Description: <b>B Vitamin supplement.</b> Helps form red blood cells.<br>
Folic acid (vitamin B9) is converted into tetrahydrofolate (THF) and its derivatives. These folate coenzymes are essential for one‐carbon transfer reactions, which are critical for the synthesis of purines and thymidylate—key components of DNA.<br>
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• Folate Deficiency and ROS: A deficiency in folic acid can exacerbate oxidative stress. Insufficient folate has been linked to increased ROS levels, which are capable of damaging cellular macromolecules, including DNA, proteins, and lipids. This oxidative DNA damage further increases mutation rates and contributes to carcinogenesis.<br>
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The evidence suggests that while adequate dietary folate is important for cancer prevention (by maintaining genomic stability and proper methylation), excessive folate supplementation in individuals with undiagnosed or existing neoplasms might be problematic.<br>
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-supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF).<br>
-5-MTHF also known as L-methylfolate<br>
-Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects<br>
-Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation<br>
-Large RCT meta-analyses generally do not show a moderate increase in overall cancer incidence from folic acid during trial periods.<br>
-High-dose folic acid has a long-running concern about “timing” (before vs after neoplasia), and NIH ODS cautions against >1,000 µg/day from supplements (UL) largely due to masking B12 deficiency and risk-uncertainty contexts.<br>
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-It’s best categorized as a “growth substrate / one-carbon cofactor” with high chemo-interaction relevance, not as a standalone anticancer natural product.<br>
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<!-- Folic Acid / Folate (Vit B9) — Cancer-Oriented Time-Scale Flagged Pathway Table -->
<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>One-carbon metabolism → nucleotide synthesis (dTMP & purines)</td>
<td>DNA/RNA synthesis capacity ↑ (supports proliferation if limiting)</td>
<td>Essential for normal cell replication/repair</td>
<td>R, G</td>
<td>Replication substrate support</td>
<td>Folate carries one-carbon units used for thymidylate and purine synthesis (core reason antifolates exist in oncology).</td>
</tr>
<tr>
<td>2</td>
<td>Methylation capacity (methionine cycle coupling: SAM/SAH balance)</td>
<td>Epigenetic tone can shift (context-dependent)</td>
<td>Supports normal methylation/homeostasis</td>
<td>G</td>
<td>Epigenetic/biochemical regulation</td>
<td>Folate status influences methyl donor availability; effects can differ by tumor type and baseline folate state.</td>
</tr>
<tr>
<td>3</td>
<td>Homocysteine remethylation (folate-B12 axis)</td>
<td>Indirect; not a primary tumor pathway</td>
<td>Homocysteine ↓ when deficient state corrected</td>
<td>G</td>
<td>Systemic metabolic effect</td>
<td>Clinically important for deficiency correction; not a direct anticancer mechanism.</td>
</tr>
<tr>
<td>4</td>
<td>Interaction with antifolate chemotherapy (methotrexate class)</td>
<td>Can counter antifolate effect depending on form/timing</td>
<td>Used to reduce toxicity in specific regimens (folinic acid/leucovorin rescue)</td>
<td>R</td>
<td>Chemo interaction (high-impact)</td>
<td>Folinic acid (leucovorin) is used as “rescue” after high-dose methotrexate to mitigate toxicity; this is regimen-specific. </td>
</tr>
<tr>
<td>5</td>
<td>5-FU modulation via reduced folate pool (leucovorin synergy)</td>
<td>Can enhance 5-FU thymidylate synthase inhibition (when folinic acid used)</td>
<td>Also increases toxicity risk (regimen-dependent)</td>
<td>R</td>
<td>Chemo potentiation (protocol-defined)</td>
<td>Leucovorin (folinic acid) is used clinically to enhance 5-FU efficacy by stabilizing TS inhibition; this is not “general folic acid supplementation.” :contentReference[oaicite:2]{index=2}</td>
</tr>
<tr>
<td>6</td>
<td>Cancer risk signal (supplement timing/dose debates)</td>
<td>Overall RCT meta-analyses: no moderate overall increase during trials</td>
<td>—</td>
<td>—</td>
<td>Translation constraint</td>
<td>Large meta-analyses of RCTs generally do not show a moderate increase in overall cancer incidence from folic acid supplementation during trial periods; timing and subgroup questions remain debated. :contentReference[oaicite:3]{index=3}</td>
</tr>
<tr>
<td>7</td>
<td>Upper intake constraint (supplemental folic acid)</td>
<td>High-dose use should be cautious without indication</td>
<td>UL for folic acid from supplements/fortified foods: 1,000 µg/day (adults)</td>
<td>—</td>
<td>Safety/monitoring</td>
<td>NIH ODS notes the adult UL is 1,000 µg/day for folic acid; excess can mask B12 deficiency and may be undesirable in some contexts. :contentReference[oaicite:4]{index=4}</td>
</tr>
<tr>
<td>8</td>
<td>Bioavailability / form distinction (folate vs folic acid vs folinic acid)</td>
<td>Form matters for chemo interactions and interpretation</td>
<td>Form matters for deficiency correction</td>
<td>P, R</td>
<td>Interpretation constraint</td>
<td>“Folate” (food forms), “folic acid” (synthetic), and “folinic acid/leucovorin” (reduced folate used in oncology protocols) are not interchangeable clinically.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (absorption/early availability; limited “instant” pathway effects)</li>
<li><b>R</b>: 30 min–3 hr (acute pool shifts; relevant mainly in drug-modulation contexts)</li>
<li><b>G</b>: >3 hr (methylation/nucleotide supply effects; phenotype-level outcomes)</li>
</ul>
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Chemo Interaction Mini-Table<br>
<!-- Folic Acid / Reduced Folates — Chemo Interaction Mini-Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Drug / Regimen</th>
<th>Folate-Related Agent</th>
<th>Interaction Type</th>
<th>Mechanism (What’s happening)</th>
<th>Clinical Use / Practical Note</th>
<th>Net Effect</th>
</tr>
<tr>
<td><b>High-dose Methotrexate (HD-MTX)</b></td>
<td><b>Leucovorin</b> (folinic acid; calcium folinate)</td>
<td>Rescue (toxicity mitigation)</td>
<td>Provides reduced folate to “rescue” normal cells from MTX-induced reduced-folate depletion; not given simultaneously because it can blunt MTX effect.</td>
<td>Standard component of HD-MTX supportive care (timing is protocol-defined; typically starts after MTX).</td>
<td><b>↓ toxicity</b> while preserving efficacy when timed correctly :contentReference[oaicite:0]{index=0}</td>
</tr>
<tr>
<td><b>5-Fluorouracil (5-FU) regimens</b><br>(e.g., colorectal protocols)</td>
<td><b>Leucovorin</b> (folinic acid)</td>
<td>Potentiation (efficacy enhancement)</td>
<td>Increases and stabilizes thymidylate synthase (TS) inhibition by promoting formation of the inhibitory ternary complex (5-FU metabolite + TS + reduced folate cofactor).</td>
<td>Intentional synergy; also increases risk of GI and marrow toxicity vs 5-FU alone (protocol-dependent).</td>
<td><b>↑ efficacy</b> + often <b>↑ toxicity</b> :contentReference[oaicite:1]{index=1}</td>
</tr>
<tr>
<td><b>Pemetrexed</b> (antifolate chemotherapy)</td>
<td><b>Folic acid</b> (oral) + <b>Vitamin B12</b> (IM)</td>
<td>Required supplementation (toxicity reduction)</td>
<td>Supplementation reduces severity of hematologic and GI toxicity during pemetrexed therapy.</td>
<td>Start before first dose, continue during treatment, and continue after last dose per label/protocol.</td>
<td><b>↓ toxicity</b> (standard of care) :contentReference[oaicite:2]{index=2}</td>
</tr>
<tr>
<td><b>“Folic acid” vs “Leucovorin”</b><br>(naming pitfall)</td>
<td>Folic acid (synthetic) vs Leucovorin (reduced folate)</td>
<td>Non-interchangeable</td>
<td>Leucovorin is a reduced folate used for MTX rescue and 5-FU potentiation; folic acid is mainly a nutritional supplement and not a direct substitute in these oncology protocols.</td>
<td>Use the specific agent indicated by protocol; don’t swap terms in notes.</td>
<td><b>Interpretation / protocol-critical</b> :contentReference[oaicite:3]{index=3}</td>
</tr>
<tr>
<td><b>General supplementation safety note</b></td>
<td>High-dose folic acid supplements</td>
<td>Monitoring issue</td>
<td>Large folate intakes can mask hematologic signs of B12 deficiency while neurologic injury progresses.</td>
<td>Relevant when documenting “high-dose folate” use outside oncology protocols.</td>
<td><b>Safety constraint</b> :contentReference[oaicite:4]{index=4}</td>
</tr>
</table>