Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators.

We report the screening of analogues of indomethacin to investigate the structure-activity relationship (SAR) of indomethacin-mediated multidrug resistance associated protein-1 (MRP-1) inhibition. By examining the activities of compounds with minor variations of the parent structure, we were able to separate MRP-1, glutathione-S-transferase (GST), cyclooxygenase (COX)-1 and COX-2 inhibitory activities. Combination cytotoxicity assays were utilised to identify agents which possess synergistic potential in MRP-1-expressing cell lines. MRP-1 Inside Out Vesicles (IOVs) were utilised to demonstrate the ability of the indomethacin analogues to inhibit the pump directly. Most of the indomethacin analogues active as MRP-1 inhibitors were poor GST inhibitors when compared with the GST-inhibitory activity of indomethacin. Two of the MRP-1 inhibitory analogues were found to have no COX-1 inhibitory activity and low COX-2 inhibitory activity, suggesting potentially reduced clinical toxicity. One MRP-1 inhibitory indomethacin analogue was also found to have low COX-1 inhibitory activity, but significant COX-2 inhibitory activity, making this analogue again interesting in terms of low potential toxicity, but with the possibility of direct inhibitory effects on tumour growth.

Synthesis of indomethacin analogues for evaluation as modulators of MRP activity.

Synthesis of a range of indomethacin analogues, required for investigation in combination toxicity assays, bearing both N-benzyl and N-benzoyl groups, is described.

Effects of tumor status on the regulation of natural killer cell activity by tumor-associated fetal antigens.

In the present study we examined the effects of a tumor-associated fetal antigen (TAFA-II) on the activity of natural killer (NK) cells isolated from human cancer patients. TAFA-II suppressed the NK cell response of some patients, and the level of suppression appeared to be independent of tumor type or stage of cancer therapy. No significant correlations were found between lymphocyte, neutrophil, monocyte, or eosinophil populations and TAFA-induced suppression of NK cell activity. TAFA-II effects were also not attributable to Ia+ cells or to OKT3, OKT4, or OKT8 positive cells. This work confirmed results obtained in the rat model, in which suppression appeared to be directly mediated on the NK cell.

A phase I trial of recombinant leukocyte alpha 2 interferon in patients with advanced malignancy.

Seventeen patients with advanced, previously treated malignancies were entered into a phase I trial utilizing recombinant DNA produced alpha 2 leukocyte interferon (rIFN-alpha 2). Sixteen patients were evaluable. Patients were to receive rIFN-alpha 2 by either the I.V. or I.M. route for 35 consecutive days. The dosage was identical by both routes, and patients were escalated from 3 X 10(6) to 10 X 10(6) to 30 X 10(6) to 50 X 10(6) and to 100 X 10(6) I.U. every 7 days. No patient was able to tolerate the consecutive treatment protocol as planned. Dose-limiting toxicity was a flu-like syndrome in 10 patients and was usually associated with a fall in performance status. Confusion resulted in study withdrawal for five patients, four receiving rIFN-alpha 2 by the I.M. route. Hematologic and liver function abnormalities were common, usually transient, and not associated with clinical sequelae. One patient with non-Hodgkin's lymphoma showed substantial improvement; otherwise, all had stable or progressive disease. Pharmacologic studies indicated substantial serum levels at doses greater than or equal to 10 X 10(6) I.U. regardless of route. No consistent changes in NK activity, lymphocyte subpopulations, or immunoglobulin levels were noted, and no patient developed antibodies to rIFN-alpha 2. The dose and schedule used here indicate that high levels of serum rIFN-alpha 2 activity are obtainable by either the I.M. or I.V. route. Intermittent rather than daily dosage is more likely to be better tolerated and should be considered for phase II trials.

Prostaglandin F2 alpha for lactating dairy cows with a palpable corpus luteum but unobserved estrus.

Two experiments in 17 dairy herds were for the effectiveness of prostaglandin F2 alpha (treatment) in reducing luteolysis and inducing intervals to conception of 308 cycling lactating dairy cows. Cows with unobserved estrus before first insemination (Experiment 1) and nonpregnant cows with unobserved estrus after insemination (Experiment 2) were eligible for treatment. Cows in Experiment 1 were assigned alternately either to an untreated control group of 85 or to a group of 138 that received 25 mg prostaglandin F2 alpha after detection of a corpus luteum by ovarian palpation. Cows were inseminated either at estrus or at 72 and 96 h posttreatment in the absence of detected estrus. Intervals from treatment to estrus, to first service, and to conception were longer for controls than for treated cows. Conception at first service was similar for controls (39%) and for treated (43%) cows. Procedures were similar for Experiment 2. Intervals from treatment to estrus and treatment to first service were longer for control cows, and treatment to conception tended to be longer for 39 controls than for 46 treated cows. Conception at first service was similar controls (52%) and treated (44%) cows. Prostaglandin F2 alpha was 91% effective for inducing luteolysis based on progesterone concentrations in blood serum. Successful treatment was dependent upon accurate diagnosis of a functional corpus luteum. Days from treatment to conception were reduced for cows with unobserved estrus if treated cows were inseminated at estrus or by appointment in the absence of detected estrus.