Description: <b>5-FU</b> is a chemotherapy medication used to treat various types of cancer, including colorectal, breast, stomach, and pancreatic cancer. It belongs to a class of drugs known as antimetabolites, which work by interfering with the growth and replication of cancer cells.<br>
<b>Mechanisms:</b><br>
- functionally irreversibly inhibits Thymidylate Synthase (TS), thereby depleting the deoxythymidine monophosphate (dTMP) pool required for DNA synthesis. The resulting “thymineless death” prevents DNA replication and repair, particularly affecting rapidly proliferating tumor cells.<br>
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5-FU is a cornerstone in chemotherapy with a dual mechanism of action—primarily inhibiting thymidylate synthase (leading to disruption of DNA synthesis) and interfering with RNA processing by misincorporation. Its metabolism via activation (OPRT) and degradation (DPD) plays a crucial role in both its effectiveness and toxicity. Clinically, 5-FU is extensively used in treating a variety of cancers, most notably colorectal cancer, and remains a mainstay in multi-agent chemotherapeutic regimens due to its proven efficacy across diverse cancer types.<br>
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5-FU is one of the most common chemotherapeutic agents worldwide, particularly noted in gastrointestinal (GI) cancers.<br>
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<!-- 5-Fluorouracil (5-FU) — Time-Scale Flagged Pathway Table (web-page ready) -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Thymidylate synthase (TS) inhibition → dTMP depletion</td>
<td>dTMP ↓ → DNA synthesis ↓ → replication stress ↑</td>
<td>Also affects normal proliferating tissues (marrow, GI mucosa)</td>
<td>P, R</td>
<td>Core cytotoxic mechanism</td>
<td>5-FU is converted to FdUMP, which forms a ternary complex with TS and folate, blocking thymidylate production (“thymineless death”).</td>
</tr>
<tr>
<td>2</td>
<td>RNA misincorporation (FUTP incorporation)</td>
<td>RNA processing/translation defects ↑</td>
<td>Contributes to mucositis and systemic toxicity</td>
<td>P, R</td>
<td>Transcription/translation disruption</td>
<td>RNA effects are a major contributor to cytotoxicity, particularly with bolus dosing.</td>
</tr>
<tr>
<td>3</td>
<td>DNA misincorporation (FdUTP incorporation)</td>
<td>DNA damage signaling ↑; apoptosis ↑ (context)</td>
<td>DDR activation in normal tissues contributes to toxicity</td>
<td>R, G</td>
<td>Genome instability</td>
<td>Misincorporation triggers mismatch repair and DNA damage responses.</td>
</tr>
<tr>
<td>4</td>
<td>S-phase specificity (cell-cycle dependence)</td>
<td>Greater killing in actively cycling/S-phase cells</td>
<td>Bone marrow & GI epithelium vulnerability ↑</td>
<td>R, G</td>
<td>Cell-cycle–linked cytotoxicity</td>
<td>Antimetabolite activity is strongest in proliferating cells.</td>
</tr>
<tr>
<td>5</td>
<td>Folate modulation (leucovorin synergy)</td>
<td>TS inhibition ↑ when combined with leucovorin</td>
<td>—</td>
<td>R</td>
<td>Mechanism amplification</td>
<td>Leucovorin stabilizes the FdUMP–TS–folate complex, enhancing cytotoxicity.</td>
</tr>
<tr>
<td>6</td>
<td>Myelosuppression</td>
<td>—</td>
<td>Neutropenia/anemia risk ↑</td>
<td>R, G</td>
<td>Dose-limiting toxicity</td>
<td>Expected on-target effect in rapidly dividing marrow progenitors.</td>
</tr>
<tr>
<td>7</td>
<td>Gastrointestinal toxicity (mucositis/diarrhea)</td>
<td>—</td>
<td>GI epithelial injury ↑</td>
<td>R, G</td>
<td>Dose-limiting toxicity</td>
<td>Reflects RNA/DNA effects in rapidly renewing GI mucosa.</td>
</tr>
<tr>
<td>8</td>
<td>Cardiotoxicity (vasospasm; rare cardiomyopathy)</td>
<td>—</td>
<td>Chest pain/ischemia risk ↑ (rare but important)</td>
<td>R</td>
<td>Serious adverse effect</td>
<td>Coronary vasospasm is the most recognized mechanism; monitoring required in symptomatic patients.</td>
</tr>
<tr>
<td>9</td>
<td>DPD metabolism (DPYD enzyme)</td>
<td>Severe toxicity risk ↑ if DPD deficient</td>
<td>—</td>
<td>—</td>
<td>Pharmacogenetic constraint</td>
<td>Dihydropyrimidine dehydrogenase (DPD) metabolizes 5-FU; deficiency can cause life-threatening toxicity. Pre-treatment DPYD testing is increasingly recommended.</td>
</tr>
<tr>
<td>10</td>
<td>Infusion vs bolus pharmacodynamics</td>
<td>Continuous infusion → more TS-driven DNA effect</td>
<td>Bolus → more RNA-mediated toxicity</td>
<td>P, R, G</td>
<td>Dosing-dependent mechanism balance</td>
<td>Administration schedule alters relative DNA vs RNA contribution and toxicity profile.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (metabolic activation begins rapidly)</li>
<li><b>R</b>: 30 min–3 hr (TS inhibition, RNA/DNA incorporation, DDR activation)</li>
<li><b>G</b>: >3 hr (cell-cycle arrest, apoptosis, tissue-level toxicities)</li>
</ul>