Increased activity of alkyl-N-purine DNA glycosylase (ANPG; a.k.a. N3-methyladenine DNA glycosylase) has been correlated with resistance to both chloroethylnitrosoureas and nitrogen mustards. Also, overexpression of the human glycosylase in Escherichia coli results in resistance to alkylating agents. To determine how overexpression of the protein affects resistance to these bifunctional alkylating agents in mammalian cells, wild-type CHO-AA8 cells were transfected with an expression construct containing the human ANPG cDNA. Several clonally isolated lines that expressed increasing levels of glycosylase activity were selected. None of these lines displayed increased resistance to either bis-chloroethylnitrosourea or melphalan. To determine how overexpression of this protein affects cells in the absence of nucleotide excision repair, the mutant CHO-UV20 cell line was transfected with the same expression construct. This cell line lacks functional ERCC-1 protein and displays extreme hypersensitivity to bifunctional alkylating agents. Again, none of the UV20 transfectants displayed increased resistance. The results of these experiments indicate that unlike E. coli, overexpression of the glycosylase alone is not sufficient to confer resistance to bifunctional alkylating agents in this system. Structural differences between mammalian cells and E. coli may explain the interesting result that a mammalian gene can confer drug resistance in E. coli but not in mammalian cells.

Alkylating Agents↗

PubMed1995

Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in vivo cardiopulmonary bypass.

Granulocyte adhesion to ischemic tissue, mediated in large part by beta 2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this agent might modulate up-regulation of this adhesion receptor. In vitro, whole blood was incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucyl-phenylalanine, and granulocyte CD11b measured. Acadesine significantly (p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low- and high-dose treatment groups, there was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte CD11b in vitro, and acadesine is capable of a similar inhibition during in vivo cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury.

Adenosine↗

PubMed1995

The dependence of the detection limit of reagent-limited immunoassay on antibody affinity.

Explore the source record for details and available documents.

Animals↗

PubMed1995

Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol.

PURPOSE: Here we report the results of a phase III study, to evaluate whether the addition of cisplatin to radiation therapy (XRT) would improve progression-free survival or overall survival for patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Two hundred forty patients with biopsy-proven unresectable NSCLC without distant metastases or lower-stage medically inoperable patients were randomized to one of two treatment arms. Arm A consisted of thoracic XRT alone, 60 to 65 Gy total tumor dose in daily fractions of 1.80 to 2.00 Gy; and arm B consisted of identical XRT with the addition of cisplatin 70 mg/m2 every 3 weeks for three cycles beginning on the first day of irradiation. RESULTS: Two hundred fifteen patients were eligible and assessable. The overall response rate was 50% on the combination arm versus 38% on the XRT-alone arm (P = .076). The median progression-free survival time was 23 versus 22 weeks, respectively (P = .0537). The median survival time was 43 weeks on the combination arm versus 46 weeks on the XRT arm (Poverall = .3469). The 1-, 2-, and 5-year survival rates were 43%, 18%, and 5% on the combination arm versus 45% 13%, and 2% on the XRT arm, respectively. CONCLUSION: Cisplatin, administered every 3 weeks, does not significantly improve response rate, progression-free survival, or overall survival when added to thoracic XRT for locally advanced unresectable NSCLC.

Adult↗

PubMed1995

Raising nurses' awareness.

Explore the source record for details and available documents.

Cross Infection↗

PubMed1995

When does palliative care begin? A needs assessment of cancer patients with recurrent disease.

This cross-sectional study compared the prevalence and intensity of needs expressed by cancer patients at the time of first recurrence (n = 75) with those of patients at the time of disease progression (n = 75). On a 72-item Likert-type scale participants rated from "none" to "very much" the severity of physical symptoms; emotional, psychological, and social problems; and difficulties with activities of daily living. The progressive disease group reported more problems than the first recurrence group in 11 of 24 (47%, p < 0.05) symptom-related questions. The progressive disease group also expressed greater needs in 19% of the function-related questions. There were no differences in reported psychological problems, responses to recurrence, or greatest concern between the two groups. These results support the need for palliative care throughout the entire course of illness.

Adult↗

PubMed1995