Disease relevance of leucovorin

• Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer [1].
• In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours) [2].
• We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors [3].
• METHODS: We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone [4].
• High-dose methotrexate (500 to 33,600 mg per square meter of body-surface area) with leucovorin rescue is a common component of therapy for acute lymphocytic leukemia [5].

High impact information on leucovorin

• One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart [6].
• All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200) [7].
• Biochemical modulation of 5-FU with leucovorin and biologic response modifiers such as interferon has achieved complete response rates as high as 66%, but severe mucositis continues to be the dose-limiting toxic effect [8].
• Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients [9].
• Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer [10].

Chemical compound and disease context of leucovorin

• Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer [11].
• Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial [12].
• Since toxoplasma organisms lack a transmembrane transport system for physiologic folates, host toxicity can be prevented by co-administration of the reduced folate, leucovorin, without reversing the antiprotozoal effect [13].
• Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines [14].
• Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome [15].

Biological context of leucovorin

• Failure of high-dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance [16]?
• Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously [17].
• FasL expression also correlated with acute apoptosis induced in parental GC3/cl cells, commencing at 48 hr, following thymidylate synthase inhibition by 5-fluorouracil/leucovorin exposure [18].
• With lower equitoxic levels of the trimetrexate (7.5 nM), the provision of leucovorin allowed for a restoration of cell growth to a level greater than 90% of control [19].
• These results suggest that the kinetics of marrow recovery is quite different for thymidine and leucovorin rescue [20].

Anatomical context of leucovorin

• Although leucovorin had been shown to selectively spare normal bone marrow and intestine in animals from the killing effect of MTX on tumor cells, we demonstrate the preferential killing of neoplastic over non-neoplastic cells of the same derivation [21].
• This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity [22].
• Our results indicate that, in HDMTX-treated mice, leucovorin protection involves the earliest stages of hemopoiesis, assuring the maintenance of a satisfactory endowment of stem and progenitor cells [23].
• After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol [24].
• However, the effect of leucovorin on peripheral blood cell reduction was less significant [23].

Associations of leucovorin with other chemical compounds

• To determine the maximum tolerated dose of 5-FU with leucovorin for use in combination with cyclophosphamide and doxorubicin, we conducted a phase I/II trial in 20 patients [25].
• The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides [26].
• Chemotherapy consisted of two cycles of protracted infusion (PI) 5FU 200 mg/m2/d administered for 3 weeks with leucovorin 20 mg/m2/w. Cisplatin 100 mg/m2 was administered on day 1 [27].
• Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium [28].
• These studies reveal an increased stabilization of the 5-fluorodeoxyuridylate (FdUMP)-thymidylate synthase (TS) folate ternary complex with the addition of leucovorin [29].

Gene context of leucovorin

• Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation [30].
• We have demonstrated previously that interferon (IFN)-gamma sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53 [31].
• MTX, FA, and leucovorin are subject to high capacity [V(max(MTX)), 0.24 +/- 0.05 nmol/mg/min; V(max (FA)), 0.68 +/- 0.14 nmol/mg/min; V(max(leucovorin)), 1.95 +/- 0.18 nmol/mg/min], low affinity [K(m(MTX)), 0.22 +/- 0.01 mM; K(m(FA)), 0.17 +/- 0.02 mM; K(m (leucovorin)), 0.64 +/- 0.23 mM] transport by MRP4 [32].
• Replenishment of LCV in the growth medium of CEM-7A cells resulted in resumption of normal MRP1 expression [33].
• CONCLUSIONS: We were unable to demonstrate a survival difference between those stage III colon cancer patients receiving leucovorin therapy that carried the MTHFR C677T allele and those that were wild type for this allele [34].

Analytical, diagnostic and therapeutic context of leucovorin

• CONCLUSIONS: Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival [35].
• Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration [36].
• To examine these questions, we conducted a phase I trial using protracted infusion of 5-FU by indwelling catheter and pump, with leucovorin given by bolus injection, and reported 40% partial response [37].
• Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01 [38].
• Pharmacokinetics of diastereoisomers of (6R,S)-folinic acid (leucovorin) in humans during constant high-dose intravenous infusion [39].

References