Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer
The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed i...
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/1/258 |
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| author | Helena Taflin Elisabeth Odin Göran Carlsson Bengt Gustavsson Yvonne Wettergren Elinor Bexe Lindskog |
| author_facet | Helena Taflin Elisabeth Odin Göran Carlsson Bengt Gustavsson Yvonne Wettergren Elinor Bexe Lindskog |
| author_sort | Helena Taflin |
| collection | DOAJ |
| description | The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed in patients with colon cancer. Thirty patients were enrolled, receiving 60, 200 or 500 mg/m<sup>2</sup> LV as a single two-hour infusion. Blood, tumor, mucosa, and resection margin biopsies were collected. Folate concentrations were analyzed with LC-MS/MS and gene expression with qPCR. Data from a previous study where patients received LV as bolus injections were used as comparison. Saturation of methylenetetrahydrofolate (MeTHF) and tetrahydrofolate (THF) levels was seen after two-hour infusion and polyglutamated MeTHF + THF levels in tumors decreased with increasing LV dosage. The decrease was associated with decreased <i>FPGS</i> and increased <i>GGH</i> expression, which was not observed after LV bolus injection. In the bolus group, results indicate activation of a metabolic switch possibly promoting TYMS inhibition in response to 5-FU. Different metabolic mechanisms appear to be induced when LV is administered as infusion and bolus injection. Since maximal inhibition of TYMS by the 5-FU metabolite 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) requires excess polyglutamated MeTHF, the results point in favor of the bolus regimen. |
| first_indexed | 2024-03-11T10:06:04Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T10:06:04Z |
| publishDate | 2022-12-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a0f6f526129540c1a2ebf8c3b53192032023-11-16T15:03:45ZengMDPI AGCancers2072-66942022-12-0115125810.3390/cancers15010258Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon CancerHelena Taflin0Elisabeth Odin1Göran Carlsson2Bengt Gustavsson3Yvonne Wettergren4Elinor Bexe Lindskog5Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, 41685 Gothenburg, SwedenDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, 41685 Gothenburg, SwedenDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, 41685 Gothenburg, SwedenDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, 41685 Gothenburg, SwedenDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, 41685 Gothenburg, SwedenDepartment of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, 41685 Gothenburg, SwedenThe combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed in patients with colon cancer. Thirty patients were enrolled, receiving 60, 200 or 500 mg/m<sup>2</sup> LV as a single two-hour infusion. Blood, tumor, mucosa, and resection margin biopsies were collected. Folate concentrations were analyzed with LC-MS/MS and gene expression with qPCR. Data from a previous study where patients received LV as bolus injections were used as comparison. Saturation of methylenetetrahydrofolate (MeTHF) and tetrahydrofolate (THF) levels was seen after two-hour infusion and polyglutamated MeTHF + THF levels in tumors decreased with increasing LV dosage. The decrease was associated with decreased <i>FPGS</i> and increased <i>GGH</i> expression, which was not observed after LV bolus injection. In the bolus group, results indicate activation of a metabolic switch possibly promoting TYMS inhibition in response to 5-FU. Different metabolic mechanisms appear to be induced when LV is administered as infusion and bolus injection. Since maximal inhibition of TYMS by the 5-FU metabolite 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) requires excess polyglutamated MeTHF, the results point in favor of the bolus regimen.https://www.mdpi.com/2072-6694/15/1/258pharmacokineticsleucovorintwo-hour infusionbolus injectioncolon cancergene expression |
| spellingShingle | Helena Taflin Elisabeth Odin Göran Carlsson Bengt Gustavsson Yvonne Wettergren Elinor Bexe Lindskog Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer Cancers pharmacokinetics leucovorin two-hour infusion bolus injection colon cancer gene expression |
| title | Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer |
| title_full | Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer |
| title_fullStr | Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer |
| title_full_unstemmed | Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer |
| title_short | Increasing Dosage of Leucovorin Results in Pharmacokinetic and Gene Expression Differences When Administered as Two-Hour Infusion or Bolus Injection to Patients with Colon Cancer |
| title_sort | increasing dosage of leucovorin results in pharmacokinetic and gene expression differences when administered as two hour infusion or bolus injection to patients with colon cancer |
| topic | pharmacokinetics leucovorin two-hour infusion bolus injection colon cancer gene expression |
| url | https://www.mdpi.com/2072-6694/15/1/258 |
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