TY - JOUR
T1 - A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin
AU - Grem, Jean L.
AU - Quinn, Mary G.
AU - Keith, Bruce
AU - Monahan, Brian P.
AU - Hamilton, J. Michael
AU - Xu, Yan
AU - Harold, Nancy
AU - Nguyen, Dat
AU - Takimoto, Chris H.
AU - Rowedder, Anthony
AU - Pang, Janet
AU - Morrison, Geraldine
AU - Chen, Alice
N1 - Funding Information:
Blood was collected in 10-ml draw heparinized tubes to which 10 nmol tetrahydrouridine (Sigma, St. Louis, Mo.) had been added. The tubes were placed on ice immediately and centrifuged for 10 min at 800 g; and the plasma was removed and stored at )70°C. Blood samples were taken during the infusions at the following time points: 24-h infusion, 22 and 23 h; 2-h infusion, 90 and 105 min; 1-h infusion, 30, 40 and 50 min. dFdU was provided by Lilly Research Laboratories (Indianapolis, Ind.) through a material transfer agreement with the National Cancer Institute. The internal standard, 5¢-deoxy-5-fluorouridine (5¢-DFUR), was obtained from Sigma (St. Louis, Mo.). Ammonium acetate was from Aldrich (Milwaukee, Wis.). HPLC-grade water and methanol were from Fisher (Fair Lawn, N.J.). Tetrahydrouridine (lot no. 112907-J/22) was provided by the Drug Synthesis and Chemistry Branch at the National Cancer Institute (Bethesda, Md.). Pooled donor plasma was provided by the Department of Transfusion Medicine, Warren G. Magnusen Clinical Center, National Institutes of Health (Bethesda).
PY - 2003/12
Y1 - 2003/12
N2 - Purpose: Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2′-deoxyuridine (FUDR), we studied this combination in a phase I trial. Methods: Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. Results: During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n = 6) or diarrhea (n = 1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 μM (24 h), 16.3 μM (2 h), and 31.9 μM (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. Conclusions: Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.
AB - Purpose: Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2′-deoxyuridine (FUDR), we studied this combination in a phase I trial. Methods: Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. Results: During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n = 6) or diarrhea (n = 1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 μM (24 h), 16.3 μM (2 h), and 31.9 μM (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. Conclusions: Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.
KW - Antimetabolites
KW - Pharmacodynamics
KW - Pharmacokinetics
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U2 - 10.1007/s00280-003-0698-5
DO - 10.1007/s00280-003-0698-5
M3 - Article
C2 - 12955469
AN - SCOPUS:0344513359
SN - 0344-5704
VL - 52
SP - 487
EP - 496
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -