5-10-methylenetetrahydrofolic-acid and Rectal-Neoplasms

Modufolin® ([6R]-5,10-methylene tetrahydrofolate; [6R]-MTHF) is an endogenous biomodulator that is being developed as an alternative to leucovorin, a folate prodrug used in the treatment of colorectal cancer. The objective of this phase 1 dose de-escalation trial was to estimate the minimum tolerated dose of [6R]-MTHF to be used in combination with pemetrexed 500 mg/m(2) in the neoadjuvant treatment of patients with rectal cancer.. Adult patients (≥18 years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10 mg/m(2) in combination with pemetrexed 500 mg/m(2). [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1 week prior to the first dose of pemetrexed and then once weekly for 9 weeks; pemetrexed was administered by i.v. infusion once every 21 days for three cycles.. Twenty-four patients (mean [SD] age, 63.1 [12.9] years) were enrolled in the study. A total of 72 treatment-related adverse events (AEs) were reported, of which the most common were fatigue (n = 17; 23.6 %), nausea (n = 10; 13.9 %), and diarrhea (n = 5; 6.9 %). The incidence of treatment-related AEs by [6R]-MTHF dose level (500, 100, 50, 10 mg/m(2)) was 11.1 % (n = 8), 13.9 % (n = 10), 45.8 % (n = 33), and 29.2 % (n = 21), respectively. There were no dose-limiting toxicities, and only two (2.8 %) treatment-related AEs were grade 3 in severity. Of the 11 serious AEs reported, none were considered to be related to [6R]-MTHF treatment.. The results of this phase 1 study indicate that the estimated minimum tolerated dose of [6R]-MTHF was 100 mg/m(2) once weekly in combination with pemetrexed 500 mg/m(2). The low toxicity profile of [6R]-MTHF supports its further evaluation as a component of systemic chemotherapy in the management of colon and rectal cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoadjuvant Therapy; Pemetrexed; Rectal Neoplasms; Tetrahydrofolates

This study was designed to examine the endogenous concentrations of 5,10-methylenetetrahydrofolate (CH2FH4) in human colorectal adenocarcinoma xenografts, and to determine the ability of other folate derivatives to increase the formation of the ternary covalent complex between CH2FH4, [6-3H]-5-fluorodeoxyuridylate (FdUMP) and thymidylate synthetase (TS, EC 2.1.1.45). Levels of CH2FH4 were determined by measuring the release of [3H]2O from [5-3H]-dUMP using TS from Lactobacillus casei. The reaction was linear from 1.9 X 10(-13) to 2.4 X 10(-11) mol of CH2FH4 assayed. Concentrations of CH2FH4 were low, ranging from 66 to 233 nM in cell water. Tetrahydrofolate (FH4) and dihydrofolate (FH2) increased complex formation, while 5-formyltetrahydrofolate (5-CHOFH4) and 5-methyltetrahydrofolate (5-CH3FH4) decreased the covalent binding of [6-3H]-FdUMP in vitro. Administration of FH4 or FH2 to tumor-bearing mice reduced subsequent formation of the covalent complex in vitro. Since 5-CH3FH4 is a major derivative of folate in mammalian tissues, its effect on the covalent binding of [6-3H]-FdUMP was examined further; even in the presence of homocysteine and cyanocobalamin (B12), the formation of the covalent complex was not increased. The fate of [5-14CH3]-FH4 was subsequently examined in vivo. In tumors at 1 hr after injection, 72% of the radiolabel remained as [5-14CH3]-FH4, while 17% had been converted to [14C]-methionine or incorporated into protein. By contrast, however, the incorporation of radiolabel into the protein fraction of liver was almost 30-fold greater at this time. At 4 hr, radioactivity in tumors (dpm/g) and in the fraction associated with [5-14CH3]-FH4 was decreased by over 60%, while metabolism was increased by only 13%. No polyglutamate forms of [5-14CH3]-FH4 were detected in tumors at 4 hr after treatment.

Topics: Adenocarcinoma; Animals; Cell Line; Colonic Neoplasms; Deoxyuracil Nucleotides; Female; Fluorodeoxyuridylate; Folic Acid; Homocysteine; Humans; Methyltransferases; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Rectal Neoplasms; Tetrahydrofolates; Thymidylate Synthase; Transplantation, Heterologous; Vitamin B 12