High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into fluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renal failure due to tubular obstruction. In order to find out whether there are similar findings in the clinical setting, we investigated 8 patients (pts.) with metastatic gastrointestinal cancer who were treated with this chemotherapy. We used the following parameters: 1. excretion of four urinary enzymes (LDH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i.v. on days 1-5 and 5-fluorouracil 400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. We found a constant decrease in the excretion of all 4 enzymes from normal to subnormal values which was statistically significant (p less than .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-fluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.

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A quantitative sandwich ELISA for E-selectin in the fluid phase (soluble E-selectin, sEs) has been developed that is sensitive to 100 pg/ml. The assay shows no reactivity with either L- or P-selectins. We have used this to determine the fate of E-selectin after cell-surface expression and to test whether levels measured in vivo may represent the state of endothelial activation. E-selectin was first detectable in supernatants of IL-1-stimulated endothelial cells at 24 h, and increased slowly up until 72 h. However, over this time period the total E-selectin detectable in the system (cells plus supernatants) declined dramatically. 125I-surface-labeled endothelial cells cultured for 24 h show an E-selectin of reduced m.w. in the supernatant, indicating that the molecule is shed from the surface. The shed form also appears to be slightly smaller than the intact membrane form as determined from immunoprecipitation and molecular sieving studies. In addition, the cytoplasmic domain of the molecule found in supernatants of activated endothelial cells and in serum is not intact as determined by loss of reactivity with an antipeptide antibody specific for the cytoplasmic domain. We have examined the sera of 71 normal individuals. Without exception, sEs was found in serum in the range of 0.13 to 2.8 ng/ml, suggesting that even in the absence of overt inflammatory processes E-selectin is being synthesized and released into the bloodstream. In addition, bacteremic patients with hypotension, but not those without, showed markedly elevated sEs values. As determined by cell-binding studies, the blood-derived form of E-selectin is biologically active.

In 6 patients on continuous ambulatory peritoneal dialysis we investigated the inhibition of intraperitoneal fibrin formation by heparin. A continuous addition of 500 U of heparin per liter dialysate was used for 52 h. In plasma no heparin activity could be detected, even 52 h after intraperitoneal administration of heparin. The fibrin formation was determined by fibrinopeptide A, a thrombin-induced split product of fibrinogen. In patients under regular continuous ambulatory peritoneal dialysis we determined the fibrinopeptide A concentrations in plasma. The values were comparable with the fibrinopeptide A concentrations measured in disseminated intravascular coagulopathy. They decreased during intraperitoneal administration of heparin from 63.2 ± 11.8 to 4.9 ± 1.7 ng/ml. The fibrinopeptide A concentration in the 4-hour intraperitoneal dialysate (155.8 ± 15.7 ng/ml) decreased after heparin administration to 8.5 ± 2.0 ng/ml and was always higher than in plasma. We conclude that 500 U heparin per liter dialysate prevents the intraperitoneal fibrin formation. The low antithrombin III concentration (0.44 ± 0.13 mg/dl) in protein-poor dialysate seems to be sufficient to inhibit the thrombin activity after acceleration by heparin.

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