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PubMed1989

Evaluation of spin labeled TEPA and CCNU analogs against osteosarcoma and MNU-induced mammary carcinoma of the SD-rat.

The effectiveness to reduce tumor growth by 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6-tetramethylpiperidinyl)- 1-nitrosourea (SLCNU) and N,N,N,'N'- bis(1,2-ethanediyl)-N"-(1-oxyl-2,2,6,6-tetramethyl- 2-piperidinylaminocarbonyl)-phosphoric triamide (SLDU) was studied in osteosarcoma and MNU-induced mammary carcinoma in the SD-rat. Both compounds elicited neither an inhibitory effect on these tumors nor an increase in the mean/median life span as compared to the control group.

Animals↗
PubMed1989

[Detection of cellular DNA strand breaks induced by antitumor drug and heat using in situ nick translation].

Cellular DNA strand break induced by an alkylating agent: Carboquone (CQ), and heat (43 degrees C) was detected in HeLa cells in vitro and mouse sarcoma-180 cells in vivo. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3H]-labeled dTTP and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks increased in a dose and time dependent manner, compared to findings in the control cells. Our findings show that the surviving response of cells decreases while the level of DNA strand breaks increases following exposure to CQ or heat. The nick translation method is a rapid in situ assay for determining drug and heat induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semi-quantitative manner.

Azirines↗
PubMed1989

Changes in conformation upon agonist binding, and nonequivalent labeling, of the membrane-spanning regions of the nicotinic acetylcholine receptor subunits.

All four subunits of the acetylcholine receptor (AChR) are labeled by the lipid-soluble photolabel 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine [( 125I]TID) with different stoichiometries and levels of saturable modification sites, dependent on the conformational state of the AChR. This probe is specific for hydrophobic targets such as the membrane-spanning regions of intrinsic proteins. In the resting state, the gamma subunit is labeled 4.5 times greater and the beta and delta subunits 1.65-1.69 greater than the alpha subunit. Carbamylcholine-induced desensitization of the AChR lowers the level and alters the stoichiometry of [125I]TID incorporation into each subunit. This effect is shown to be specific in two ways. First, it is eliminated by prior equilibration with excess alpha-bungarotoxin, which does not change the [125I]TID-labeling pattern of the AChR from that of the resting state. Second, bacteriorhodopsin is labeled by [125I]TID to the same extent both in the presence and absence of carbamylcholine. The noncompetitive blocker phencyclidine does not alter [125I]TID labeling of the AChR relative to the resting state. The 43-kDa protein, which is believed to cross-link the AChR to the cytoskeleton at the synapse, is not modified by [125I]TID, in agreement with earlier conclusions that the 43-kDa protein is not an intrinsic membrane protein.

Animals↗
PubMed1989

[Effect of natural human leukocyte interferon on cell cycle kinetics, the frequency of sister chromatid exchanges and chromosome aberrations in fopurin-treated human lymphocytes].

Natural human leukocyte interferon (50 IU/ml), added to human lymphocytes for 24 hour incubation time, increased the background sister chromatid exchange (SCE) frequency and shortened the average generation time (AGT). Interferon pretreatment decreased the levels of the SCE induced by antineoplastic alkylating drug fopurin (2-dimethylamino-6-diethylene iminophosphamido-7-methylpurine; treatment conditions: the 20-24 hour incubation time, 25 and 50 microM), but no statistically significant changes were noticed in AGTs, in the number of aberrant metaphases, and in the total number of induced chromosome aberrations (CA). The increased number of the exchange-type CA induced by fopurin (50 microM) was observed in interferon pretreated cells. The results obtained indicate different formation mechanisms for SCE and CA, as well as different modification ways of SCE and CA formation by interferon.

Antineoplastic Agents↗
PubMed1989

Two forms of plasma membrane-intercalated heparan sulfate proteoglycan in rat ovarian granulosa cells. Labeling of proteoglycans with a photoactivatable hydrophobic probe and effect of the membrane anchor-specific phospholipase C.

The structures of cell-associated heparan sulfate (HS) proteoglycans and their interaction with the plasma membrane was studied using rat ovarian granulosa cell culture. HS proteoglycans were either metabolically labeled by incubating cell cultures with [3H] leucine and [35S]sulfate or labeled in plasma membrane preparations with a photoactivatable reagent, 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine (TID), a compound which has been shown to selectively label the hydrophobic membrane-binding domains of several proteins. After purification of HS proteoglycans from the labeled cell cultures or from the labeled membrane preparations by repeated Q-Sepharose ion exchange chromatography in 8 M urea, they were analyzed by Superose 6 gel filtration and octyl-Sepharose chromatography both in 4 M guanidine HCl. The results indicated that the HS proteoglycans were labeled with 125I and therefore have an intramembranous domain. Phospholipase C (Bacillus thuringiensis), which specifically cleaves phosphatidylinositol membrane anchors, released approximately 25% of the 35S-labeled HS proteoglycans from the cell surface as well as 20-30% of the 125I-label from the 125I-TID-labeled HS proteoglycans. These data indicate that a subpopulation of HS proteoglycans are intercalated into the plasma membrane through a linkage structure involving phosphatidylinositol. Phospholipase C-resistant, 125I-labeled HS proteoglycans represent those species inserted into membrane through an intercalated peptide sequence. Core protein size of phosphatidylinositol-anchored species estimated by polyacrylamide gel electrophoresis after heparitinase digestion was approximately 80 kDa, and it was significantly larger than that of the directly intercalated species (approximately 70 kDa).

Affinity Labels↗
PubMed1986

A phase I study of intravenous azimexon therapy in human cancer.

Azimexon, a synthetic derivative of the 2-cyanaziridines, was given intravenously daily for 5 days to 19 cancer patients in a Phase I trial designed to determine the drug's tolerable dose, toxicity, and effects on immune and nonimmune host defense parameters. No myelosuppression, neurologic, renal, hepatic, or gastrointestinal toxicities could be detected. The only toxic side effect observed after 5 days of intravenous azimexon was a self-limiting dose-dependent hemolysis. Absolute lymphocyte count (ALC) increased from a pretreatment value of 0.96 X 10(3)/microliter to 1.56 X 10(3)/microliter on day 21 (p less than 0.05). This increase was induced primarily by the less hemolytic 200-250 mg/m2 doses of azimexon. Among 12 patients given this lower dosage. ALC increased from an average initial value of 0.90 X 10(3)/microliter to 1.86 X 10(3)/microliter on day 21 (p less than 0.01). Absolute number of OKT3+ cells increased from 0.524 to 0.914 X 10(3)/microliter (p less than 0.05) with lower drug doses. The mean absolute number of OKT4+ cells increased from 0.294 on day 0 to 0.574 X 10(3)/microliter on day 21 (p less than 0.05), and the number of OKT8+ cells increased from 0.202 to 0.388 X 10(3)/microliter, with no significant changes in helper/suppressor ratio. Significant increases in mitogenic responses to phytohemagglutinin (PHA) [from 13.4 to 35.7 X 10(3) net cpm (p less than 0.05)] and to concanavalin A (con A) [from 6.4 to 25.6 X 10(3) net cpm (p less than 0.05)] were also observed with higher drug doses. Azimexon may have a role in managing cancer-associated dysregulation of the immune response.

Adjuvants, Immunologic↗
PubMed1987

The toxic effects of ethylcholine mustard aziridinium ion on cholinergic cells in the chicken retina.

The chicken retina has been used to examine the toxicity of a highly reactive chemical analog of choline, ethylcholine mustard aziridinium ion (ECMA). Following a single intravitreal injection, retinas were analyzed biochemically for CAT and AChE activities, and GABA, glycine, and dopamine levels. Retinas were also examined using histofluorescence for dopamine histochemistry, for AChE, and immunohistochemistry with antibodies to CAT, tyrosine hydroxylase, GABA, 5-HT, Leu-enkephalin, and somatostatin. A dose of 50 nmol ECMA caused a prolonged 70% depletion of CAT activity and a 40% depletion of AChE activity. The other biochemical parameters were unchanged. This result corresponds to the morphological finding that 2 populations of cholinergic cells were destroyed and that the AChE activity associated with their terminal arbors was lost. A third population of cholinergic cells, located towards the middle of the inner nuclear layer, was resistant to the toxic effects of ECMA. The other cell types, except for somatostatin-immunoreactive cells and photoreceptors, which showed transient effects, were unaffected. ECMA therefore appears to be a highly specific toxin for cholinergic cells in the retina.

Acetylcholine↗
PubMed1986

Effect of BM 12 531 on in vitro induction of suppressor cells by concanavalin A in cancer patients and normal healthy donors.

The effects of BM 12 531, a 2-cyanaziridinyl derivative, on in vitro generation of Con A induced suppressor cells as well as generation of spontaneous suppressor cells in peripheral blood lymphocytes of 9 chronic myeloid leukemia (CML) patients in remission, 9 patients with active Hodgkin's disease (HD) and 12 normal healthy donors were studied. The suppressor cells generated spontaneously and with Con A, in the presence and absence of the drug, were tested for their modulating effect on mitogenic (PHA) response of autologous lymphocytes. The results indicate that the addition of the drug at the time of generation of suppressor cells decreased the spontaneous suppressor cell activity in 2/4 healthy donors, 3/7 CML patients and 4/6 HD patients. Con A induced suppressor cell activity generated in presence of the drug was significantly reduced in 7/12 healthy donors, 6/9 CML patients and 3/9 HD patients.

Aziridines↗
PubMed1988

[Biological effects of leakadin].

57 patients with disseminated tumors of various sites received 10 daily doses of 600 mg/m2 leakadin intravenously. The immunostimulating effect was observed (OKT4/OKT8 normalization). The data on leakadin pharmacokinetics are discussed.

Adjuvants, Immunologic↗
PubMed1985

[Binary ethyleneimine as an inactivator of the foot-and-mouth disease virus].

Experiments were carried out to inactivate F.M.D. viruses with the use of binary ethylene-imine. It was found that inactivation was optimal when the agent was used at the rate of 0.003 M for 18 hours at 26 degrees C. Its neutralization in the virus suspension was carried out with 3 mM sodium thiosulfate. The inactivated F.M.D. viruses retained their complement-fixing and immunogenic properties. Discussed are the advantages of using binary ethyleneimine as an inactivating agent as against other agents of the asiridine order.

Antigens, Viral↗
PubMed1986

Phase I-II evaluation of intra-arterial diaziquone for recurrent malignant astrocytomas.

Diaziquone (AZQ) is a lypophilic alkylating agent that crosses the blood-brain barrier and has shown broad activity in animal tumor models. Five of 12 patients with malignant astrocytoma treated with iv AZQ had clinical and/or radiographic improvement (Schold, Neurology 34:615, 1984). Intra-arterial administration of AZQ to patients with brain tumors should produce higher peak levels of drug in the tumor and should reduce systemic toxicity. Twenty-one patients with astrocytoma (grade II, four; grade III, 11; and grade IV, six), in all of whom irradiation and intra-arterial carmustine chemotherapy failed, received intra-arterial AZQ as a single dose every 28 days. Two of 20 evaluable patients experienced partial responses of 5 and 8+ months, respectively. Four patients had disease stabilization of 3, 4, 5, and 8 months' duration, respectively, and one of these patients had tumor shrinkage (partial response) after seven courses of AZQ. The initial dose in the first three patients was 10 mg/m2, and doses in subsequent groups of three patients were begun at increases of 5 mg/m2. The within-group dose escalation was 5 mg/m2 per course if there was no hematologic toxicity. Dose-limiting toxicity was myelosuppression, which occurred at doses greater than 15 mg/m2. The maximum tolerated dose was 25 mg/m2. Intra-arterial AZQ appears to be of marginal effectiveness in patients refractory to carmustine and offers no advantage over iv AZQ in efficacy or toxicity.

Adult↗
PubMed1986

Different type of DNA damage caused by three aziridinyl substituted cyclophosphazenes in a human small cell lung carcinoma cell line.

Aziridinyl substituted cyclophosphazenes are a new group of inorganic chemical agents with in vitro and in vivo cytotoxic activity. We investigated the mode of action on DNA of three different compounds, 1,3,3,5,5-pentakis (1-aziridinyl)-1 lambda 6,2,4,6,3 lambda 5,5 lambda 5-thiatriazadiphosphorine -1-oxide (SOAz), trans-1,3-bis(1-aziridinyl)-1,3,5,5-tetrakis (methylamino)-2,4,6,1 lambda 5,3 lambda 5,5 lambda 5-triazatriphosphorine (AZP), and 1,trans-5-bis(1-azaridinyl)-gem-1,3,3'-cis-5,7,7'-hexakis (methylamino)-2,4,6,8,1 lambda 5,3 lambda 5,5 lambda 5,7 lambda 5 -tetraazatetraphosophocine (AZM), of this group in the Ehrlich ascites tumor cell line (EAT) and a human small cell carcinoma cell line. The DNA damage was evaluated by alkaline elution and ethidium bromide fluorescence assay. Each compound gave a different pattern of DNA damage. SOAz caused neither single strand breaks nor cross-links, AZP gave cross-links, and AZM gave single strand breaks and cross-links in both cell lines after drug incubation for 6 h. The range of concentrations leading to cytoxicity of AZP and AZM in the clonogenic assay coincided with the concentrations leading to DNA damage. Cell kill occurred with SOAz in the same range of concentrations, however, without detectable evidence of DNA damage. It was concluded that cyclophosphazenes are probably a heterogeneous group as far as their mode of action as cytostatic agents is concerned.

Animals↗
PubMed1986

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.

Aziridines↗