Topoisomerase I Inhibitors – The Camptothecins

Newton, Michael; Wetzstein, Gene A.; Sullivan, Daniel M.

doi:10.1007/978-90-481-9704-0_6

Cited by 2 publications

(3 citation statements)

References 130 publications

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“…After chemical modification 9 , 10 , the prodrug irinotecan (CPT-11) can be formulated to have a pharmacokinetic profile suitable for treating colon cancer and other cancer types. However, similar to many other water-soluble prodrug designs, irinotecan is still limited by its unpredictable, patient-dependent conversion to the parent drug SN-38, unwanted degradation in the physiological environment, and variable dose-related toxicities 4 , 11 , 12 . Furthermore, the small molecule and lipophobicity nature contributes to rapid rental clearance and poor intracellular uptake that further reduces irinotecan's therapeutic efficacy 13 .…”

Section: Introductionmentioning

confidence: 99%

Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

Su¹,

Zhang²,

Cheetham³

et al. 2016

Theranostics

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Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

Su¹,

Zhang²,

Cheetham³

et al. 2016

Theranostics

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“…6,12,15 Camptothecin (CPT) is a cytotoxic drug extracted from the bark of a tree, Camptotheca acuminata (family Nyssaceae), 11,16 that inhibits the activity of the TopoI enzyme. 17,18 CPT is found to be an anticancer agent; however, because of its low water solubility and adverse drug reaction, 19 it is not suitable for clinical use. Derivatives of CPT, topotecan (Hycamine, GlaxoSmithKline) and irinotecan (Campostar, Pfizer), are more water-soluble and are currently being used to treat ovarian and small-cell lung cancers.…”

mentioning

confidence: 99%

“…Camptothecin (CPT) is a cytotoxic drug extracted from the bark of a tree, Camptotheca acuminata (family Nyssaceae), , that inhibits the activity of the TopoI enzyme. , CPT is found to be an anticancer agent; however, because of its low water solubility and adverse drug reaction, it is not suitable for clinical use. Derivatives of CPT, topotecan (Hycamine, GlaxoSmithKline) and irinotecan (Campostar, Pfizer), are more water-soluble and are currently being used to treat ovarian and small-cell lung cancers. − Topotecan {TPT, 9-[(dimethylamino)methyl]-10-hydroxy-camptothecin} was shown to be more stable than CPT and exhibits a lower toxicity. , It was shown that the presence of TPT increases the half-life of the DNA/TopoI cleavable complex more than CPT does .…”

mentioning

confidence: 99%

Activity of Topotecan toward the DNA/Topoisomerase I Complex: A Theoretical Rationalization

et al. 2018

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Topotecan (TPT) is a nontoxic anticancer drug characterized by a pH-dependent lactone/carboxyl equilibrium. TPT acts on the covalently bonded DNA/topoisomerase I (DNA/TopoI) complex by intercalating between two DNA bases at the active site. This turns TopoI into a DNA-damaging agent and inhibits supercoil relaxation. Although only the lactone form of the drug is active and effectively inhibits TopoI, both forms have been co-crystallized at the same location within the DNA/TopoI complex. To gain further insights into the pH-dependent activity of TPT, the differences between two TPT:DNA/TopoI complexes presenting either the lactone (acidic pH) or the carboxyl (basic pH) form of TPT were studied by means of molecular dynamic simulations, quantum mechanical/molecular mechanical calculations, and topological analysis. We identified two specific amino acids that have a direct relationship with the activity of the drug, i.e., lysine 532 (K532) and asparagine 722 (N722). K532 forms a stable hydrogen bond bridge between TPT and DNA only when the drug is in its active lactone form. The presence of the active drug triggers the formation of an additional stable interaction between DNA and protein residues, where N722 acts as a bridge between the two fragments, thus increasing the binding affinity of DNA for TopoI and further slowing the release of DNA. Overall, our results provide a clear understanding of the activity of the TPT-like class of molecules and can help in the future design of new anticancer drugs targeting topoisomerase enzymes.

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Topoisomerase I Inhibitors – The Camptothecins

Cited by 2 publications

References 130 publications

Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

Activity of Topotecan toward the DNA/Topoisomerase I Complex: A Theoretical Rationalization

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