Activity of sequential low-dose methotrexate and fluorouracil in advanced colorectal carcinoma: attempt at correlation with tissue and blood levels of phosphoribosylpyrophosphate.

Abstract

Forty-five patients with metastatic colorectal carcinoma were treated with low-dose methotrexate (MTX) and 5-fluorouracil (5-FU) given sequentially. The dose of MTX was 40 mg/m2 intravenously (IV) on days 1 and 8 followed 24 hours later by 5-FU at 600 mg/m2 IV on days 2 and 9; the drugs were recycled every 28 days. Fourteen (32%) of 43 adequately treated patients had a complete or partial response lasting a median of nine months (range, 6-15 + months). Four patients had a minor response and seven patients had stable disease for a median of nine and 10 months, respectively. Toxicity included mucositis in 28 (65%) patients, diarrhea in 18 (40%), nausea in 11 (24%), and vomiting in seven (16%). Hematologic toxicity was mild: six patients had nadir white blood cell counts less than 3.5 X 10(3) cells/microL, and seven patients had a nadir platelet count less than 100 X 10(3) cells/microL. Serial biopsies and blood samples were obtained in selected patients to evaluate the effect of MTX on tissue and lymphocyte phosphoribosylpyrophosphate (PRPP) and PRPP synthetase levels.

19F NMR monitoring of in vivo tumor metabolism after biochemical modulation of 5‐fluorouracil by the uridine phosphorylase inhibitor 5‐benzylacyclouridine

“…BAU at the dose of 120 mg/kg preceded the administration of 5-FU by 30 min. At 2,4,6,10,15,30,45,60, and 120 min after the administration of the radiolabeled dose of 5-FU. 300 pl of blood were collected from two animals for each group in heparinized Natelson pipettes.…”

“…Sequential '"F NMR spectra were acquired from the Colon 38 tumors by averaging 900 FIDs at a repetition time of 1.0 s. Four thousand samples were acquired from the FID over a sweep width = 16 kHz, giving a spectral resolution of 4 Hz/point in the processed spectra. The resulting time interval between spectra was 15 min.…”

“…Differences in the overall SNR of the spectra in Figs. 4 and 3 are attributed primarily to the slightly broader line width of the spectra (140 versus 90 Hz) and the smaller tumor volume (0.28 versus 0.33 cm") from the animal data shown in Fig. 4. A comparison of the two regimens evaluating the ratios between FUXP + FUrd and 5-F1J and FUPA + FPAL and 5-FU (Fig.…”

“…5-FU is also incorporated into RNA in the form of 5-fluorouridine triphosphate, thus interfering with the maturation of nuclear RNA, again inhibiting cell proliferation. Drug regimens with methotrexate (4,5) and leucovorin (6,7) were developed to increase the inhibition on thymidylate synthetase. Combinations with N-(phosphonoacety1)-L-aspartic acid (8)(9)(10) and brequinar sodium (11,12) lowered the uridine pools, resulting in enhanced 5-FU incorporation into RNA.…”

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

“…There is strong preclinical evidence that the optimal sequence for combining DHFR inhibitors with 5-FU involves pretreatment with the DHFR inhibitor followed by 5-FU. [1][2][3][4] Administration of 5-FU followed by MTX is antagonistic in both in vitro and in vivo studies. The antipurine action of MTX is believed to result from 2 factors: 1) partial depletion of 10-formyl-tetrahydrofolate, which is required for purine synthesis; and 2) buildup of dihydrofolate, which is an inhibitor of de novo purine synthesis.…”