Description: <b>Doxorubicin</b>, (brand name Adriamycin) is a chemotherapy medication used to treat breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. Often used together with other chemotherapy agents. Given by injection into a vein.<br>
Doxorubicin is an anthracycline chemotherapy whose core anticancer activity is driven by DNA intercalation and topoisomerase II poisoning (DNA double-strand break stress), with additional contributions from redox cycling/iron-linked oxidative injury in some contexts. Its major clinical limitations are myelosuppression and cumulative dose–dependent cardiomyopathy, plus severe tissue injury if extravasated (leaks outside the vein).<br>
-Cumulative cardiomyopathy risk is real and dose-dependent; labels note higher risk at higher cumulative doses (often cited around >550 mg/m², with lower limits in higher-risk patients).<br>
-Mechanism split: tumor kill is primarily Topo II + DNA damage, while cardiotoxicity is strongly linked to TOP2β/mitochondrial pathways (redox/iron biology remains discussed, but not the only story).<br>
-Administration hazard: extravasation can cause severe local injury;<br>
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<!-- Doxorubicin (DOX) — 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>Topoisomerase II poisoning (DNA double-strand break stress)</td>
<td>Topo II–DNA cleavage complexes ↑ → DNA breaks ↑ → apoptosis/senescence ↑ (context)</td>
<td>Also affects normal proliferating tissues (marrow, mucosa)</td>
<td>P, R</td>
<td>Core cytotoxic mechanism</td>
<td>Primary anticancer mechanism: stabilization of Topo II–DNA cleavage complexes blocks repair and drives lethal DNA damage responses.</td>
</tr>
<tr>
<td>2</td>
<td>DNA intercalation → replication/transcription disruption</td>
<td>DNA/RNA synthesis ↓; replication stress ↑</td>
<td>Off-target in normal dividing cells</td>
<td>P, R</td>
<td>Replication/transcription blockade</td>
<td>Intercalation contributes to replication fork stress and complements Topo II poisoning.</td>
</tr>
<tr>
<td>3</td>
<td>Redox cycling / iron-associated oxidative injury (context-dependent)</td>
<td>ROS / oxidative damage ↑ (reported; model-dependent)</td>
<td>Oxidative injury risk in sensitive tissues (esp. heart) ↑</td>
<td>P, R, G</td>
<td>Stress amplification</td>
<td>Often described as semiquinone redox cycling and iron interactions; the relative importance vs Topo II varies by tissue/model.</td>
</tr>
<tr>
<td>4</td>
<td>Cardiotoxicity axis (TOP2β + mitochondrial injury; cumulative-dose dependent)</td>
<td>—</td>
<td>Risk of cardiomyopathy/heart failure ↑ with cumulative exposure</td>
<td>R, G</td>
<td>Major dose-limiting toxicity</td>
<td>Clinically important boxed-warning toxicity; risk increases with cumulative dose (labels cite higher risk above ~550 mg/m²; higher-risk patients often use lower limits).</td>
</tr>
<tr>
<td>5</td>
<td>Myelosuppression (bone marrow progenitors)</td>
<td>—</td>
<td>Neutropenia/anemia/thrombocytopenia risk ↑</td>
<td>R, G</td>
<td>Dose-limiting toxicity</td>
<td>Expected on-target effect in rapidly dividing marrow cells; infection risk increases when neutrophils are low.</td>
</tr>
<tr>
<td>6</td>
<td>p53 / DNA-damage response programs</td>
<td>DDR signaling ↑; p53 pathway engagement ↑ (context)</td>
<td>DDR activation in normal tissues contributes to toxicity</td>
<td>R, G</td>
<td>Cell fate commitment</td>
<td>Downstream of DNA breaks: checkpoint activation, apoptosis, senescence, or mitotic catastrophe depending on genotype and dose.</td>
</tr>
<tr>
<td>7</td>
<td>Immunogenic cell death signals (DAMP exposure; context-dependent)</td>
<td>Potential ICD features ↑ (reported in some systems)</td>
<td>—</td>
<td>G</td>
<td>Immune engagement (conditional)</td>
<td>Anthracyclines are often discussed as capable of immunogenic cell death in certain settings; not universal across regimens.</td>
</tr>
<tr>
<td>8</td>
<td>Extravasation tissue injury (local)</td>
<td>—</td>
<td>Severe local tissue damage risk if IV leakage occurs</td>
<td>P, R</td>
<td>Administration hazard</td>
<td>Boxed warning emphasizes severe tissue injury with extravasation; requires strict IV administration controls.</td>
</tr>
<tr>
<td>9</td>
<td>Secondary malignancy risk (therapy-related AML/MDS; exposure-dependent)</td>
<td>—</td>
<td>Rare long-term risk signal ↑</td>
<td>—</td>
<td>Late toxicity constraint</td>
<td>Listed in boxed warnings/labels as a potential late effect, especially with combination regimens.</td>
</tr>
<tr>
<td>10</td>
<td>Cardioprotection strategy (dexrazoxane; selected settings)</td>
<td>—</td>
<td>Cardiotoxicity risk ↓ (when used appropriately)</td>
<td>R, G</td>
<td>Risk mitigation</td>
<td>Dexrazoxane is used to reduce anthracycline cardiotoxicity; mechanistic literature includes TOP2β-linked protection and other hypotheses.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (direct DNA/Topo interactions begin rapidly)</li>
<li><b>R</b>: 30 min–3 hr (acute DNA-damage response + stress signaling)</li>
<li><b>G</b>: >3 hr (gene programs, apoptosis/senescence, phenotype-level outcomes)</li>
</ul>