Dihydropyrimidine dehydrogenase activity in cancer patients.

Dihydropyrimidine dehydrogenase (DPD) is the major catabolic enzyme of pyrimidines and fluoropyrimidines. The clinical course of 2 patients with suspected DPD deficiency is described. Both patients had significantly delayed clearance of fluorouracil (5-FU), elevated plasma uracil concentrations, and subsequent lethal toxicity. The prevalence of DPD deficiency in the general population is unknown, but given the large number of cancer patients treated with 5-FU, it may be of great clinical significance. Lymphocytes have been previously shown to be a useful marker of systemic DPD activity. Because DPD activity has not been previously reported in a large population of cancer patients using 5-FU as the substrate, we determined DPD activity in lymphocytes from 66 patients with cancer. DPD activity was determined by a sensitive high performance liquid chromatography method. The mean DPD activity (S.D.) in 66 patients with head and neck cancer was 0.189 (0.071) nomol/min/mg protein with wide interpatient variability (range 0.058-0.357). DPD activity was not correlated to age (r = -0.164, P = 0.188). The mean DPD activity in men [0.192 (0.074)] was not significantly different from that in women [0.172 (0.057); t-test P = 0.418]. Likewise, there was no statistical difference in DPD activity in patients who had not received prior chemotherapy [0.195 (0.066)] to patients receiving one or more cycles of chemotherapy [0.186 (0.074); t-test P = 0.638].

Pharmacokinetic study in carboplatin, cisplatin and 5-fluorouracil regimen for advanced oesophageal cancer.

A chemotherapy using carboplatin, cisplatin and 5-fluorouracil in continuous infusion for advanced oesophageal cancer showed a high response rate in a previous feasibility study. The overall CT-scan response rate of 85% was obtained with a haematological dose-limiting toxicity: neutropenia and thrombopenia grade 3-4 of 23% and 30% respectively. In order to correlate myelosuppression with pharmacokinetic parameters, a pharmacological study was undertaken. The area under curve (AUC) of ultrafiltrable platinum and the residual rate of total platinum in 16 patients were tested. The measured creatinine clearance was found to be predictive of the subsequent myelosuppression. Plasma samples were using daily using the atomic absorption spectrometry technique. A strong relationship in individual patients was underlined between the AUC of ultrafiltrable platinum or residual rate of total platinum and the lowest platelet count for the first 3 days of treatment (p < 0.05). Conversely, the threshold value of the AUC at day one and residual rate at days two and three were calculated to prevent a highly probable haematotoxicity. Therefore, an optimal dose of carboplatin is determined in relation to the renal function of each patient.

Serum alpha-1 acid glycoprotein in chronic renal failure and hemodialysis.

The total concentration and concanavalin A (ConA)-dependent microheterogeneity of alpha-1 acid glycoprotein (AAG) were studied in thirty hemodialyzed uremic patients and eighteen non-dialyzed uremic patients, by comparison with healthy volunteers. Serum concentrations of AAG were significantly higher in the non-dialyzed uremic (1.27 +/- 0.47 g/l) and hemodialyzed patients (1.29 +/- 0.33 g/l) than in the volunteers (0.79 +/- 0.09 g/l). The proportions of strongly ConA-reactive AAG fractions were also higher in non-dialyzed uremic (16.7%) and hemodialyzed patients (18.5%) than in volunteers (14.1%). These data may be related to an increase in bi-antennary glycans, as observed in patients on peritoneal dialysis, together with a probable change in sialylation. AAG serum levels and microheterogeneity were similar in non-dialyzed and hemodialyzed patients and did not appear in the dialyzed patients to depend on the type of dialysis membrane used, i.e. cuprophan (CU), cellulose acetate (CA), hemophan (HE), polyacrylonitrile (PAN), and polysulfon (PS), in spite of differences in biocompatibility. In patients dialyzed with CA membranes, there was a distinct decrease in the ConA non-reactive fraction (38.0%) and an increase in ConA slightly-reactive (42.2%) and strongly-reactive (19.7%) fractions. Differences in AAG serum levels and ConA reactivity between patients dialyzed with CA and PAN membranes seem to justify further investigations of other acute-phase reactants and immunological parameters.

Serum and urinary alpha-1 acid glycoprotein in chronic renal failure.

The concentration and concanavalin A (ConA)-dependent microheterogeneity of serum and urinary alpha 1-acid glycoprotein (AGP) were studied in patients with various degrees of renal impairment and compared with healthy control values. Serum concentrations of AGP were significantly higher in hemodialyzed and uremic patients than in the control subjects (1.54 +/- 0.42 g/l, p < 0.05, and 1.20 +/- 0.40 g/l, p < 0.05, respectively, versus 0.83 +/- 0.17 g/l). There was a similar increase in serum alpha 1-protease inhibitor and haptoglobin concentrations in the uremic patients (r = 0.87 and r = 0.70; p < 0.001). Urinary concentrations of AGP were also significantly higher in the hemodialyzed and uremic patients than in the control subjects, despite wide variability in the patients (20 +/- 14 mg/24 h, p < 0.05, and 126 +/- 160 mg/24 h, p < 0.05, respectively, versus 3 +/- 1 mg/24 h). AGP clearance was significantly higher in the uremic patients than in the hemodialyzed patients (p < 0.01) and the control subjects (p < 0.01). The proportions of strongly ConA-reactive AGP fractions were higher in the serum of the hemodialyzed (18.6 +/- 5.2%; p < 0.05) and uremic patients (18.1 +/- 5.3%; p < 0.05) than in the control subjects (14.5 +/- 2.5%). There was a similar difference in the urine samples (26.7 +/- 8.2%, p < 0.01; 20.1 +/- 6.2%, p < 0.01, respectively, versus 10.3 +/- 4.8%), with also a significant difference between the hemodialyzed and uremic patients (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)