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Biomedical subjects

R D Armstrong

Publications and source records attributed to R D Armstrong.

At least 55 records · Page 3Linked to original sources
PubMed1983

Histocompatibility antigens in psoriasis, psoriatic arthropathy, and ankylosing spondylitis.

Patients with ankylosing spondylitis, psoriatic arthritis, and psoriasis alone were typed for HLA A, B, Cw, and DR antigens, and the antigen frequencies were compared with those in a normal control population and in patients with rheumatoid arthritis. Patients with psoriasis had a significantly raised frequency of Cw6. Those with arthritis in addition to their psoriasis also had raised frequencies of B27 and DR7. Patients with ankylosing spondylitis were characterised by the expected high frequency of HLA B27. Again, those with peripheral arthritis had a higher B27 and DR7 frequency than those without. DR3 is associated with the development of erosions in psoriatic arthritis.

Arthritis↗
PubMed1983

5'-Deoxy-5-fluorouridine selective toxicity for human tumor cells compared to human bone marrow.

Studies were completed to establish the comparative cytotoxicity of 5'-deoxy-5-fluorouridine (5'-dFUrd) and other fluoropyrimidines in human bone marrow stem cells and several cultured human tumor cell lines (i.e., 47-DN and MCF-7 breast carcinomas, MG-63 osteosarcoma, HCT-8 colon tumor, Colo-357 pancreatic tumor, and HL-60 promyelocytic leukemia). In vitro clonogenic assays were used to measure cytotoxicity following a 3-hr drug exposure. 5'-dFUrd was less potent than was 5-fluorouracil or 5-fluoro-2'-deoxyuridine in all cells examined, exhibiting its best activity against the 47-DN [concentration that prevented 50% clonal growth compared to untreated control (LD50) = 32 microM] and MCF-7 (LD50 = 35 microM) breast carcinomas and MG-63 osteosarcoma (LD50 = 41 microM). Intermediate activity was observed against HCT-8 (LD50 = 200 microM) and Colo-357 (LD50 = 150 microM) gastrointestinal tumors. 5'-dFUrd had very poor activity against the HL-60 leukemia (LD50 = 470 microM). The suppression of the clonal growth of human bone marrow stem cells required the greatest amount of 5'-dFUrd (LD50 = 580 microM). With use of these studies, a therapeutic ratio (concentration that prevented 25% clonal growth compared to untreated control of bone marrow divided by LD50 of tumor) was calculated for each drug in each tumor. 5'-dFUrd had values ranging from 1.2 to 7.5 for the solid tumors and 0.5 in HL-60 cells. This was in marked contrast to 5-fluorouracil, or 5-fluoro-2'-deoxyuridine, which failed in all cases to have ratios greater than or equal to one. The results indicate that 5'-dFUrd can exhibit a cytotoxic selectivity for human tumor cells compared to human bone marrow stem cells that does not exist for 5-fluorouracil or 5-fluoro-2'-deoxyuridine. This suggests that 5'-dFUrd may be of greater therapeutic benefit in the treatment of certain human cancers than the fluoropyrimidines used currently.

Antineoplastic Agents↗
PubMed1983

Decreased immunosuppression associated with antitumor activity of 5-deoxy-5-fluorouridine compared to 5-fluorouracil and 5-fluorouridine.

5-Fluorouracil (5-FUra), 5-deoxy-5-fluorouridine (5'dFUrd), and 5-fluorouridine were compared for their relative antitumor activity, their capacity to inhibit leukocyte exudation and macrophage (macrophage) killing of tumor cells in vivo and in vitro, and their ability to induce leukopenia and monocytopenia. 5'dFUrd was less toxic than 5-FUra and exhibited anti-Ehrlich ascites activity over a wider range of drug doses. Inflammatory exudates induced by thioglycollate or pyran were inhibited up to 91% by prior 5-FUra injection but were inhibited not more than 62% by 5'dFUrd. Pyran-induced macrophage inhibition of Ehrlich ascites proliferation in vivo was diminished up to 5-fold by 5-FUra but was never diminished more than 2-fold by 5'dFUrd, while neither agent suppressed in vitro macrophage cytotoxicity of in vivo pyran-activated macrophage. At high doses, 5-FUra reduced white blood cell counts 73%, in contrast to the 8% reduction caused by 5'dFUrd, while at their optimal anti-Ehrlich ascites doses, 5-FUra and 5'dFUrd both lowered white blood cell counts by only 20%. However, 5-FUra caused a severe monocytopenia not seen in animals given injections of comparable doses of 5'dFUrd. Therefore, 5-FUra appeared to inhibit the inflammatory response and antitumor activity by inhibiting the influx of immature macrophage into the peritoneal cavity, not by inhibiting the function of mature effector cells.

Animals↗
PubMed1983

Cytotoxic activity of 5'-deoxy-5-fluorouridine in cultured human tumors.

The cytotoxic activity of 5'-deoxy-5-fluorouridine (5'-ddFUrd) was established in six cultured human tumor lines: 47-DN and MCF-7 breast carcinomas, MG-63 osteosarcoma, HCT-8 colon carcinoma, Colo-357 pancreatic carcinoma, and HL-60 promyelocytic leukemia. Cells were exposed to a wide range of 5'-dFUrd concentrations (from 0.1 microM to 1.0 mM) for 3, 6, or 24 hrs, and then cloned using standard in vitro clonogenic assays. 5'-dFUrd exhibited its best activity in the 47-DN and MCF-7 breast cell lines and in the MG-63 osteosarcoma line (3-hr LD50 values of 32, 34, and 38 microM, respectively). Less activity was observed in the HCT-8 colon (LD50 = 195 microM) and Colo-357 pancreatic (LD50 = 155 microM) tumor lines, and ver poor activity was noted in the HL-60 leukemia cell line (LD50 = 465 microM). The metabolism of 5'-dFUrd to 5-FU (FUra) and FUra-nucleotides was determined and found to directly correlate with the potency of 5'-FUrd in these cell lines. These results suggest that: (a) there is a marked variation in sensitivity of human cancer cells of different tissue origin to 5'-dFUrd, (b) there is a direct relationship between the sensitivity of human cells to 5'-dFUrd and the ability of the cell to metabolize 5'-dFUrd to FUra, and (c) increasing exposure period of cells to 5'-dFUrd did not markedly alter 5'-dFUrd potency in all human cancer cells examined, with the exception of the 47-DN breast cancer cells.

Breast Neoplasms↗
PubMed1983

Histocompatibility antigens in polymyalgia rheumatica and giant cell arteritis.

Fifty-five Caucasoid patients with polymyalgia rheumatica or giant cell arteritis were typed for HLA, A, B, C and DR locus antigens. In the total patient group, DR4 had a significantly increased frequency. The prevalence of CW3 and CW6 was also significantly increased, the rise of CW3 possibly being attributable to its well-documented linkage disequilibrium with DR4. The rise in CW6 cannot be attributed to its known linkage disequilibrium with DR7.

Genes, MHC Class II↗
PubMed1982

Improved measurement of thymidylate synthetase activity by a modified tritium-release assay.

Accurate quantitation of thymidylate synthetase activity using a tritium-release assay is dependent upon measurement of only that tritium released from deoxy[5-3H]uridine monophosphate ([3H]dUMP) during the biosynthesis of thymidylate. Removal of remaining [3H]dUMP on completion of the assay by charcoal adsorption and correction for the nonenzymatic release of tritium are necessary. Although over 99% of [3H]dUMP is removed immediately following addition of charcoal, these studies demonstrate that sufficient [3H]dUMP can remain to prevent accurate measurement of low levels of thymidylate synthetase activity. By delaying measurement of radioactivity for at least 24 h following addition of charcoal, this problem is minimized. To account for nonenzymatic release of tritium, a blank containing enzyme extract with omission of +/- ,L-5,10-methylenetetrahydrofolate is demonstrated to be more effective than the commonly used blank in which water is substituted for enzyme extract. In samples containing 5-fluoro-2'-deoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthetase activity, an alternative blank containing a high concentration of FdUMP (approximately 1 mM) is useful in demonstrating a theoretical maximal or complete inhibition of thymidylate synthetase activity.

Animals↗
PubMed1982

Rheumatoid lung disease, pneumothorax, and eosinophilia.

Four cases of the triad of rheumatoid lung disease, spontaneous pneumothorax, and peripheral blood eosinophilia are reported. Cavitation of a rheumatoid lung nodule caused the pneumothorax in at least 1 case. The significance of eosinophilia and its value as a marker of extra-articular manifestations of rheumatoid disease are discussed.

Adult↗
PubMed1982

Scleroderma and erosive polyarthritis: a disease entity?

We describe 4 patients with scleroderma in whom a major clinical feature was a deforming, erosive polyarthritis accompanied by positive tests for rheumatoid factor. In all but 1 case the skin involvement preceded joint symptoms, and in some cases there was evidence of systemic involvement. This destructive arthritis may represent the coexistence of 2 diseases or an extreme form of the inflammatory arthritis seen in scleroderma. Alternatively, the clinical presentation may represent an 'overlap syndrome' with features of both scleroderma and rheumatoid arthritis.

Aged↗
PubMed1981

Serum methylprednisolone levels following intra-articular injection of methylprednisolone acetate.

Twenty-one patients with rheumatoid arthritis received injections of either 40 mg or 80 mg of methylprednisolone acetate into one or both knee joints. Serum methylprednisolone and cortisol levels were measured at intervals up to 1 week following injection. Peak serum levels of methylprednisolone were reached at between 2 and 12 hours following injection, and increasing the injected dose resulted in correspondingly higher serum levels. Injection of 80 mg of methylprednisolone as 40 mg into each knee produced consistently higher peak serum levels than when given as a single intra-articular injection. Serum cortisol levels were substantially suppressed for up to 1 week, and this effect was seen at all dose levels.

Arthritis, Rheumatoid↗
PubMed1981

Selective activation of 5'-deoxy-5-fluorouridine by tumor cells as a basis for an improved therapeutic index.

The intracellular metabolism of a new fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-dFUrd), was compared with the metabolism of 5-fluorouracil (FUra), 5-fluorouridine (FUrd), and 5-fluoro-2'-deoxyuridine (FdUrd) in freshly isolated bone marrow cells and Ehrlich ascites tumor cells. Following exposure to tumor cells, all four fluoropyrimidines were metabolized to identical products (i.e., FUra, 5-fluorouridine 5'-monophosphate, 5-fluorouridine 5'-diphosphate, 5-fluorouridine 5'-triphosphate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate), all produced an incorporation of FUra into RNA (FUd greater than FUra greater than FdUrd greater than 5'-dFUrd), and all completely inhibited thymidylate synthetase activity by 1 hr. However, in bone marrow cells, very different patterns were observed. 5'-dFUrd accumulated in the cells, but there were no measurable metabolism, no incorporation of FUra into RNA, and no inhibition of thymidylate synthetase activity. In contrast, both FUra and FUrd were metabolized and produced an incorporation of FUra into RNA (2.7 pmol FUra per micrograms RNA and 4.8 pmol FUra per micrograms RNA at 2 hr, respectively) in bone marrow. Only a minor inhibition of thymidylate synthetase activity was detected. FdUrd also was metabolized by bone marrow cells, produced a low level of FUra incorporation into RNA (0.23 pmol FUra per micrograms RNA at 2 hr), and produced a complete inhibition of thymidylate synthetase activity. Since 5'-dFUrd is not directly cytotoxic itself, its superior therapeutic index compared to other fluoropyrimidines may largely reflect the selective activation of 5'-dFUrd by sensitive tumor cells as opposed to bone marrow cells, which can activate FUra, FUrd, and FdUrd.

Animals↗
PubMed1980

Metabolism and biological activity of 5'-deoxy-5-fluorouridine, a novel fluoropyrimidine.

5'-Deoxy-5-fluorouridine (5'-dFUrd; Roche 21-9738) is a recently synthesized antineoplastic agent with therapeutic potential. The sensitivity of Ehrlich ascites tumor cells in CF-1 mice to 5'-dFUrd, as well as to 5-fluorouridine, was established. 5'-dFUrd was a more effective antitumor agent and was less toxic over a wide dosage range (50 to 400 mg/kg) than the other agents tested as measured by: (a) the ability to prevent gross development of inoculated tumor; (b) 45-day survival; and (c) weight change over the treatment period. With use of these sensitive tumor cells, the intracellular metabolism of 5'-dFUrd in vitro was investigated. Utilizing liquid chromatographic methodology for separation of acid-soluble metabolites, the only detectable metabolic products of 5'-dFUrd were FUra, 5-fluorouridine 5'-monophosphate, and 5-fluorouridine 5'-triphosphate. Novel metabolites of 5'-dFUrd were not detectable in the acid-soluble fraction or in plasma isolated from mice given [14C]5'-dFUrd. The formation of FUra appears to result from the action of nucleoside phosphorylase. 5'-dFUrd was shown to have a Km of 0.633 mM for this enzyme isolated from Ehrlich ascites tumor cells, an affinity similar to that for 5-fluoro-2'-deoxyuridine (Km, 0.278 mM) but much lower than that for 5-fluorouridine (Km, 0.049 mM). Incorporation of radiolabeled drug into the acid-insoluble fraction (representing greater than 95% incorporation into RNA) was also significant. 5-Fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) was not detectable as an acid-soluble metabolite. However, significant inhibition of thymidylate synthetase activity was detectable by 20 min in cells incubated with 30 microM 5'-dFUrd, suggesting that FdUMP was produced. The production of both 5-fluorouridine 5'-triphosphate and FdUMP appears dependent on the initial expansion of the FUra pool. This correlates with the inability of 5'-dFUrd to form nucleotide directly due to the absence of a 5'-hydroxyl group. It is concluded that the antineoplastic activity of 5'-dFUrd may be dependent on its enzymatic conversion of FUra. The basis for the possible increase in therapeutic index compared with other fluoropyrimidines may involve the rate and duration of the production of the biologically active nucleotides 5-fluorouridine 5'-triphosphate and FdUMP.

Animals↗