604 Secretory phospholipase A2 as tumour specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids

Jensen, Simon Skøde; Jensen, L.T.; Davidsen, Jesper Rømhild; Gill, Jason H.; Shnyder, Steven D.; Bibby, Michael C.; Høyrup, Pernille; Jørgensen, Kent

doi:10.1016/s1359-6349(04)80612-8

Cited by 26 publications

(34 citation statements)

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“…The role of sPLA2 in TFT resistance was evident because the sPLA2 inhibitor 4-BPB reversed resistance almost completely, although the exact role of sPLA2 remains to be identified. sPLA2 is currently also under investigation in liposome-mediated drug target-delivered therapies, in which increased sPLA2 activity in the tumor microenvironment is used as a trigger for the release of anticancer etherlipids (47,48). In addition, TFT may also be combined with sPLA2 inhibitors, such as varespladib methyl (1-H-indole-3-glyoxamide; A-002), LY311727 (3-[1-benzyl-3-carbamoylmethyl)-2-ethyl-indol-5-yl]-oxypropylphosphonic acid), and LY374388 (3-aminooxalyl-1-benzyl-2-ethyl-6-methyl-1H-indol-4-yloxy-acetic acid methyl ester; ref.…”

Section: Discussionmentioning

confidence: 99%

Trifluorothymidine Resistance Is Associated with Decreased Thymidine Kinase and Equilibrative Nucleoside Transporter Expression or Increased Secretory Phospholipase A2

Temmink

Bijnsdorp

Prins

et al. 2010

Molecular Cancer Therapeutics

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Trifluorothymidine (TFT) is part of the novel oral formulation TAS-102, which is currently evaluated in phase II studies. Drug resistance is an important limitation of cancer therapy. The aim of the present study was to induce resistance to TFT in H630 colon cancer cells using two different schedules and to analyze the resistance mechanism. Cells were exposed either continuously or intermittently to TFT, resulting in H630-cTFT and H630-4TFT, respectively. Cells were analyzed for cross-resistance, cell cycle, protein expression, and activity of thymidine phosphorylase (TP), thymidine kinase (TK), thymidylate synthase (TS), equilibrative nucleoside transporter (hENT), gene expression (microarray), and genomic alterations. Both cell lines were cross-resistant to 2′-deoxy-5-fluorouridine (>170-fold). Exposure to IC 75 -TFT increased the S/G 2 -M phase of H630 cells, whereas in the resistant variants, no change was observed. The two main target enzymes TS and TP remained unchanged in both TFT-resistant variants. In H630-4TFT cells, TK protein expression and activity were decreased, resulting in less activated TFT and was most likely the mechanism of TFT resistance. In H630-cTFT cells, hENT mRNA expression was decreased 2-to 3-fold, resulting in a 5-to 10-fold decreased TFT-nucleotide accumulation. Surprisingly, microarray-mRNA analysis revealed a strong increase of secretory phospholipase-A2 (sPLA2; 47-fold), which was also found by reverse transcription-PCR (RT-PCR; 211-fold). sPLA2 inhibition reversed TFT resistance partially. H630-cTFT had many chromosomal aberrations, but the exact role of sPLA2 in TFT resistance remains unclear. Altogether, resistance induction to TFTcan lead to different mechanisms of resistance, including decreased TK protein expression and enzyme activity, decreased hENT expression, as well as (phospho)lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

Trifluorothymidine Resistance Is Associated with Decreased Thymidine Kinase and Equilibrative Nucleoside Transporter Expression or Increased Secretory Phospholipase A2

Temmink

Bijnsdorp

Prins

et al. 2010

Molecular Cancer Therapeutics

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“…One example is LiPlaCis a liposomal formulation of cisplatin encapsulated in pro-anticancer ether lipids. This liposome is designed to release cisplatin inside cancer cells upon its degradation by the secretory phospholipase A2 (sPLA 2 ) enzyme (Jensen et al 2004). This enzyme is overexpressed in many different types of cancers and therefore provides some specificity for tumour tissue over normal tissue.…”

Section: Liplacismentioning

confidence: 99%

The state-of-play and future of platinum drugs

Apps

Choi

Wheate

2015

Endocrine-Related Cancer

233

142

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The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects.

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“…Hydrolytic cleavage of the polymer at endosomal pH releases both the conjugated drug in the polymer carrier as well as the cargo drug. Finally, hydrophobic anticancer ether lipids have been conjugated as phosphoglycerol and phosphocholine analogs that self-assemble into stable liposomes (58). Cleavage of the phospholipids by secretory phospholipase PLA2 (sPLA2), which is elevated in a variety of epithelial cancers, releases the toxic ether lipids.…”

Section: Trageted Macromolecular Prodrugsmentioning

confidence: 99%

Prodrug Applications for Targeted Cancer Therapy

Giang

Boland

Poon

2014

AAPS J

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Abstract. Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.

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604 Secretory phospholipase A2 as tumour specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids

Cited by 26 publications

References 0 publications

Trifluorothymidine Resistance Is Associated with Decreased Thymidine Kinase and Equilibrative Nucleoside Transporter Expression or Increased Secretory Phospholipase A2

Trifluorothymidine Resistance Is Associated with Decreased Thymidine Kinase and Equilibrative Nucleoside Transporter Expression or Increased Secretory Phospholipase A2

The state-of-play and future of platinum drugs

Prodrug Applications for Targeted Cancer Therapy

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