The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy

Although 5-fluorouracil (Fura) is the drug of choice for the treat ment of patients with advanced colorectal cancer, this agent has limited effectiveness with a reported response rate of 10-20% and a duration of response of only 6-9 months. The large percentage of treatment failures with this agent has spurred a continuing effort to delineate the mechanism(s) of resistance to Fura and to evaluate approaches that would selectively modulate the therapeutic efficacy of this agent. The therapeutic efficacy of FUra has been attributed to its selec tive incorporation into RNA and to its inhibition of thymidylate syn thase, leading to potent inhibition of DNA synthesis. Studies of cell lines in vitro and model systems in vivo have demonstrated that although mechanism~sensitivity and resistanc; to Fura are multifactorial, in the presence of citrovorum factor (CF, 5-formyltetrahydrofolate) the site of action of Fura becomes predominantly the pronounced and pro longed inhibition of thymidylate synthase. This action is the result of stabilization of the covalent ternary complex between FdUMP, an active metabolite of FUra, 5,10-methylenetetrahydrofolates, and thymidylate synthase. This effect of CF is thus an example of the concept of meta bolic modulation.

Klappentext

Although 5-fluorouracil (Fura) is the drug of choice for the treat­ ment of patients with advanced colorectal cancer, this agent has limited effectiveness with a reported response rate of 10-20% and a duration of response of only 6-9 months. The large percentage of treatment failures with this agent has spurred a continuing effort to delineate the mechanism(s) of resistance to Fura and to evaluate approaches that would selectively modulate the therapeutic efficacy of this agent. The therapeutic efficacy of FUra has been attributed to its selec­ tive incorporation into RNA and to its inhibition of thymidylate syn­ thase, leading to potent inhibition of DNA synthesis. Studies of cell lines in vitro and model systems in vivo have demonstrated that although mechanism~sensitivity and resistanc; to Fura are multifactorial, in the presence of citrovorum factor (CF, 5-formyltetrahydrofolate) the site of action of Fura becomes predominantly the pronounced and pro­ longed inhibition of thymidylate synthase. This action is the result of stabilization of the covalent ternary complex between FdUMP, an active metabolite of FUra, 5,10-methylenetetrahydrofolates, and thymidylate synthase. This effect of CF is thus an example of the concept of meta­ bolic modulation.

Inhalt
Determinants of Response to Fluopopyrimidines in Combination with CF.- Overview: Rational Basis for Development of Fluoropyrimidine/5-Formyltetrahydrofolate Combination Chemotherapy.- The Natural and Unnatural Diastereomers of Leucovorin: Aspects of Their Cellular Pharmacology.- Distribution and Metabolism of Calcium Leucovorin in Normal and Tumor Tissue.- Pole of Dose, Schedule and Route of Administration of 5-Formyltetrahydrofolate: Preclinical and Clinical Investigations.- Pharmacokinetic Analysis of (6S)-5-Formyltetrahydrofolate (1-CF), (6R)-5-Formyltetrahydrofolate (d-CF) and 5-Methyltetrahydrofolate (5-CH3-THF) in Patients Receiving Constant i. v. Infusion of High-Dose (6R,S)-5-Formyltetrahydrofolate (Leucovorin).- Evidence for Thymidylate Synthase as the Critical Site of Action of Fluoropyrimidines in Combination with CF.- The Role of Thymidylate Synthase in the Response to Fluoropyrimidine-Folinic Acid Combinations.- Tumor Cell Responses to Inhibition of Thymidylate Synthase.- Selectivity of CF and 5-Fluorouracil: Critical Role of Polyglutamylation.- Methods for Thymidylate Synthase Pharmacodynamics: Serial Biopsy, Free and Total TS, FdUMP and dUMP, and H4PteGlu and CH2-H4PteGlu Assays.- The Treatment of Metastatic Breast Cancer with 5-Fluorouracil and Leucovorin.- Thymidylate Synthase and Fluorouracil.- Mechanisms for Cisplatin-FUra Synergism and Cisplatin Resistance in Human Ovarian Carcinoma Cells both In Vitro and In Vivo.- Summation of Sessions 1 and.- Summation of Session 1.- Summation of Session 2.- Therapeutic Efficacy and Toxicity of Fluoropypimidines in Combination with CF.- The Roswell Park Memorial Institute and Gastrointestinal Tumor Study Group Phase III Experience with the Modulation of 5-Fluorouracil by Leucovorin in Metastatic Colorectal Adenocarcinoma.- Mount Sinai Clinical Experience with Leucovorin and 5-Fluorouracil.- High-Dose Weekly Oral Leucovorin and 5-Fluorouracil in Previously Untreated Patients with Advanced Colorectal Carcinoma: A Phase I Study.- A Controlled Clinical Trial Including Folinic Acid at Two Distinct Dose Levels in Combination with 5-Fluorouracil (5FU) for the Treatment of Advanced Colorectal Cancer: Experience of the Mayo Clinic and North Central Cancer Treatment Group.- 5-Fluorouracil (FUra) and Folinic Acid (FA) Therapy in Patients with Colorectal Cancer.- A Northern California Oncology Group Randomized Trial of Single Agent 5-FU vs. High-Dose Folinic Acid + 5-FU vs. Methotrexate + 5-FU + Folinic Acid in Patients with Disseminated Measurable Large Bowel Cancer.- Clinical Experience with CF-FUra.- A Randomized Trial of 5-Fluorouracil Alone versus 5-Fluorouracil and High Dose Leucovorin in Untreated Advanced Colorectal Cancer Patients.- Pharmacodynamics of 5-Fluorouracil and Leucovorin.- 5-Fluorouracil and 5-Formyltetrahydrofolate in Advanced Malignancies.- Folinic Acid (CF)/5-Fluorouracil (FUra) Combinations in Advanced Gastrointestinal Carcinomas.- Fffective Salvage Therapy for Refractory Disseminated Breast Cancer with 5-Fluorouracil and High-Dose Continuous Infusion Folinic Acid.- Progress Report on a Phase II Trial of 5-Fluorouracil Plus Citrovorum Factor in Women with Metastatic Breast Cancer.- Adjuvant Therapy for Colorectal Cancer: The NSABP Clinical Trials.- Chemotherapy of Advanced and Relapsed Squamous Cell Cancer of the Head and Neck with Split-Dose Cisplatinum (DDP), 5-Fluorouracil (Fura) and Leucovorin (CF).- 5-Fluorouracil/Folinic Acid/Cisplatin-Combination and Simultaneous Accelerated Split-Course Radiotherapy in Advanced Head and Neck Cancer.- Progress Report on Studies of FAM-CF for Gastric Cancer and Intra-peritoneal Administration of FUra-CF Followed by Cisplatin (DDP).- Clinical Experience with 5-FU/DDP ± OHDW Combination Chemotherapy in Patients with Advanced Colorectal Carcinoma.- 5-Fluorouracil and Folinic Acid: Summary of Clinical Experience.- Panel Discussion of Future Directions.- Abbreviations.- Author Index.