Combination clinical trials with thymidine and fluorouracil: a phase I and clinical pharmacologic evaluation

Abstract

Phase I observations of combined therapy with thymidine (TdR) and 5-fluorouracil (FU) have demonstrated that when TdR is administered by rapid infusion at a dose of 7.5 or 15g and FU is given by bolus injection 60 minutes after the start of the TdR dose, the biologic activity of Fu is increased five- to eight-fold. The observed toxicity is primarily hematopoietic: 15g TdR and 7.5 or 10mg/kg FU produced median white blood count nadirs of 2,600 on day 16 and platelet count nadirs of 150,000 on day 14. The combined therapy produced two partial remissions in 18 patients with colon cancer, 17 of which had experienced progression of disease on FU containing regimens. Partial remissions were also obtained in two heavily pretreated patients with ovarian cancer and diffuse, poorly differentiated lymphocytic lymphoma. Plasma analyses for TdR and FU and their metabolic products by high pressure liquid chromatography have demonstrated a marked elevation and prolongation of FU levels. The beta phase T 1/2 for 7.5mg/kg FU were: FU alone 6 minutes, 7.5g TdR + FU 135 minutes, 15g TdR + FU 188 minutes, and TdR 45g + FU 190 minutes. The addition of TdR all but eliminated oxidative metabolism of FU; renal clearance became the primary detoxification route. Thymidine levels exceeded 10(-3)M; the beta phase T 1/2 of TdR varied with the administered dose: 3gTdR, 7 minutes; 7.5g TdR, 24 minutes; 15g TdR, 52 minutes; and 45g TdR, 98 minutes.