![]() The rationale for evaluating sequential i.v. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%) all four responders had a 2/3 genotype.Ĭonclusions: Doses (mg/m 2) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated. Patients with UDP-glucuronosyltransferase (UGT1A1 TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with ≥1 (TA)7 allele. ![]() The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m 2/24 hours. The mean 5-FU plasma concentration was 5.1 μmol/L at 3,900 mg/m 2/48 hours. Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. Results: Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery grade 3 nausea despite antiemetics) one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). 5-FU was then increased in three cohorts up to 3,900 mg/m 2/48 hours. Purpose: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions.Įxperimental Design: CPT-11 was first given at four levels (70-140 mg/m 2/24 hours), followed by leucovorin 500 mg/m 2/0.5 hours and 5-FU 2,000 mg/m 2/48 hours on days 1 and 15 of a 4-week cycle.
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