ISSN:
1432-0843
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary A phase II study of intermittent high-dose 6-thioguanine (6-TG) was undertaken in 19 patients with metastatic colorectal carcinoma. Fourteen patients had received prior myelosuppressive therapy. 6-TG was administered as a single dose by IV bolus over 15–30 min, with retreatment every 3 weeks. The starting dose was 700 mg/m2 in ten patients, 900 mg/m2 in one patient, 1,000 mg/m2 in four patients, and 1,200 mg/m2 in two patients. Two patients received reduced doses (350 mg/m2) because of liver dysfunction. There was no regression of measurable disease after treatment with 6-TG in this study. Eight patients achieved stabilization of previously progressive disease for periods of 10–32 weeks. Toxicities were nausea and vomiting (19 patients), mucositis (3 patients), reversible renal dysfunction with creatinine〉2 mg/dl (4 patients), nasal congestion (3 patients), diarrhea (1 patient), and skin blistering at the infusion site (1 patient). Seven patients had white blood count nadirs below 3,000/μl (the lowest nadir was 900/μl). Only one patient had a platelet count nadir below 100.000/μl. There were no infections or hemorrhage. 6-TG, as administered in this study, has no antitumor activity against colorectal carcinoma. Concentrations of 6-TG and metabolites were assessed in the plasma of six patients by a reversed-phase HPLC system. 6-TG and metabolites were extracted from human plasma at 50%–100% efficiency by cold 2 N perchloric acid (1 : 1). Neutralized extracts were chromatographed on a μ-Bondapak C18 column by two separate isocratic conditions. 6-TG, 6-thiouric acid, 6-thioguanosine, and 6-thioxanthine were analyzed with 0.01 M Na acetate, pH 3.5/10% methanol as the mobile phase and were detected at 340 nm. 6-Methyl TG and three unknown metabolites were eluted with Na acetate/25% methanol and were detected at 310 nm. External standard calibration was used for quantitation. The 6-TG detection limit was 0.8 nmol/ml. In six patients who received 1–1.2 g 6-TG/m2 IV, 6-TG achieved peak plasma concentrations of 61–118 nmol/ml (95.6 ± 23.0, mean ± SD). Plasma 6-TG concentrations decayed bi-exponentially, with initial t1/2 of 3 h and terminal t1/2 of 5.9 h. 6-Thiouric acid, 6-methyl TG, 6-thioguanosine, 6-thioxanthine, and three major unidenitified metabolites were also observed in plasma. The three unknowns were extracted with ethyl acetate from alkalinized pooled plasma extracts and were purified by HPLC.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00255484
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