tbResList Print — EP Electrical Pulses

Description: <p><b>Electrical Pulses (Pulsed Electric Field therapies; PEF)</b> are a bioelectromagnetic <i>modality</i> in oncology that delivers brief, high-voltage (or high-field) pulses to tissue to permeabilize membranes and/or ablate tumors. Clinically relevant categories commonly discussed: <br>
<b>(1) Reversible electroporation for drug/ion delivery</b> (Electrochemotherapy, <b>ECT</b>; Calcium electroporation), <br>
<b>(2) Irreversible electroporation ablation</b> (<b>IRE</b>; e.g., NanoKnife-type approaches), and <br>
<b>(3) Nanosecond PEF</b> (<b>nsPEF</b>) aimed at intracellular targets. <br>
Primary mechanisms (ranked):<br>
1) <b>Membrane electroporation</b> → rapid loss of ionic homeostasis / enhanced transport (ECT) or irreversible disruption (IRE).<br>
2) <b>Ca²⁺ dysregulation</b> (influx + organelle Ca²⁺ stress) → mitochondrial depolarization, ER stress, apoptosis/necrosis spectrum (pulse-width dependent).<br>
3) <b>Stress biology</b> (ROS↑, inflammatory/DAMP signaling) → immunogenic cell death signals and microenvironment remodeling (often secondary/adaptive).<br>
<b>PK/Bioavailability relevance:</b> systemic PK is mainly relevant only for <b>ECT</b> (bleomycin/cisplatin timing, tissue exposure); field-based effects themselves are local and device/geometry-limited rather than concentration-limited.<br>
<b>In-vitro vs systemic exposure:</b> not concentration-driven (electric field–driven); however, many in-vitro protocols use idealized field homogeneity not achievable in heterogeneous tumors without image-guided electrode placement.<br>
<b>Clinical evidence:</b> <b>ECT</b> and <b>IRE</b> have substantial human use (ECT for cutaneous/superficial tumors; IRE for selected solid tumors near critical structures). <b>nsPEF</b> remains mostly preclinical/early human and is still device- and protocol-evolving.</p>



<h3>Electrical Pulses / PEF Oncology Modality — Ranked Mechanistic Axes</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells (↑ / ↓ / ↔)</th>
<th>Normal Cells (↑ / ↓ / ↔)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>

<tr>
<td>1</td>
<td><b>Membrane electroporation</b> (Reversible vs Irreversible)</td>
<td>↑ permeabilization / disruption</td>
<td>↑ permeabilization / disruption</td>
<td>P</td>
<td>Immediate loss of membrane barrier</td>
<td><b>Category mapping:</b> Reversible EP → <b>ECT / Ca-EP</b>; Irreversible EP → <b>IRE</b>. Selectivity is largely geometric (field distribution) and cellular (repair capacity), not “cancer-only”.</td>
</tr>

<tr>
<td>2</td>
<td><b>ECT drug uptake</b> (bleomycin/cisplatin) / intracellular access</td>
<td>↑ intracellular drug delivery</td>
<td>↑ intracellular drug delivery</td>
<td>P→R</td>
<td>Local chemosensitization</td>
<td><b>Category:</b> <b>ECT</b> is a delivery amplifier; efficacy depends on timing + local perfusion. Often enables potent effect from otherwise poorly permeant agents.</td>
</tr>

<tr>
<td>3</td>
<td><b>Ca²⁺ axis</b> (influx, overload, ER–mitochondria coupling)</td>
<td>↑ Ca²⁺ dysregulation</td>
<td>↑ Ca²⁺ dysregulation</td>
<td>P→R</td>
<td>Mitochondrial stress, apoptosis/necrosis spectrum</td>
<td>Pulse width and repetition strongly shape outcome; <b>Ca electroporation</b> leverages Ca²⁺-driven bioenergetic collapse as a drug-free approach.</td>
</tr>

<tr>
<td>4</td>
<td><b>Mitochondria / MPTP</b> + bioenergetic collapse</td>
<td>↑ depolarization / ATP loss</td>
<td>↑ depolarization / ATP loss</td>
<td>R</td>
<td>Cell death execution + metabolic failure</td>
<td>Often downstream of Ca²⁺ overload + membrane failure; nsPEF is frequently framed as more “intracellular/organellar” stress-forward than classic µs EP.</td>
</tr>

<tr>
<td>5</td>
<td><b>ROS</b> (oxidative burst → signaling)</td>
<td>↑ (context-dependent)</td>
<td>↑ (context-dependent)</td>
<td>R→G</td>
<td>Stress signaling, damage amplification</td>
<td>ROS can be secondary to Ca²⁺/mitochondria and/or electrochemical effects at electrodes. Direction and magnitude depend on pulse protocol, conductivity, and oxygenation.</td>
</tr>

<tr>
<td>6</td>
<td><b>NRF2</b> antioxidant response / adaptation</td>
<td>↑ (context-dependent; resistance role)</td>
<td>↑ (protective role)</td>
<td>G</td>
<td>Redox adaptation</td>
<td>NRF2 upshifts can protect normal tissue but may also support tumor survival post-sublethal EP (repair/tolerance). Relevance rises when aiming for non-ablative or fractionated protocols.</td>
</tr>

<tr>
<td>7</td>
<td><b>Vascular axis</b> (perfusion, endothelial effects)</td>
<td>↓ perfusion (often) / local ischemia</td>
<td>↓ perfusion (local)</td>
<td>R</td>
<td>Secondary tumor control via antivascular effects</td>
<td>Prominent in <b>ECT</b> literature (composite antivascular + cytotoxic). In IRE, ECM sparing may preserve larger structures while still affecting microvasculature.</td>
</tr>

<tr>
<td>8</td>
<td><b>Immunogenic cell death</b> / DAMP release</td>
<td>↑ immune priming signals</td>
<td>↔ (tissue-dependent)</td>
<td>G</td>
<td>Local-to-systemic immune modulation (adjunct potential)</td>
<td>Most compelling as an <b>adjunct</b> (combo with checkpoint blockade, RT, etc.). Strength varies with ablation completeness, antigen burden, and microenvironment.</td>
</tr>

<tr>
<td>9</td>
<td><b>Clinical Translation Constraint</b></td>
<td>↔</td>
<td>↔</td>
<td>—</td>
<td>Deliverability / safety / field heterogeneity</td>
<td>Constraints are dominated by <b>geometry</b> (electrode placement, tumor shape, conductivity), <b>safety</b> (muscle contractions, arrhythmia risk near heart, anesthesia needs), and protocol standardization; nsPEF still has broader device/protocol variability than ECT/IRE.</td>
</tr>
</table>