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Biomedical subjects

A D Lewis

Publications and source records attributed to A D Lewis.

47 records · Page 3Linked to original sources
PubMed1988

Glutathione S-transferase isoenzymes and glutathione peroxidase activity in normal and tumour samples from human lung.

An increasing body of evidence suggests that glutathione-dependent enzymes are an important factor in determining the sensitivity of tumours to cytotoxic drugs. Ten randomized normal and tumour samples from individuals with lung cancer were analysed for glutathione S-transferase isoenzyme (GST) content and glutathione peroxidase (Gpx) activity. The normal tissue samples exhibited a 5.1- and 7.0-fold variation in GST and Gpx activity respectively. High levels of the pi class, acidic Yf, GST subunit were found in all the samples, with little variation between individuals. The concentration of alpha and mu class subunits was 5- to 10-fold lower and were subject to significant individual variability. The mu class subunit identified had a faster mobility on SDS-PAGE than the hepatic GST mu standard and did not appear subject to the genetic polymorphism associated with certain members of this gene family. This suggests the presence of a novel pulmonary protein which may correspond to the rat Yn Yn protein. The normal to tumour ratio for GST activity varied significantly between the samples and tended to follow the relative expression of the mu class subunit, and to a lesser extent the alpha class GST subunit. The pi subunit was present in the normal and tumour cells in very similar concentration. The expression of the mu class GST appeared to follow the differences in GST enzymic activity and although the numbers were small appeared to segregate according to tumour type. Gpx activity was also elevated in certain tumours. Of particular interest were the two adenocarcinomas which had a 20- to 30-fold higher tumour Gpx activity.

Enzyme Induction↗
PubMed1987

Reduced levels of drug-induced DNA cross-linking in nitrogen mustard-resistant Chinese hamster ovary cells expressing elevated glutathione S-transferase activity.

We have reported previously (C. N. Robson et al., Cancer Res., 46: 6290-6294, 1986) the isolation of a Chinese hamster ovary cell line, designated CHO-Chlr, that exhibits resistance to bifunctional nitrogen mustards while maintaining the normal parental level of sensitivity to several other alkylating agents. We have compared the rate of formation and repair of DNA cross-links induced by mechlorethamine in CHO-Chlr and parental CHO-K1 cells, both in intact cells and in isolated nuclei. Equimolar doses of mechlorethamine induce significantly fewer DNA interstrand cross-links in CHO-Chlr cells than in CHO-K1 cells, but levels of DNA-protein adducts are approximately equivalent in the two lines. There is a correlation between the relative resistance of CHO-Chlr cells to mechlorethamine (34-fold) and the amount of drug required to induce approximately equal numbers of DNA interstrand cross-links in the two cell lines. This strongly implicates DNA-DNA adducts in the cytotoxic action of mechlorethamine. DNA cross-linking studies on isolated nuclei reveal only minor differences between the two lines even with identical drug treatments. The rate of cross-link repair is comparable in the two cell lines. These results, taken together with our earlier observation that the rate of drug accumulation is identical in these two lines, suggest that enhanced cytoplasmic drug detoxification is the underlying resistance mechanism in CHO-Chlr cells. We have measured cellular glutathione S-transferase activity, using both the general substrate 1-chloro-2,4-dinitrobenzene, and substrates with some specificity for the different classes of transferase isoenzymes. Total enzyme activity (as measured with 1-chloro-2,4-dinitrobenzene) is elevated 3-fold in the resistant cells. A 2- and 5-fold increase, respectively, in activity against ethacrynic acid and cumene hydroperoxide is detectable in CHO-Chlr cells. This elevation in catalytic activity in the resistant cells is reflected in higher levels of both the Yf- and Ya-type transferase subunits.

Animals↗
PubMed1987

Cellular heterogeneity and drug resistance in two ovarian adenocarcinoma cell lines derived from a single patient.

Two ovarian cell lines were derived from the ascites of a patient before and after the onset of resistance to chemotherapy involving cis-platinum, chlorambucil and 5-fluorouracil. Characterization of these lines shows them to have various features in common and some significant differences. Cytologically the lines cannot be distinguished and they both contain high concentrations of oestrogen receptor. However, they do differ with respect to their growth characteristics, karyotype, glutathione content and sensitivity to cis-platinum. The karyotypes of the 2 lines show several marker chromosomes in common but the resistant line contained a chromosome 8 and a 17 which were absent from the earlier sensitive line. This suggests a clonal origin with subsequent divergence to a heterogeneous population.

Adenocarcinoma↗
PubMed1987

Induction and suppression of glutathione transferases by interferon in the mouse.

The administration of interferon-alpha/beta to female nude (nu/nu) mice caused significant changes in the levels of the cytosolic hepatic glutathione transferases. Antibodies raised against rat subunits, Ya, Yc, Yb1, Yb2, and Yk, and the subunits of the human transferases, mu (YbYb), lambda (YfYf), and epsilon (B1B1) all reacted with enzymes in the mouse and were used to demonstrate suppression and induction of transferase levels. Western blot analysis followed by semiquantitation by laser scanning showed the Ya, Yb1, Yb2, Yc, Yk, mu, and B1 subunits to be suppressed by 11, 11, 44, 30, 12, 14, and 47%, respectively, by interferon treatment. In contrast to these findings, the Yf subunit was induced 5-7-fold. A concomitant 220% increase was observed in the specific activity of the hepatic cytosol for ethacrynic acid, a substrate for the Yf subunit. Changes in the levels of transferase enzymes in normal and tumor cells may have significant implications when cytotoxic drugs are used in combination with interferons in cancer therapy. The Yf subunit, an enzyme found in human tumors and in placenta (Polidoro, G., Di Mio, C., Del Boccio, G., Zulli, P., and Fererici, G. (1980) Biochem. Pharmacol. 29, 1677-1680) has also been shown to be elevated in hepatic preneoplastic lesions (Kitahara, A., Satoh, K., Nishimura, K., Ishikawa, T., Ruike, K., Sato, K., Tsuda, H., and Ito, N. (1984) Cancer Res. 44, 2698-2703). These data indicate that the Yf subunit represents a potentially important interferon-inducible gene product.

Animals↗
PubMed1984

The effect of the immunomodulator corynebacterium parvum on hemisplenectomized mice.

The immunomodulator Corynebacterium parvum stimulates the reticuloendothelial system and causes splenic hypertrophy. The ability of C parvum to stimulate splenic regeneration in hemisplenectomized mice and decrease susceptibility to intranasal pneumococcal challenge was studied. Mice were divided into two groups, control sham-operated (n = 48) and hemisplenectomized (n = 47) animals. Ten days later, each group was divided into two subgroups, those injected with C parvum (700 mcg IVP) and those injected with an equivalent volume of saline. The animals were challenged with Streptococcus pneumoniae, which was injected into one nostril three weeks postoperatively, and mortality was assessed. Four and one-half weeks postoperatively, splenic tissue was removed, measured, weighed, and submitted for histologic examination. The number of spleen cells per gram of tissue was assessed. Treatment with C parvum resulted in a significant increase in the splenic weight in both hemisplenectomized and control animals compared to similar saline-injected mice (P less than 0.001). The percentage increase in spleen weight of hemisplenectomized mice (106%) was significantly greater than that for control animals (56%; P less than 0.01). There was no significant difference among experimental groups in the number of spleen cells per gram of splenic tissue or in the histologic characteristics, indicating that C parvum stimulated relatively normal splenic growth. Survival following pneumococcal challenge was significantly increased for hemisplenectomized mice by C parvum treatment to a level that did not significantly differ from control mice. This study demonstrates that in mice the deficits related to resistance to infection and spleen size following hemisplenectomy are significantly improved by treatment with C parvum.

Adjuvants, Immunologic↗
PubMed1980

The mechanism of hyperlipidaemia in nephrotic syndrome--role of low albumin and the LCAT reaction.

Diminished autologous LCAT activity was found in patients with proteinuria. This was due to substrate limitation and albumin appeared the most likely limiting factors. It is suggested that low albumin can contribute to the hyperlipidaemia of nephrotic syndrome through its role on the LCAT reaction. Evidence of the ability of triglyceride to enhance homologous LCAT activity was also noted.

Adolescent↗
PubMed1978

An unusual case of North American blastomycosis.

A patient with a laryngeal tumor first diagnosed as squamous cell carcinoma was subsequently found to have North American blastomycosis. Diagnosis of this condition eventuated in eradication of the lesion as well as removal of a tracheostomy, which was thought to be permanent.

Aged↗