BACKGROUND-Prostate-specific antigen (PSA), acid phosphatase (AP), and prostatic acid phosphatase (PAP) are serum markers for adenocarcinoma of the prostate gland. Previous studies indicated that prostatic ischemia may also produce elevations of PSA. Cardiopulmonary resuscitation (CPR) is frequently associated with profound tissue hypoperfusion. The present study investigated whether PSA, AP, and PAP are influenced by prolonged CPR. METHODS AND RESULTS-PSA, AP, and PAP were assessed immediately, 12 hours, 24 hours, 2 days, 3 days, 5 days, and 7 days after prolonged CPR (>5 minutes) in 14 male and 5 female patients. No changes were noted in women. In men, serum levels increased significantly after CPR and gradually decreased to near baseline values after 7 days. PSA, AP, and PAP values above the normal range were observed in 63%, 71%, and 64% of all patients, respectively. Compared with survivors, nonsurvivors exhibited higher peak serum levels of PSA (98.6+/-14.3 versus 1.1+/-2.2 mcg/L; P<0.03), AP (57.0+/-71 versus 8.6+/-8.8 U/L; P<0.05), and PAP (47.0+/-62 versus 5.7+/-8.0 U/L; P=NS). Patients with poor neurological outcome exhibited higher peak serum levels of PSA (86.4+/-135.5 versus 12.0+/-23.8 mcg/L; P<0.05), AP (50.9+/-68.1 versus 8.7+/-9.6 U/L; P=NS), and PAP (41.6+/-59.5 versus 5.8+/-8.8 U/L; P=NS) than patients with good neurological outcome. CONCLUSIONS-Prolonged CPR is frequently associated with increases of PSA, AP, and PAP serum levels. Therefore, PSA cannot be used for diagnosis of adenocarcinoma of the prostate during the first weeks after CPR. Further evaluation of these parameters as additional prognostic markers after CPR is warranted.

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC50) at 5 microM, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 microM. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 microM, a concentration that inhibits cell proliferation by 50% (IC50) or at 100 microM for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7.5 and 50 microM, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC50 values of 12 and 87 microM, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82% in male mice and 112% in female mice). The anti-tumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.

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The influence of conjugation of doxorubicin to holotransferrin on the receptor-mediated endocytosis of and on the iron uptake from transferrin was studied using K562 cells. '251-labelled transferrin and doxorubicin-transferrin conjugates were used in the binding, dissociation, and ligandexchange experiments at 0 "C, and 5gFe,'251-labelled (double-labelled) ligands were used in the endocytosis, iron uptake, and recycling experiments at 37 "C. The binding affinity of conjugates was about half of that of transferrin. Binding of 1251-labelled ligands was blocked by both unlabelled ligands to the same degree, however, it was not blocked at all by an 8000-fold excess of doxorubicin.After saturation bindings, slightly more '251-labelled conjugates dissociated from the surface of cells than transferrin. Exchange of '251-labelled ligands for unlabelled ligands resulted in different EC,, values (defined as the concentration of unlabelled ligand at which half as much radioligand is exchanged for unlabelled ligand as would be exchanged at infinitely high concentration of unlabelled ligand under similar assay conditions). While transferrin exchanged transferrin with an EC,, value close to the binding affinity, conjugates exchanged conjugates with much lower efficiency. The heterolog exchange experiments yielded EC,, values inbetween the two extrema. For studying iron uptake, K562 cells were loaded with the double-labelled ligands either at 37 "C (endosome-loading only) or at 0°C (surface-loading only). Results obtained for the endocytosis of, the iron uptake from, and the recycling of double-labelled ligands indicate that (a) the rate of iron uptake is smaller from conjugates than from transferrin, (b) there are at least two parallel recycling processes for both ligand . receptor complexes, and (c) each time constant characterizing the different steps of iron uptake via receptor-mediated endocytosis is smaller for conjugates than for transfenin (or, the half times characterizing the different steps are higher for conjugates than for transferrin). Endocytosis and iron uptake were unaffected by free doxorubicin (12.5 pM) or colchicin (1 mh4). Benzyl alcohol (30 mM) slowed down the rate of both endocytosis and iron uptake, while dithiothreitol (5 mM) decreased the rate of iron uptake and increased the rate of endocytosis. N-Ethylmaleimide (1 mMj completely stopped both endocytosis and iron uptake. The results suggest that the binding of conjugates to the surface of cells is governed by the binding of the transfenin part of conjugates to the transferrin receptor. However, conjugation of doxorubicin to transferrin seems to influence all properties of transfenin. A minor alteration in the structure may modify the binding affinity and stability of conjugates as well as decrease the accessibility of competing ligand to displace the bound ligand. Either of them could be responsible for the longer endocytosis and recycling time for conjugates. Our results also point to the importance of both the sulfhydryl groups and the fluidity of p...

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