Enhanced 5-Fluorouracil Nucleotide Formation After Methotrexate Administration: Explanation for Drug Synergism

Cadman, Ed; Heimer, Robert; Davis, Lynn

doi:10.1126/science.472732

Cited by 227 publications

(53 citation statements)

References 11 publications

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“…The mechanism of synergistic effects in the MTX-5-fluorouracil sequence is considered to be the elevation of intracellular phosphoribosyl pyrophosphate by MTX, which results in increased 5-fluorouracil nucleotide formation. 22) This mechanism does not operate in the MTX-raltitrexed sequence.…”

Section: Discussionmentioning

confidence: 99%

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Schedule‐dependent Synergism and Antagonism between Raltitrexed (“Tomudex”) and Methotrexate in Human Colon Cancer Cell Lines in vitro

Kano

Akutsu

Tsunoda

et al. 2001

Japanese Journal of Cancer Research

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The folate-dependent enzymes are attractive targets for cancer chemotherapy. Methotrexate (MTX), which inhibits dihydrofolate reductase, has been widely used for the treatment of solid tumors and hematological cancers. Raltitrexed ("Tomudex"), which inhibits thymidylate synthase, is a novel anticancer agent active against colorectal cancer and some other solid tumors. We studied the optimal schedule of raltitrexed and MTX in combination against four human colon cancer cell lines Colo201, Colo320, LoVo, and WiDr. These cells were simultaneously exposed to raltitrexed and MTX for 24 h, or sequentially exposed to raltitrexed for 24 h followed by MTX for 24 h, or vice versa. Cell growth inhibition after 5 days was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of drug combinations at the concentrations of drug that produced 80% and 50% cell growth inhibition (IC 80 and IC 50 ) were analyzed by the isobologram method (Steel and Peckham, 1979). Cytotoxic interactions between raltitrexed and MTX were schedule-dependent. The simultaneous exposure to raltitrexed and MTX showed additive effects in Colo201, LoVo and WiDr cells and antagonistic effects in Colo320 cells. The sequential exposure to raltitrexed followed by MTX produced additive effects in all four cell lines. The sequential exposure to MTX followed by raltitrexed produced synergistic effects in Colo201, LoVo and WiDr cells and additive effects in Colo320 cells. These findings suggest that the sequential administration of MTX followed by raltitrexed produces more than the expected cytotoxicity and may be the optimal schedule at the cellular level. Further in vivo and clinical studies will be necessary to determine the toxicity and to test the antitumor effects of sequential administration of MTX followed by raltitrexed proposed on the basis of the in vitro synergism.Key words: Raltitrexed -Methotrexate -Synergism -Isobologram -Colon cancerThe folate-dependent enzymes are attractive targets for cancer chemotherapy because of their critical role in the synthesis of the nucleotide precursors of DNA. Methotrexate (MTX), the classical antifolate, is one of the oldest and still most commonly used anti-cancer agents. 1) Although the precise cytotoxic mechanism of MTX remains controversial, the main target of MTX is considered to be dihydrofolate reductase. The inhibition of this enzyme results in a lack of tetrahydrofolate coenzyme, which is required for the de novo synthesis of thymidylate, purines, and methionine. Thymidylate is required for the synthesis and repair of DNA, and inhibition of thymidylate synthesis is considered to be the major cytotoxic mechanism of MTX.Currently, several new folate analogs with unique biochemical properties are being tested for clinical application.2) Raltitrexed ("Tomudex") is a promising new agent that targets thymidylate synthase, the enzyme responsible for the final step of thymidylate synthesis.2, 3) Like MTX, this agent relies on the reduced folate carrier for cellular...

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Section: Discussionmentioning

confidence: 99%

“…21,22) 5-Fluorouracil is believed to have two mechanisms of action responsible for cytotoxicity. The mechanism of synergistic effects in the MTX-5-fluorouracil sequence is considered to be the elevation of intracellular phosphoribosyl pyrophosphate by MTX, which results in increased 5-fluorouracil nucleotide formation.…”

Section: Discussionmentioning

confidence: 99%

Schedule‐dependent Synergism and Antagonism between Raltitrexed (“Tomudex”) and Methotrexate in Human Colon Cancer Cell Lines in vitro

Kano

Akutsu

Tsunoda

et al. 2001

Japanese Journal of Cancer Research

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“…Biochemical modulation of 5-FU (F) by methotrexate or leucovorin (L) has been found to enhance 5-FU-induced cytotoxicity (Cadman et al, 1979;Keyomarsi and Morar, 1988). The combination of 5-FU, doxorubicin (adriamycin), methotrexate (FAMTX) and FL has resulted in 29-59% response rates (Klein et al, 1983;Berenberg et al, 1995).…”

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confidence: 99%

Weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin: an effective chemotherapy in advanced gastric cancer

Chi

Chao²,

Chan³

et al. 1998

Br J Cancer

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Summary In order to optimize the therapeutic index of combining etoposide, epirubicin, cisplatin, 5-fluorouracil (5-FU), leucovorin (EEPFL) chemotherapy in the treatment of advanced gastric cancer, a trial of a novel schedule of weekly administration was conducted. Weekly EEPFL treatment consisted of a concomitant boost of etoposide 40 mg m-2 i.v. over 30 min, epirubicin 10 mg m-2 i.v. over 5 min to a backbone regimen, weekly PFL chemotherapy with cisplatin 25 mg m-2, 5-FU 2200 mg m-2, leucovorin 120 mg m-2 given simultaneously by 24-h i.v. infusion. Response, survival and toxicity were evaluated. Forty-two patients were studied. Median age was 69 (range 31-84) years. Twentysix per cent of patients showed complete response and 45% partial response. The overall response rate was 71% (95% confidence interval 58-84%). For a total of 507 weekly EEPFL cycles delivered, the incidence of grade 4 leucopenia was 1% of cycles. One patient died of neutropenia septicaemia. There was no other grade 4 toxicity. Grade 3 and 2 leucopenia occurred in 7% and 14% of cycles. The incidence of grade 3 and 2 mucositis was 1 % and 3% of cycles. Grade 3 and 2 diarrhoea occurred in 0.4% and 1.6% of cycles. Overall median survival was 10 months (range 3-41 + months). Weekly EEPFL chemotherapy is an effective regimen with tolerable toxicities in the treatment of advanced gastric cancer. A randomized controlled clinical trial to formally assess the efficacy and benefit of EEPFL chemotherapy is under way.

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“…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.…”

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confidence: 99%

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

Grem

Kos

Evande

et al. 2015

Cancer

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BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m 2 on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m 2 /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m 2 . A subset of heavily pretreated patients had PFS durations of 6 months with this regimen. Cancer 2015;121:3862-8. INTRODUCTION 5-fluorouracil (5-FU) and folate inhibitors of dihydrofolate reductase (DHFR), including methotrexate (MTX), are active in a variety of malignancies. 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. 1-4 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. Ongoing thymidylate synthesis is required to deplete the cellular reduced-folate pool. Pretreatment with 5-FU inhibits thymidylate synthase (TS) thereby blocking the conversion of reduced folates to dihydrofolate. The reduced-folate pool is thus spared for purine synthesis, and the dihydrofolate pool does not expand. When MTX precedes 5-FU, ongoing thymidylate synthesis depletes reduced folates and dihydrofolate pools accumulate, thus allowing blockade of purine biosynthesis. Inhibition of de novo purine synthesis expands the intracellular pool of phosphoribosyl pyrophosphate, which is then available for the anabolism of 5-FU to fluorouridine monophosphate by orotate phosphoribosyl transferase. Enhancement o...

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Enhanced 5-Fluorouracil Nucleotide Formation After Methotrexate Administration: Explanation for Drug Synergism

Cited by 227 publications

References 11 publications

Schedule‐dependent Synergism and Antagonism between Raltitrexed (“Tomudex”) and Methotrexate in Human Colon Cancer Cell Lines in vitro

Schedule‐dependent Synergism and Antagonism between Raltitrexed (“Tomudex”) and Methotrexate in Human Colon Cancer Cell Lines in vitro

Weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin: an effective chemotherapy in advanced gastric cancer

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

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