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Biomedical subjects

K R Harrap

Publications and source records attributed to K R Harrap.

At least 109 records · Page 6Linked to original sources
PubMed1979

Enhancement of the nuclear reactivity of alkylating agents by prednisolone.

We have compared the nuclear reactions of the alkylating agents chlorambucil, melphalan, and cyclophosphamide used alone, with those produced when the same drugs were used in combination with the corticosteroid prednisolone. Studies were performed in vivo in Wistar rats bearing ascites forms of either the Yoshida sarcoma or the Walker carcinosarcoma. Strains of both tumor lines, which were sensitive to alkylating agents, showed loss of condensed chromatin, increased phosphorylation of nuclear proteins, and increased DNA cross-linking after exposure to the alkylating agents alone; these changes were generally enhanced in the presence of prednisolone. When paired tumor lines which exhibited acquired resistance to alkylating agents were studied, no nuclear changes were detected when individual alkylating agents were given alone. However, in combination with prednisolone, each of the three alkylating agents produced loss of condensed chromatin, increased nuclear protein phosphorylation, and DNA cross-linking. These chromatin changes were associated with tumor cell death and may determine drug sensitivity in the tumors studied.

Alkylating Agents↗
PubMed1977

Some effects of chlorambucil on nuclear protein phosphorylation in the Yoshida ascites sarcoma.

The ability of nuclei, isolated from Yoshida ascites sarcoma cells, to phosphorylate nuclear proteins in the presence of [gamma-32P]ATP has been investigated. Comparisons were made between a strain sensitive to the effects of the alkylating agent, chlorambucil, with a corresponding resistant strain both before and after drug-treatment of tumour-bearing animals. There was no gross quantitative differences between the drug-sensitive and-resistant untreated cells but treatment resulted in increased levels in the sensitive strain. Qualitative differences were seen before treatment in the phosphorylation pattern of the tris-saline-soluble nuclear sap fraction. The high molecular weight species in the fraction from sensitive cells showed phosphorylations which were absent, or present at very low levels, in the corresponding fraction from drug-resistant cells. Changes were observed in the tris-saline-soluble and non-histone protein fractions from drug-sensitive cells following treatment of tumour-bearing animals. Only minor alterations in patterns of phosphorylation were seen in fractions from drug-resistant cells.

Animals↗
PubMed1977

Some observations on the reversibility of methotrexate toxicity in normal proliferating tissues.

Thymidine, in the absence of hypoxanthine, failed to protect normal mice from the acute toxicity of methotrexate, though tumor-bearing animals could be protected with thymidine alone, probably as a result of the availability of DNA degradation products released from drug-sensitive tumor cells. Although metrotrexate induced an early purine deficiency in gut cells, this effect was not detected in bone marrow. Later, purine deficiency became apparent in the gut and bone marrow of methotrexate-treated animals.

Animals↗
PubMed1977

Some observations on the human pharmacology of methotrexate.

Plasma and urinary levels of methotrexate (MTX) have been measured enzymatically in 18 patients receiving doses of 5-1250 mg. When tritium-labeled MTX was administered, plasma levels measured by radioisotope counting were significantly higher than those measured enzymatically, the difference being accounted for by the presence of tritium label in plasma water as a result of drug metabolism. Renal clearance of MTX correlated well with glomerular filtration rate (GFR) and was consistently lower than the GFR, suggesting tubular reabsorption of the drug at the rate of urine flow studied. Plasma clearance measured by an infusion method was consistently greater than renal clearance, suggesting drug metabolism. Biliary MTX levels have been measured in three patients and are very much higher than plasma levels, suggesting a quantitatively important biliary recirculation of the drug. Plasma levels of MTX measured after 24 hours were not significantly different following iv or im administration, but were higher if an infusion was used.

Bile↗
PubMed1976

The reaction of Cytembena with cellular thiol compounds.

Cytembena has been shown to undergo a rapid addition reaction with a number of thiol compounds, including glutathione and cysteine, resulting in alkylation of the sulphur. Administration of Cytembena to Yoshida sarcoma cells and to L1210 leukemia cells resulted in a loss of titratable thiol groups within the cells, though the loss of thiol groups caused by pharmacologically active doses of the drug was not sufficient to account, in itself, for the observed toxicity. The addition product of Cytembena and glutathione was isolated and tested for cytotoxicity; it was much less effective than free Cytembena. It is concluded that this reaction acts as a route of detoxification of Cytembena.

Acrylates↗
PubMed1976

Intrinsic resistance to methotrexate of cultured mammalian cells in relation to the inhibition kinetics of their dihydrololate reductases.

Four cultured mammalian cell lines, differing in intrinsic resistance to methotrexate over a 70-fold range, have been compared with respect to several biochemical factors that might influence response to the drug. Cellular activity of the enzymes dihydrofolate reductase and thymidylate synthetase and the total levels of folate cofactors did not vary by more than a factor of 2 among the cell lines. All the cell types were able to transport extracellular methotrexate efficiently across the cell membrane, and at comparable rates. A kinetic study of highly purified dihydrofolate reductases from the four sources revealed small differences in the Km values for dihydrofolate and reduced nicotinamide adenine dinucleotide phosphate. A study was made of the inhibition of the four dihydrofolate reductases by methotrexate, and Ki values were obtained by fitting the Zone B equation of Goldstein (Goldstein, A., J. Gen. Physiol., 27: 529-580, 1944) to the resulting data. Values Ki determined by this method correlated with intrinsic resistance of the cell lines and showed a 25-fold range from the most sensitive to the most resistant line. It is concluded that the response of a cell to methotrexate is significantly influenced by the dissociation constant of its dihydrofolate reductase-methotrexate complex.

Biological Transport↗