2-0.9%) estimated for propylene imine (PI) in NER+ genotypes showed no relation to dose in the range from 1,500 to 48,000 ppm x h. In the absence of NER, mutant frequencies were increased up to 29-fold, and a dose-dependent increase in mutations was observed for PI over the entire dose range. This study shows mutation induction by EO in postmeiotic Drosophila germ cells at exposure doses that are 800-fold below those applied previously in the mouse specific-locus test on spermatogonia [with negative response; Russell et al. (1984): Mutat Res 129:381-388] and 11-fold below the EO dose for which increased dominant-lethal responses and heritable translocations were documented in mice spermatozoa and spermatids [Generoso et al. (1990): Environ Mol Mutagen 16:126-131].

Animals↗
PubMed1985

Sensitizers and protectors in radiotherapy.

The rationale for hypoxic cell radiosensitizers, of which misonidazole (MISO) is the most widely used drug, is based on the premise that hypoxic cells limit the cure rate of tumors to conventional radiotherapy. There is evidence that this is the case for tumors of the head and neck and possibly also for carcinoma of the cervix and lung. Despite numerous trials, however, MISO has not shown a significant clinical benefit. However, it can be demonstrated that little or no effect would have been expected at the doses of MISO used. New and more efficient radiosensitizers are now available which are more likely to produce significant improvements in local control with radiotherapy. The sulfhydryl radioprotector WR-2721 protects normal more than malignant tissues in animals from damage by radiation and chemotherapy agents. Evidence for protection of bone marrow and kidney has now been obtained for cyclophosphamide and cisplatin, respectively, in Phase I clinical trials. Sensitizers and protectors demonstrate that chemical modification of the therapeutic index is possible for both radiation and chemotherapy treatment of cancer.

Amifostine↗
PubMed1985

Aziridinylbenzoquinone in recurrent, progressive glioma of the central nervous system. A Phase II study by the Illinois Cancer Council.

Aziridinylbenzoquinone (AZQ) was studied in a Phase II protocol for persons with glioma of the central nervous system (CNS) recurrent or progressive after surgery and radiotherapy. Patients received AZQ, 30 mg/m2 intravenously every 3 weeks if previously untreated or 27.5 mg/m2 if previously exposed to cytotoxic drugs. Partial response was defined as a reduction of at least 50% reduction in the product of the two longest perpendicular diameters of the indicator lesion persisting for a minimum of 28 days. Twenty-eight patients are evaluable for response at this time. Objective response (OR) occurred in four (14.3%): two complete and two partial. Stabilization of disease (SD) was seen in 7 (25.0%). Median survival, in weeks, was greater than 46.0 for responders, 41.7 for SD, and 19.3 for those with progressive disease. The survival experiences are significantly different (P = 0.030 [Breslow]). The OR rate was 21.1% in 19 without prior chemotherapy and 0% in 9 previously treated patients. There were two AZQ-related deaths in patients with prior exposure to nitrosoureas (1 CNS hemorrhage; 1 aspiration pneumonia). One patient had an anaphylactic reaction. Three patients whose tumor initially increased in size subsequently had marked tumor shrinkage. AZQ is an active agent that must be used with added caution in patients who have received nitrosoureas. Initial tumor enlargement may precede response. Although response appears to prolong survival, the correlation between stabilization of disease and survival is not well-defined.

Adolescent↗
PubMed1989

Diaziquone and 2,2'-anhydro-arabinosyl-5-fluorocytosine for the treatment of children with relapsed or refractory acute nonlymphoblastic leukemia.

The authors treated 30 patients ages 1 to 19 with relapsed or refractory acute non-lymphoblastic leukemia (ANLL) with the combination of diaziquone (AZQ) and 2,2'-anhydro-arabinosyl-5-fluorocytosine (AAFC) intravenously in two dose schedules. The first 12 patients were treated with 19 courses of AZQ 30 mg/m2 X 3 days and AAFC 600 mg/m2/dose every 12 hours X 10 doses. An additional patient was treated with three courses at 80% of the above doses. Hepatic toxicity was National Cancer Institute Grade III in eight of 22 and Grade IV in one of 22 courses. Infectious complications were severe in all patients, including responders. One patient achieved a complete remission and one a partial remission; the latter died with marrow aplasia after a second course. Altogether three patients developed profound aplasia and died before marrow recovery. The authors treated a second group of 17 patients with AZQ 22.5 mg/m2/day X 3 days and AAFC 450 mg/m2/dose every 12 hours X 10 doses. Three patients achieved a complete remission and one patient a partial remission for 3, 4, 9, and 9 months, respectively. The remainder had progressive disease or no response. All patients developed profound myelosuppression but no toxic deaths occurred. Hepatic toxicity was reduced. Therapy induced cytoreduction of bone marrow was determined by flow cytometry in ten patients; none of these patients responded during the interval studied. Although AZQ and AAFC are active in childhood ANLL with acceptable toxicity, the combination does not appear more active than AZQ used alone. Future studies should define the role of AZQ in combination with other agents.

Adolescent↗
PubMed2001

Detecting treatment-by-centre interaction in multi-centre clinical trials.

This paper considers several permutation tests for treatment-by-centre interaction in multi-centre clinical trials in which the endpoint is survival time subject to censoring. Some of the tests are based on existing tests and some are new. To evaluate and compare the tests with respect to power under different conditions, we generated survival times and censoring times through simulation. We used special methodology to handle the unusual problems that arise in power simulations when the tests under study are permutation tests. Different conditions yielded different interaction tests as the best performers. Although one test gave comparatively good power under almost all conditions, some of the other tests also appear to be useful. For the sample sizes and configurations in the simulations, power is generally low; thus it may not be possible to detect interaction reliably when it exists, a finding in agreement with the known low power for interaction tests in general.

Aged↗