TY - JOUR
T1 - Phase I trial of a 5-day infusion of L-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies
AU - Valone, Frank H.
AU - Gandara, David R.
AU - Luce, Judith A.
AU - Wall, Susan
AU - Perez, Edith A.
AU - Braham, Natalie
AU - George, Martine
AU - Letvak, Laurie
PY - 1993/5
Y1 - 1993/5
N2 - The combination of leucovorin [(6 d,l)-5-formyltetrahydrofolate] and 5-fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as treatment of advanced colorectal cancer. Leucovorin is metabolized to methylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxyuridine and methylene tetrahydrofolate. Only l-leucovorin is metabolized to methylene tetrahydrofolate and forms this ternary complex. However, d-leucovorin may not be inert. d-Leucovorin may impair cellular uptake and metabolism of l-leucovorin, thereby inhibiting the actions of l-leucovorin. Because of this possible limitation to the effectiveness of racemic leucovorin, we have begun to explore the effects of the pure, biologically active isomer, l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion of l-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose of l-leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The most common severe toxicities (and the number of patients affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose of l-leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination of l-leucovorin and 5-FU is well tolerated by patients and appears active for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine if l-leucovorin is more effective than d,l-leucovorin for modulating the effectiveness of 5-FU.
AB - The combination of leucovorin [(6 d,l)-5-formyltetrahydrofolate] and 5-fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as treatment of advanced colorectal cancer. Leucovorin is metabolized to methylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxyuridine and methylene tetrahydrofolate. Only l-leucovorin is metabolized to methylene tetrahydrofolate and forms this ternary complex. However, d-leucovorin may not be inert. d-Leucovorin may impair cellular uptake and metabolism of l-leucovorin, thereby inhibiting the actions of l-leucovorin. Because of this possible limitation to the effectiveness of racemic leucovorin, we have begun to explore the effects of the pure, biologically active isomer, l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion of l-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose of l-leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The most common severe toxicities (and the number of patients affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose of l-leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination of l-leucovorin and 5-FU is well tolerated by patients and appears active for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine if l-leucovorin is more effective than d,l-leucovorin for modulating the effectiveness of 5-FU.
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U2 - 10.1007/BF00685838
DO - 10.1007/BF00685838
M3 - Article
C2 - 8500227
AN - SCOPUS:0027238857
SN - 0344-5704
VL - 32
SP - 215
EP - 220
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 3
ER -