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Inactivation of Newcastle Disease Virus (NDV) by binary ethylenimine (BEI) is reported. The activity of an oil vaccine prepared with BEI-inactivated NDV was compared to a vaccine prepared with formalin-inactivated NDV. The BEI inactivated vaccine had almost twice the efficacy.
Acute renal papillary necrosis was produced in rats by the administration of ethyleneimine. Low doses resulted in necrosis of interstitial cells, thin limbs of the loops of Henle and vasa recta, while collecting ducts were spared (subtotal renal papillary necrosis). High doses resulted in necrosis of all elements of the papilla (total renal papillary necrosis). Athough the ranges of the doses that produced these two patterns of necrosis overlapped, it is clear that there is a dose dependent selective vulnerability or renal medullary structures to injury by the toxic agent studied.
Ethylcholine mustard aziridinium ion (AF64A) is a neurotoxin which is specific for cholinergic nerve terminals. Besides its effects on elements of the acetylcholine system, we observed that, after 2 and 8 days, a single 20-nmol intracerebroventricular dose altered the Timm's staining of certain regions of the central nervous system and reduced the tissue levels of trace metals. In the hippocampal formation, there was a considerable decrease in the staining of the neuropil of the stratum radiatum and stratum oriens, which contain cholinergic nerve terminals. A reduction in staining was also demonstrated in the perikarya of cortical pyramidal cells. The diminished trace-metal level in both regions was confirmed by quantitative measurements of zinc and copper levels. A similar reduction was not observed at a lower dose (8 nmol) of the cholinotoxin. The results led to the conclusion that AF64A may cause the decrease of the trace-metal content of the postsynaptic neurons through an indirect mechanism.
1. The activities of some cholinergic compounds were investigated on the terminal ileum of the guinea-pig and their muscarinic potencies were found to be in the following order: acetylcholine (ACh) greater than diazoacetylcholine (DACh) greater than iodoacetylcholine (IACh) greater than azidoacetylcholine (AACh). 2. Protection experiments with atropine showed a decreased affinity of the four cholinergic compounds for the muscarinic receptor, demonstrating a direct interaction of the drugs and the receptor. 3. The maximal contractions (intrinsic activity) caused by DACh were greater than those casued by ACh, IACh and AACh. 4. Incubation of the ileum with ACh was followed by a reversible loss of its ability to contract (desensitization). The time course of recovery was similiar to that after incubation with AACh. 5. IACh caused a partial (50%), irreversible paralysis of the muscle. 6. The furaziridines seem to react partially irreversibly (30%), whereas paranitrophenyldiazonium fluoborate (p-NDP) caused a complete, irreversible blockade of the muscarinic receptor.
Fluorescence of skinned psoas fibres reconstituted with the troponin C subunit labelled with the fluorescent probe dansylaziridine (TnCDANZ) increases upon activation with Ca2+. This fluorescence enhancement is due to Ca2+ binding to the Ca(2+)-specific binding sites of TnCDANZ and attachment of cross-bridges to the actin filament. We found that approximately 20% of the enhanced fluorescence signal derived from Ca2+ binding to TnCDANZ and 80% from cross-bridge attachment during maximal activation. Furthermore we studied the effects of different cross-bridge states on TnCDANZ fluorescence. "Weakly" bound, non-force-generating cross-bridge states (pCa 8, low ionic strength) and rigor cross-bridges revealed similar effects on the TnCDANZ fluorescence. "Strongly" attached, force-generating states, however, increased fluorescence to the greatest extent. These results suggests a complex system of reciprocal couplings between TnC and different attached cross-bridge states. Cooling or increase of inorganic phosphate decreased isometric force but hardly decreased fluorescence, suggesting the accumulation of attached cross-bridge states with low tension output.
A cholinotoxin, ethylcholine mustard aziridinium ion, (AF64A) specifically and irreversibly blocks the intraaxonal transport of acetylcholinesterase in the rat. Impairment of the transport of this enzyme in the septo-hippocampal cholinergic fibres and in the sciatic nerve has been studied, using different doses of AF64A. It is demonstrated that the effect on the axonal transport is dose-dependent, but is not related to the mode of drug application. AF64A thus may exert its neurotoxic effects on cholinergic neurons at several target sites of action. In addition to the localized presynaptic mechanisms, it may also be compromising cholinergic function by inhibiting axonal transport in vivo.
The aim of this study was to design a stable parenteral dosing form of the investigational cytotoxic drug, encoded EO9. EO9 exhibits poor aqueous solubility and stability characteristics. Freeze-drying was selected as the manufacturing process. Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters. A stable lyophilized formulation of EO9 was developed. The prototype, containing 8.0 mg EO9 and 200 mg lactose/vial, was found to be the optimal formulation in terms of solubility, length of the freeze-drying cycle, stability, and dosing requirements for phase I clinical trials. Quality control of the freeze-dried formulation showed that the manufacturing process does not change the integrity of EO9. Shelf-life studies demonstrated that the formulation remains stable for at least 1 year when stored at +4 degrees C in a dark environment.
Bioreductive drugs undergo metabolic reduction to generate cytotoxic metabolites. This process is facilitated by bioreductive enzymes and the lower oxygen conditions present in solid tumours compared to normal tissues. Because of this specificity, bioreductive drugs have enormous potential to contribute to modern cancer therapy. Examples undergoing clinical trials include N-oxides such as tirapazamine, aziridinylnitroimidazoles RSU 1069/RBU 6145 and quinones such as indoloquinone EO9. Other novel structures are also under study. Here we review the experimental development of bioreductive drugs and their role in cancer therapy.
Diaziquone (AZQ) is a lipid soluble alkylating agent which was designed for increased CNS penetration. Its principle toxicity is myelosuppression. We conducted a phase I trial using AZQ in combination with GM-CSF to determine if the maximal tolerate dose (MTD) of AZQ could be escalated. Using GM-CSF on a standard schedule, we were unable to escalate the previously determined MTD of diaziquone with the use of this colony stimulating factor.
We have attempted to design novel neurotoxins based on the use of hemicholinium derivatives. Three compounds were tested for their neurochemical effects on cholinergic, gabaergic and catecholaminergic markers in the hippocampus, striatum and cortex following intracerebroventricular administration. The effects were compared with those of the non-specific alkylating agent (nitrogen mustard) and the previously reported ethylcholine mustard aziridinium ion (AF 64A). The results indicate that only one of these derivatives (HcM-9) exhibits comparable neurotoxic effects on cholinergic markers with a similar pattern of specificity to that of AF 64A. In addition, HcM-9 showed less overall toxicity, this being reflected in a higher survival rate. The present results indicate that hemicholinium derivatives could be good substrates for further molecular modifications, thus a step towards the design of a more specific cholinergic neurotoxin.
Multiple injections of 2 nmols of cyclised ethylcholine mustard aziridinium ion (ECMA), a putative cholinergic neurotoxin, were made (unilaterally) into the cortical terminal field of cholinergic neurons projecting from the nucleus basalis of Meynert (NBM) in the rat basal forebrain. After 30 days, choline acetyltransferase enzymatic activity, a marker for cholinergic function, was significantly lowered in both ipsilateral cortex and NBM, and cholinergic cell bodies in the latter reduced in cross-sectional area, a spectrum of effects characteristic of retrograde degeneration of this pathway. These results are discussed in the context of neurodegenerative diseases affecting cholinergic function.
Ethylcholine mustard aziridinium ion (ECMA) was infused intracerebroventricularly (icv) to rats followed by measurement of two markers of presynaptic cholinergic neurons, choline acetyltransferase (ChAT) activity and high affinity choline transport (HAChT), in the hippocampus and cortex. Bilateral icv administration of 1, 2, or 3 nmol of ECMA per side produced dose-dependent reductions in each marker in the hippocampus, but not in the cortex, one week after treatment. Reductions of 52% and 46% for ChAT activity and HAChT, respectively, were produced in the hippocampus by 3 nmol ECMA. Measurement of these two markers at different times after icv infusion of 2 nmol ECMA/ventricle revealed that the activity of ChAT was reduced to a greater extent than was HAChT in the hippocampus 1 day and 1, 2, 4, and 6 weeks after treatment. The maximal reductions of ChAT activity and HAChT (61% and 53%, respectively) were reached between 1 and 2 weeks after ECMA administration. There was no evidence of regeneration of either marker at 4 or 6 weeks posttreatment. HAChT and ChAT activity in the cortex were not altered at any of the posttreatment times examined. ECMA-induced deficits in hippocampal ChAT activity and HAChT were not counteracted by the following treatments: (i) daily administration of GM1 ganglioside (10 mg/kg, intraperitoneally (ip)) from the day prior to infusion of ECMA until 2 weeks later; (ii) daily administration of GM1 ganglioside between 2 and 6 weeks after infusion of ECMA; and (iii) icv administration of nerve growth factor (NGF) twice per week for 2 weeks after ECMA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Three new diaziridine platinum(II) complexes (4a)-(4c), and a new azetidine platinum(II) complex (3b) were synthesized and tested against the lymphocytic leukemia P388 in mice. (formula; see text) Moderate to good activity was found for all compounds as evidenced by a T/C value of 162 at a dose of 32 mg/kg for (3b), 190 at a dose of 32 mg/kg for (4a), 139 at a dose of 4 mg/kg for (4b), and 142 at a dose of 20 mg/kg for (4c).
The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and approaches that might be applicable to the management of high-grade malignant brain tumors in man. When tumor cells are implanted intracerebrally, a solid tumor grows until its mass results in the death of the animal, typically between 20 and 30 days postinoculation. Radiation therapy (either single or fractionated doses) is effective at prolonging survival in a dose-dependent manner. Numerous cancer chemotherapeutic agents, by a variety of doses, schedules, and routes of delivery, have demonstrated therapeutic efficacy in the 9L model. The combination of radiation and agents such as AZQ, BCNU, bleomycin, and cis-platinum has resulted in prolongation of survival that is significantly better than either agent used alone, without exceeding the tolerance of critical normal tissues. These pre-clinical data suggest that combining standard fractionated radiation therapy with appropriate concomitant cytotoxic chemotherapeutic agents might benefit patients with high-grade brain tumors.
PURPOSE: A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment of de novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies. METHODS: During 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75-100 mg/m2 intravenously (IV) every 8 weeks or AZQ 15 mg/m2 IV once a week for 4 weeks, every 6-8 weeks. All patients who had not received 'full dose' radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review. RESULTS: Median survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p = 0.01) and the VSG (p = 0.02). Life-table analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p = 0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.
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We used chemosensitive and chemoresistant variants of the neoplastic mouse MXT mammary and human J82 and T24 bladder cell lines to characterize verapamil-induced cell proliferation and morphonuclear modifications in drug-treated and untreated cells. Chemoresistance to vinorelbine (Navelbine, a Vinca alkaloid derivative), to DIAM3 (an investigational alkylating compound) and to Adriamycin (an intercalating agent) in the presence or absence of verapamil was monitored by means of the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results showed that verapamil restored a significant level of chemosensitivity in doses such as 1 microM or 10 microM in the three chemoresistant variants. The digital cell image analysis of Feulgen-stained T24-resistant cell nuclei revealed that verapamil restored the drug-treated cell kinetics and morphonuclear features observed in the sensitive counterpart especially with respect to the effects of Adriamycin. Interestingly, verapamil induced a highly significant chromatin decondensation in resistant but not in sensitive variants. Such verapamil-induced decondensation may favour the accessibility of drugs to their DNA targets. Therefore, in addition to the well-known action of the drug on the influx of a cytotoxic compound from the cellular to the intracellular compartment, verapamil might also favour the accessibility of the nucleus, to the drug.
The effects of cholinergic basal forebrain lesions on the activity of the glutamatergic and GABAergic systems were investigated in the rat frontal cortex and hippocampus. Bilateral quisqualic acid injections in the nucleus basalis magnocellularis (NBM) at the origin of the main cholinergic innervation to the neocortex induced a cholinergic deficit in the cerebral cortex 15 days later, as shown by the marked selective decrease in cortical choline acetyltransferase (CAT) activity observed. Concurrent alterations in the kinetic parameters of high affinity glutamate uptake consisting mainly of a decrease in the Vmax were observed in the cerebral cortex. These changes presumably reflect a decreased glutamatergic transmission and provide support for the hypothesis that cortical glutamatergic neurons may undergo the influence of cholinergic projections from the NBM. Surprisingly, similar alterations in the glutamate uptake process were found to occur at hippocampal level in the absence of any significant change in the hippocampal cholinergic activity. These data indicate that the NBM may contribute to regulating hippocampal glutamatergic function without interfering with the hippocampal cholinergic innervation that mainly originates in the medial septal area-diagonal band (MSA-DB) complex. No change in parameters of GABAergic activity, namely the glutamic acid decarboxylase (GAD) activity and high affinity GABA uptake, were observed in any of the structures examined. In a second series of experiments involving bilateral intraventricular injections of AF64A, marked survival time-dependent decreases in CAT and high affinity choline uptake activities but no significant change in the high affinity glutamate uptake rate were observed in the hippocampus. No significant change in either parameters of cholinergic activity or in the glutamate uptake was concurrently observed in the cerebral cortex. The GABAergic activity was again unaffected whatever the survival time and the structure considered. Taken as a whole, these data suggest that basal forebrain projections originating in the NBM may play a major role in regulating glutamatergic but not GABAergic function in both the cerebral cortex and the hippocampus; whereas the glutamatergic and GABAergic activities in these two structures may not be primarily under the influence of the cholinergic projections from the MSA-DB complex.