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At least 145 records · Page 8Linked to original sources
PubMed1988

Effect of AF64A on the cholinergic systems of the retina and optic tectum of goldfish.

AF64A, a presumed selective cholinergic neurotoxin has been used to study the effect on cholinergic systems of the goldfish retina and optic tectum. Toxin injection in the vitreum and in the optic tectum caused a selective decrease of choline acetyltransferase activity in both areas, while no significant decrease of glutamate decarboxylase and D-3H aspartate uptake were observed at different times after the injections. The effect was particularly dramatic in the retina of long term-injected animals, where choline acetyltransferase dropped to practically zero level. The ultrastructural analysis showed selective degeneration of some neurons in the amacrine and ganglion cell layer of the retina as well as of synaptic terminals and neuronal cell bodies in the optic tectum. The results favour a selective cholinotoxicity of AF64A in fish nerve tissue at doses substantially higher than those found to have additional unselective effects in mammals.

Animals↗
PubMed1987

A phase II trial of diaziquone in patients with head and neck cancer.

Diaziquone (AZQ) is a lipophilic alkylating agent which crosses the blood-brain barrier and has marked antitumor activity in a broad spectrum of murine tumor systems. Myelosuppression has been the dose-limiting toxicity in phase I trials. In this study 36 patients with head and neck cancer received diaziquone. Thirty-one of these patients (28 male, 3 female) were evaluable for efficacy. The initial starting dose was 7 mg/m2/day X 5 days i.v. repeated every 28 days. Because of the severe myelosuppression encountered in the first four patients, the starting dose was decreased by 20% to 5.5 mg/m2/day X 5 days repeated every 28 days. The majority of patients were considered to be good-risk patients as evidenced by performance status (80% 0-1 Zubrod) and prior therapy. Even with this dosage reduction, myelosuppression (especially thrombocytopenia) was again the dose-limiting toxicity with 25% of patients experiencing granulocyte and platelet nadirs below 1000/mm3 and 50,000/mm3 respectively. Thirty-five percent of patients required a subsequent dosage reduction of 20% prior to receiving a second course of therapy. There was one complete (CR), four partial (PR) and three minor (MR) responses. All but the CR were of relatively short duration (mean of 30 days). The patient with a CR has remained disease-free for nearly 3 years. In this group of patients the activity of diaziquone as a single agent at this dose and schedule (CR + PR + MR = 26%; CR + PR = 16%) is less than that of methotrexate, bleomycin, and cis-platinum but is encouraging. Further trials utilizing combinations are warranted.

Adult↗
PubMed1986

CB 1954 revisited. I. Disposition kinetics and metabolism.

Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 micrograms/ml in mice, while 25 mg/kg gave peak plasma concentrations of 27 micrograms/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t1/2 values were 1.4-2 h in mice and 2.5-4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%-90%, while brain: plasma ratios were lower, at 37%-50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%-29%, of which 16%-25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new 'mixed-function' sensitizers.

Allopurinol↗
PubMed1986

CB 1954 revisited. II. Toxicity and antitumour activity.

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.

Animals↗
PubMed1980

Phase I study of ethylbis(2,2-dimethyl-1-aziridinyl) phosphinate (AB-163).

Ethylbis(2,2-dimethyl-1-aziridinyl)phosphinate (AB-163) was used to treat 27 patients in a phase I trial. The limiting toxicity on a weekly schedule of IV administration involved nausea and vomiting associated with a variety of cholinergic side effects, including possible seizures. A starting dose of 300--400 mg/M2/week is suggested for a Phase II trial. One partial response in a patient with squamous-cell carcinoma of the cervix metastatic to the lungs was seen.

Adult↗
PubMed1983

Determination of the antitumor agent SOAz (1,3,3,5,5 pentakis(aziridino)-1 lambda 6,2,4,6,3 lambda 5, 5 lambda 5 thia-triazadiphosphorine-1-oxide) by a gas chromatographic assay suitable for pharmacokinetic studies in man.

A sensitive method, based on capillary gas chromatography using a thermionic detector, has been developed for the new antitumor agent pentakis(aziridino)-thiatriazadiphosphorine-oxide, (NPAz2)2NSOAz ('SOAz'), in order to obtain pharmacokinetic data from patients receiving this drug IV in clinical trials. A structural analog of SOAz, (NPAz2)2NSOPh ('SOPh'), was used as an internal standard. The detection limit of SOAz with this method was 0.01 mg/l for serum and 0.04 mg/l for urine. The coefficient of variation (n = 10) was 6,0% at 1.5 mg/l in serum and 1.6% at 75.0 mg/l in urine. Analytical recoveries averaged 89.9% from serum and 86.7% from urine. In two patients treated with subtoxic doses of SOAz (55 mg/m2), serum levels were found ranging from 3.0 to 0.16 mg/l at 10 min and 12 h, respectively, after administration. This assay seems to be useful for determining SOAz in samples from patients receiving subtoxic doses of SOAz.

Aged↗
PubMed1983

Clinical pharmacokinetics of (NPAz2)2NSOAz: 'SOAz'.

Pharmacokinetic studies of 1,3,3,5,5 pentakis (aziridino)-1 lambda 6,2,4,6,3 lambda 5,5 lambda 5 thiatriazadiphosphorine-1-oxide ('SOAz'), a new antineoplastic agent containing an inorganic ring system and five aziridino groups, were performed in six patients who took part in a phase I clinical trial of the agent. The drug was administered as a rapid IV infusion. Serum decay curves could be fitted to an open two-compartment model of drug disappearance. After a short initial phase with a t 1/2 (+/- SD) of 7.8 +/- 4.2 min a terminal phase with a dose-independent half-life of 203 +/- 17 min occurred. The coefficient of apparent distribution was 0.71 +/- 0.13. The renal clearance was 75 +/- 11 ml/min and the total body clearance 162 +/- 23 ml/min. A percentage of 46.5 +/- 6.6 of the administered drug could be recovered unchanged in the urine within 24 h. It is concluded that in view of concentrations known to be effective in vitro, administration in large single doses may be advantageous. Dose adjustments should be made for patients with impaired renal function.

Adult↗
PubMed1983

Phase I clinical trial of (NPAz2)2NSOAz: 'SOAz'.

(NPAz2)2NSOAz ('SOAz') is the first of a new class of cytotoxic agents containing an inorganic heterocyclic ring system to enter clinical trial. It was used to treat 31 patients with advanced cancer by IV infusion over 30 min on days 1, 2, 3, and 4 of a 21-day cycle, which was postponed if necessary to allow for hematological recovery. A total of 46 courses evaluable for toxicity was given and the tumor response was evaluable in 21 patients. Seven dose levels, ranging from 25 mg/m2 to 300 mg/m2, were studied, with three to six patients at each level. The only major toxicity was myelosuppression, especially thrombocytopenia, which was dose-limiting. Platelets decreased from the 14th day onward, with a nadir 4-5 weeks after administration. Leukopenia was less predictable and reached a nadir 3-5 weeks after administration. In most patients recovery was complete after 6-9 weeks. Myelosuppression was clearly cumulative in succeeding courses and proved irreversible in three patients. Anemia also occurred, but otherwise SOAz was remarkably well tolerated. There were no responses and no therapy-related deaths. The highest tolerated dose for patients who had received no or only minor chemotherapy prior to treatment with SOAz was 300 mg/m2, and that for heavily pretreated patients, 175 mg/m2. Because of cumulative myelotoxicity phase II studies with SOAz are not recommended.

Adult↗
PubMed1981

Anticancer drug sensitivity in vitro in the bladder cancer cell line, KK-47 and prophylactic use of carbazilquinone and urokinase in bladder cancer.

Using colony formation technique and KK-47 cell line established from a human bladder transitional cell carcinoma, the effect of 6 anticancer drugs, thio-TEPA, Bleomycin, mitomycin C, carbazilquinone, Adriamycin and cis-Platinum, were compared. On the results of tests performed to establish the drug concentration required to achive a 50% inhibition of cell survival, carbazilquinone was chosen for the prevention of recurrences of bladder cancer. The two groups studied consisted of 56 patients (previously untreated groups) who were rendered free of tumours by surgical intervention and of 19 patients (thio-TEPA failures group) who had experienced a persistent recurrence of tumours after prophylactic thio-TEPA instillations and were presumed free of the recurrence of tumours after the next surgical intervention. The 2 groups were subjected to prophylactic combined intravesical instillation therapy with carbazilquinone and urokinase. In the previously untreated group, 6 of the 56 patients (10.7%) had a recurrence of tumours, and the recurrence rate after 21 months was 16.7%, using the actuarial method. In the thio-TEPA failures group, 12 of the 19 patients (63.2%) had a recurrence of tumours, a rate at 21 months of 76.1%. A considerable drop in the recurrence rate was obtained by the combined instillation therapy in the previously untreated group. The results in the thio-TEPA failures group suggested the presence of a cross-resistance between both alkylating agents, and of a persistent susceptibility to multifocal lesions. No bone marrow depression was observed but an episode of anaphylactic shock attributable to the use of carbazilquinone occurred in 1 out of a total 75 patients.

Adult↗
PubMed1985

Combined therapeutic effects of an immunomodulator, PSK, and chemotherapy with carboquone on rat bladder carcinoma.

Responses of bladder cancer in ACI rats to combination therapy with an immunomodulator, PSK, and an alkylating agent, carboquone, are reported. PSK is a protein-bound polysaccharide isolated from Basidiomycetes, and carboquone is the alkylating agent 2,5-bis(1-aziridinyl)-3-(2-hydroxy-1-methanoxyethyl)-6-methyl-p- benzoquinone carbonate, molecular weight 3,214. The immunomodulator, PSK, was shown to enhance the effectiveness of the chemotherapeutic agent, carboquone. The therapeutic effect of combination treatment was monitored by measuring growth rates of tumors transplanted SC and by measuring decreases in metastatic spread to lungs in tumor-bearing animals. Effects of PSK on host immunity were monitored by measuring serum levels of immunosuppressive substance.

Adjuvants, Immunologic↗
PubMed1979

Effects of alkylating agents on lymphocytes from controls and from patients with Fanconi's anemia. Studies of sister chromatid exchanges, chromosome aberrations, and kinetics of cell division.

The frequency of sister chromatid exchanges (SCE) and chromosome aberrations and the dynamics of cell division in peripheral blood lymphocytes of four patients with Fanconi's anemia were studied after in vitro exposure to alkylating agents TEPA and mitomycin. SCE frequency was significantly increased even after very low doses of mutagens, while chromosome aberrations were significantly increased only after high doses (0.160 micrograms/ml mitomycin and 10(-5) M TEPA). The responses of Fanconi's anemia cells and control cells did not differ significantly. The increased frequency of both SCE and chromosome aberrations was accompanied by gradual delay of cell division, which was most conspicuous in cells from patients with Fanconi's anemia.

Anemia, Aplastic↗
PubMed1986

cis- and trans-1,2-diphenylaziridines: induction of xenobiotic-metabolizing enzymes in rat liver and mutagenicity in Salmonella typhimurium.

trans-Stilbene imine (trans-1,2-diphenylaziridine) is the nitrogen analog of trans-stilbene oxide, a potent inducer of several microsomal and cytosolic xenobiotic-metabolizing enzymes. Although the acute toxicity of cis- and trans-stilbene imines prevents their application at the usual dose for trans-stilbene oxide (400 mg/kg/day), it is apparent that the imines nevertheless potently induce several xenobiotic-metabolizing enzymes in rat liver. The IP administration of trans-stilbene imine resulted in statistically significant increases in the activities of aminopyrine N-demethylase, microsomal epoxide hydrolase, glutathione transferase (toward 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene and delta 5-androstene-3,17-dione) and UDP-glucuronosyltransferase (toward testosterone). cis-Stilbene imine was less potent in inducing these activities. Although trans-stilbene imine (total dose = 400 mg/kg) was more potent than trans-stilbene oxide (total dose = 1200 mg/kg) in inducing the activities of glutathione transferase (toward 1-chloro-2,4-dinitrobenzene) and UDP-glucuronosyltransferase (toward testosterone), both compounds belong to the class of substances which are more potent inducers of conjugating (phase II) enzymes. Because of their structural similarity with K-region arene imines which are potent mutagens, cis-stilbene imine and trans-stilbene imine were investigated for mutagenicity (reversion of his- strains of Salmonella typhimurium). cis-Stilbene imine and trans-stilbene imine were direct mutagens in the strain TA100. This result, and the finding that acenaphthene 1,2-imine efficiently reverts various strains of Salmonella typhimurium, demonstrates that not only K-region arene imines, but also other aziridines substituted at the two carbons with aromatic moieties, are mutagenic.

Animals↗
PubMed1984

Effects of the cholinotoxin, AF64A, on neuronal trace-metal distribution in the rat hippocampus and neocortex.

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.

Animals↗
PubMed1987

Influence of the tissue distribution of ThioTEPA and its metabolite, TEPA, on the response of murine colon tumours.

Disposition studies in the same animals as those used for assessment of antitumor and toxic effects could increase understanding of the variation in response to cytotoxic drugs. Tissue and plasma levels of ThioTEPA and triethylenephosphoramide (TEPA) were measured to see if any correlation existed between them and the effects of the drug on a series of mouse colon tumours (MAC). The tumour panel included an ascitic form (MAC 15A), an anaplastic (MAC 13) and a well-differentiated (MAC 26) solid tumour, all grown subcutaneously. The maximum tolerated dose of ThioTEPA was 20 mg kg-1 in females bearing MAC 13 and 15 mg kg-1 in males having MAC 15A or 26. The diverse growth characteristics of the tumour cell lines necessitated the use of different methods for assessment of response. After administration of the maximum tolerated dose, the greatest response was observed in MAC 26, in which a growth delay of 15 days-twice the doubling time of the tumour volume-occurred. ThioTEPA produced 58% inhibition of MAC 13 tumour weight, but MAC 15A was unresponsive. One hour after intraperitoneal administration of Thio-TEPA (20 mg kg-1), ratios of tissue to plasma concentration were 1.13, 0.87 and 1.17 in tumours and 0.80, 0.75 and 0.73 in spleens of mice bearing MAC 13, 15A and 26 respectively. These data show greater accumulation of drug in neoplastic than in normal tissues. The pattern of distribution of the metabolite was similar, but there was a lesser degree of tissue accumulation than by the drug. Concentrations of drug and metabolite in neoplastic tissues related to their protein content were 116.0, 126.3 and 183.3 micrograms ThioTEPA/g and 57.5, 83.1 and 78.6 micrograms TEPA/g in MAC 13, 15A and 26 respectively. Combination of these chemosensitivity and pharmacokinetic data indicates that differences in response of these tumours to ThioTEPA cannot be explained by the availability of the drug and metabolite. The therapeutic effects of ThioTEPA cannot be predicted purely from a knowledge of drug and metabolite disposition.

Adenocarcinoma↗