tbResList Print — Cisplatin Cisplatin

Description: <b>Cisplatin</b> is a chemotherapy medication used to treat various types of cancer. It is a platinum-based drug that works by interfering with the DNA of cancer cells, preventing them from reproducing and ultimately leading to cell death.<br>
Cisplatin (cis-diamminedichloroplatinum II; CDDP) is a platinum-based chemotherapeutic agent that forms covalent DNA crosslinks, primarily intrastrand adducts at adjacent guanine bases. These distort DNA structure, block replication and transcription, and activate DNA damage response pathways (ATM/ATR → p53), leading to cell-cycle arrest and apoptosis. Secondary mechanisms include ROS generation, stress MAPK activation, and modulation of NF-κB. Clinical resistance frequently involves enhanced DNA repair (ERCC1/NER), altered drug transport (CTR1, ATP7A/B), and increased antioxidant defenses. Major toxicities include nephrotoxicity, ototoxicity, and peripheral neuropathy.<br>
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<!-- Cisplatin (CDDP) — 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>DNA crosslink formation (intrastrand adducts)</td>
<td>DNA adducts ↑; replication block ↑</td>
<td>Normal dividing cells also affected</td>
<td>P, R, G</td>
<td>Direct DNA cytotoxicity</td>
<td>Cisplatin forms covalent intrastrand crosslinks (primarily at adjacent guanines), distorting DNA and blocking replication and transcription.</td>
</tr>

<tr>
<td>2</td>
<td>DNA damage response (ATM / ATR → p53)</td>
<td>Checkpoint activation ↑; p53 signaling ↑</td>
<td>↔ (toxicity in proliferating tissues)</td>
<td>R, G</td>
<td>Damage signaling cascade</td>
<td>DNA distortion activates ATM/ATR pathways leading to p53-mediated cell-cycle arrest and apoptosis.</td>
</tr>

<tr>
<td>3</td>
<td>Intrinsic apoptosis (mitochondrial pathway)</td>
<td>Bax ↑; Bcl-2 ↓; caspase-9/3 ↑</td>
<td>Nephrotoxicity & ototoxicity risk</td>
<td>G</td>
<td>Execution of cell death</td>
<td>Persistent DNA damage triggers mitochondrial outer membrane permeabilization and caspase activation.</td>
</tr>

<tr>
<td>4</td>
<td>Cell-cycle arrest (G2/M emphasis)</td>
<td>G2/M arrest ↑</td>
<td>↔</td>
<td>G</td>
<td>Cytostasis → apoptosis</td>
<td>Cells accumulate in G2/M phase due to unrepaired DNA lesions.</td>
</tr>

<tr>
<td>5</td>
<td>ROS generation / oxidative stress</td>
<td>ROS ↑ (secondary mechanism)</td>
<td>Oxidative injury ↑ (kidney, cochlea)</td>
<td>R, G</td>
<td>Stress amplification</td>
<td>Cisplatin increases mitochondrial ROS and oxidative stress, contributing to cytotoxicity and organ toxicity.</td>
</tr>

<tr>
<td>6</td>
<td>MAPK signaling (JNK / p38 activation)</td>
<td>Stress MAPK activation ↑</td>
<td>↔</td>
<td>R, G</td>
<td>Stress-response signaling</td>
<td>JNK and p38 activation contribute to apoptosis and stress signaling.</td>
</tr>

<tr>
<td>7</td>
<td>NF-κB activation (resistance axis)</td>
<td>NF-κB ↑ may promote survival</td>
<td>↔</td>
<td>R, G</td>
<td>Resistance modulation</td>
<td>NF-κB activation can reduce sensitivity; inhibition enhances cytotoxicity in some models.</td>
</tr>

<tr>
<td>8</td>
<td>DNA repair pathways (NER / ERCC1)</td>
<td>NER ↑ → resistance</td>
<td>—</td>
<td>G</td>
<td>Resistance determinant</td>
<td>Nucleotide excision repair (ERCC1) removes platinum adducts; high ERCC1 correlates with resistance.</td>
</tr>

<tr>
<td>9</td>
<td>Drug transport (CTR1 uptake; ATP7A/B efflux)</td>
<td>CTR1 ↓ or ATP7A/B ↑ → resistance</td>
<td>—</td>
<td>G</td>
<td>Exposure constraint</td>
<td>Copper transporters influence intracellular cisplatin accumulation and resistance.</td>
</tr>

<tr>
<td>10</td>
<td>Clinical toxicity profile</td>
<td>—</td>
<td>Nephrotoxicity, ototoxicity, neurotoxicity</td>
<td>—</td>
<td>Translation constraint</td>
<td>Major dose-limiting toxicities arise from DNA damage and oxidative stress in normal tissues.</td>
</tr>
</table>

<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (DNA aquation and initial adduct formation)</li>
<li><b>R</b>: 30 min–3 hr (checkpoint activation / stress signaling)</li>
<li><b>G</b>: &gt;3 hr (apoptosis, phenotype outcomes, resistance development)</li>
</ul>