Wheres can this UPI article be found that everyone keeps referring to??
The Drudge report times out.
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Announcement from ERM has made my day. :)
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What does nucleotide position mean in this context?
Each black block in the diagram represents a specific site along the DNA sequence where the polymerase was halted during nick translation due to drug binding.
These blocks mark where the drug binds or causes structural interference in the DNA.
The more positions blocked, the more extensive the drug's DNA coverage.
Bisantrene shows widespread blocks across many nucleotide positions, indicating broad and non-selective DNA interaction.
Why is this important for synergy with Doxorubicin?
Doxorubicin binds selectively to GC-rich sequences and causes double-strand breaks via topoisomerase II.
Bisantrene binds broadly, interfering at many more nucleotide positions.
This means:
They don’t compete for the same sites.
Together, they cover more of the genome, disrupting both structured and unstructured regions.
This enhances DNA damage beyond what either could do alone — blocking replication, transcription, and repair.
What does this translate to for targeted therapy synergy and broad anti-cancer action?
Because Bisantrene hits so many nucleotide sites, it:
Disrupts general transcription and replication machinery — not just in one type of cancer cell, but across many.
Can block adaptive gene responses that cancer cells use to resist targeted therapy (e.g., feedback loops, repair genes).
Doesn’t require a specific mutation or pathway — it acts at the fundamental level of gene expression.
In combination:
Targeted therapies hit a driver pathway (like EGFR or BCL2).
Bisantrene makes it harder for the cell to escape or compensate, because it blocks the transcriptional recovery needed to adapt or survive.
How does Bisantrene's binding compare to other DNA-binding drugs?
Actinomycin D binds preferentially at GC-rich promoter regions, often used to block transcription initiation — highly specific.
Doxorubicin binds intercalatively but prefers GC-pairs, and requires topo II for cytotoxicity.
Cisplatin forms covalent bonds at specific sequences, distorting the DNA.
Bisantrene is different:
It binds much more diffusely, blocking DNA synthesis at dozens of positions — not sequence-selective.
It doesn’t rely on enzyme-mediated action (like Topo II or alkylation), so it’s less dependent on cell type or context.
What Is a Nick Translation Assay?
Nick translation is a DNA labeling method where DNA polymerase I extends DNA from a nick (a break in one strand), replacing nucleotides while moving along the strand. If a DNA-binding drug interferes with polymerase movement, it creates a block—a visible termination site in this assay.
How to Interpret the Figures
You uploaded three key panels:
Figure for Bisantrene
Figure for Doxorubicin (Adriamycin)
Nucleotide sequence with position scale (used as the x-axis for both above)
Each black bar corresponds to a site where the drug caused polymerase to stop, i.e., inhibition of DNA synthesis.
Tall black blocks = Strong inhibition
Shorter blocks = Weaker inhibition
White areas = No inhibition (free polymerase movement)
Comparative Observations
Feature Bisantrene Doxorubicin (Adriamycin) 1 Binding pattern Dense, frequent blocks throughout Sparse, selective binding at fewer positions 2 Inhibition sites Distributed across many nucleotide positions Clustering in specific hotspots 3 Binding character Intercalative and possibly groove-binding Known intercalator; preferential to GC-rich 4 Concentration noted 2.5 μM and 5.0 μM 5.0 μM Biological Significance
This figure shows how each drug binds to DNA and prevents DNA synthesis:
Bisantrene shows broader inhibition, affecting many sites, suggesting widespread intercalation or groove binding. This can disrupt polymerase and transcription machinery across a larger range.
Doxorubicin has more selective binding, possibly targeting GC-rich or structural hotspots, which is consistent with its known sequence-preferential intercalation.
Implication for Combination Therapy
This matters for combination because:
Complementary Binding:
Bisantrene and Doxorubicin bind different DNA regions, so co-treatment may broaden coverage, interfering with replication and transcription more effectively.
Reduced Resistance Risk:
Cancer cells adapting to one drug's binding pattern may still be vulnerable to the other.
Different Mechanisms of Action:
While both intercalate DNA, Bisantrene also inhibits FTO demethylase and causes cell cycle re-entry, potentially enhancing doxorubicin-induced cytotoxicity.
Doxorubicin causes topoisomerase II-mediated double-strand breaks, while Bisantrene avoids cardiotoxicity through unique mechanisms.
✅ Summary
Drug Binding Coverage DNA Inhibition Profile Synergy Potential 1 Bisantrene Broad, non-specific Frequent synthesis blocks Enhances reach, overcomes resistance 2 Doxorubicin Targeted, GC-rich Specific hotspots only Powerful localized damage 3 Combo Effect Dual mechanisms Broader inhibition, fewer escape routes Potentially high synergy
Bisantrene v Doxorubicin (DNA binding Nucleotide positions)
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