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PubMed1964

CHRONIC LEUKEMIA.

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Adrenal Cortex Hormones↗
PubMed1977

Inhibition of neutrophil chemotaxis by 4-hydroxycyclophosphamide.

4-Hydroxycyclophosphamide, phosphoramide mustard, and nor-nitrogen mustard are compounds considered as candidates for the biologically active, alkylating metabolite of cyclophosphamide. These compounds were tested for inhibition of chemotaxis in neutrophils from normal human donors. Of those tested, only 4-hydroxycyclophosphamide caused a significant (p less than 0.01) decrease in the chemotactic index. The chemical precursor of 4-hydroxycyclophosphamide, 4-hydroperoxycyclophosphamide, caused a barely significant (p less than 0.05) decrease; 4-ketocyclophosphamide had no effect.

Alkylating Agents↗
PubMed1975

Influence of anti-oestrogens on the specific binding in vitro of (3H)oestradiol by cytosol of rat mammary tumours and human breast carcinomata.

The anti-oestrogenic potential of two nitrogen-mustard-containing compounds, I.C.I. 79792 and I.C.I. 85966, was studied. I.C.I. 85966 usually did not decrease specific binding of [3H]oestradiol by breast-tumour cytoplasmic proteins. I.C.I. 79792 decreased specific [3H]oestradiol binding, but not to the same extent as similar concentrations of I.C.I. 46474, diethylstilboestrol or dibutyldihydrostilboestrol.

Animals↗
PubMed1984

Antiasthmatic effects of onion extracts--detection of benzyl- and other isothiocyanates (mustard oils) as antiasthmatic compounds of plant origin.

Previous studies showed the inhibitory effects of crude ethanolic onion extracts (COE) on allergic skin reactions in man as well as on allergen-induced bronchial asthma in man and guinea-pigs. Work is in progress in order to identify both the mode of action of COE and the active substance(s). The present study describes asthma-protective effects of isothiocyanates. Groups of at least 5 guinea-pigs sensitized to ovalbumin were challenged twice (time 0 and 10 min) by the inhalation of ovalbumin 30 min after oral treatment with increasing doses of the agent tested or control solutions. Bronchial obstruction (BO) was measured by whole body plethysmography. Chloroform extracts of onions showed similar protective effects on BO as COE. The water-soluble fraction of COE was inactive. Benzyl-isothiocyanate (BITC) was identified as one component of onion lipids by combined gas chromatography/mass spectrometry. BITC inhibited BO in a dose-dependent fashion: 150 mg/kg: 89%; 75 mg/kg: 76%; 30 mg/kg: 66%; 15 mg/kg: 49%. Ethyl-isothiocyanate and allyl-isothiocyanate showed similar effects; p-hydroxy-benzyl-isothiocyanate, a very unstable mustard oil, was ineffective. Additional experiments showed no antagonistic effects of COE on histamine- or acetylcholine-induced BO. The antiasthmatic effects of onions and - perhaps - other plants may be mediated at least in part by isothiocyanates.

Administration, Oral↗
PubMed1992

The nature of cytotoxic drug-induced cell death in murine intestinal crypts.

The nature of cell death in murine small intestinal crypts caused by potentially lethal doses of four classes of cancer chemotherapeutic agents was studied. The drugs used were cytosine arabinoside, vincristine, adriamycin and nitrogen mustard. The compounds readily induced massive cell death in the proliferating compartment of the crypt. In each case, cell death was apparent within an hour, and the incidence of dead cells peaked during the following 4-8 h. By 24 h, little damage was discernible in the crypt systems. Remarkably, dead cells or dead cell fragments were phagocytosed rapidly (within about 1 h) by neighbouring healthy enterocytes. When examined by light microscopy, transmission electron microscopy and scanning electron microscopy, the dead cells showed the characteristic features of having succumbed to an apoptotic mode of cell death without any trace of cell and organelle oedema characteristic of necrosis. The study suggests that cell death by apoptosis operates even when the cells are exposed to severe pathological perturbation and that the phenomenon is not solely a process which operates in response to either physiological stimuli or to mild physical or chemical trauma.

Animals↗
PubMed1975

In vivo repair of rat intestinal DNA damage by alkylating agents.

In an effort to evaluate the possible correlation of the transforming ability of the known colon carcinogens dimethylhydrazine, 3-2'-dimethyl-4-aminobiphenyl, and methylazoxymethanolacetate to damage and repair of DNA, a series of compounds known to react with DNA-nitrogen mustard, methylmethanesulfonate, and mitomycin C--were administered to rats that had been prelabeled with 3H-thymidine. The DNA of crypt and villus of the jejunum and crypt and surface cells of the large bowel were analyzed by ultracentrifugation on an alkaline sucrose gradient. All fractions suffered degradation to such an extent that essentially no undamaged DNA was detectable. This was followed by repair and an increase in size. However, in the surface cells of the colon of animals that had received a carcinogenic insult there was far less rapid repair. Since this is the site where tumors would ultimately arise these data are supportive of the hypothesis that there is a relationship between decreased repair and carcinogenicity. In view of the age related incidence of colon cancer, repair in older animals was evaluated and was found to be less than that seen in the young. Since multiple treatment with the carcinogen dimethylhydrazine is required and there is a long latent period, the effect of this treatment on repair potential was evaluated. Similar to what was seen in the older animals, these treated rats had greatly reduced capacity to repair DNA. All these observations are consistent with the hypothesis that decreased repair of DNA alterations is a concomitant of carcinogenesis.

Alkylating Agents↗
PubMed1994

The determination of cyclophosphamide and its metabolites in blood plasma as stable trifluoroacetyl derivatives by electron capture chemical ionization gas chromatography/mass spectrometry.

A method is described for the determination of the antitumour drug cyclophosphamide and six stable metabolites in plasma of cancer patients, namely dechloroethyl-cyclophosphamide, 4-keto-cyclophosphamide, carboxy-phosphamide, alcophosphamide, nor-nitrogen mustard and the N-chloroethyl-1,3-oxazolidine-2-one, as methyl and/or trifluoroacetyl derivatives by single ion monitoring gas chromatography/mass spectrometry, mostly in the electron capture chemical ionization mode. The isolation of most metabolites was performed by solid-phase C-18 extraction in weakly acidic medium. The phosphoramide mustard isolated under these conditions decomposes readily to the nor-nitrogen mustard during derivatization. The original nor-nitrogen mustard and the chloroethyl-1,3-oxazolidine-2-one were isolated by liquid extraction with ethyl acetate in alkaline medium. Recoveries of 75-99% were measured using spiked blank plasma samples. Quantitation of metabolites in patient plasma samples was performed using two sets of calibration curves for the concentration ranges of 1-100 ng and 0.1-10 micrograms of metabolite per millilitre of original plasma.

Antineoplastic Agents↗