Etoposide and teniposide

Holthuis, J.J.M.

doi:10.1007/bf01959294

Cited by 56 publications

(10 citation statements)

References 65 publications

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“…Since unmodified PPT is too toxic for use in the treatment of neoplastic diseases in humans, it mainly serves as a precursor for the synthesis of many widely used chemotherapeutic drugs [2][3][4]. In a recent report, PPT was coupled with tumor-targeted nanoparticles for its systemic delivery to multi-drug resistant tumors in animal models [5]; this research has the potential to lead to the direct use of PPT for the future treatment of many human cancers, further increasing the need for a sustainable source of the compound.…”

Section: Introductionmentioning

confidence: 99%

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Arneaud

Porter

2015

Mol Biotechnol

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Podophyllotoxin (PPT) is a plant natural product that serves as a precursor for the synthesis of many well-known chemotherapeutic drugs. The limited availability and high demand for the source plants of PPT have led to the exploration of alternative sources for this compound. In this study, we utilized the endophytic fungus Phialocephala podophylli (strain PPE7) that we isolated from the rhizomes of Podophyllum peltatum and is known to produce detectable amounts of PPT in broth culture. To date, the complete PPT biosynthetic pathway has yet to be determined in any species. Since fungi are well known for clustering genes that belong to secondary metabolite pathways, use of a fungal system for investigation of the PPT biosynthesis genes may ultimately lead to elucidation of the entire pathway. In this study, we investigated the secoisolariciresinol dehydrogenase (SD) gene that facilitates the dehydrogenation of secoisolariciresinol to form matairesinol, a mid-pathway intermediate product in PPT biosynthesis. We utilized PCR amplification to acquire the complete SD gene sequence in PPE7 and opted to synthesize the P. peltatum SD sequence for expression. Through western blotting, we confirmed the expression of the recombinant SD (PpSD) and verified protein functionality with a bioconversion assay followed by HPLC and LC-MS analyses. Here, we report the identification of the SD gene in PPE7; this is the first report of the SD gene in an endophytic fungus. Additionally, we established the groundwork for the future expression of the complete PPT biosynthetic pathway in the heterologous host Pichia pastoris.

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Section: Introductionmentioning

confidence: 99%

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Arneaud

Porter

2015

Mol Biotechnol

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“…Structure-based design is an attractive approach for the epipodophyllotoxin drug class considering that only two closely related clinically useful analogs, teniposide and etoposide phosphate, have been introduced after nearly four decades of drug optimization using a ligand-based approach. Teniposide, a more lipophilic analog of etoposide, was developed as a means to facilitate cellular drug uptake,16, 17 whereas etoposide phosphate is a hydrolysable prodrug of etoposide that was designed to improve the aqueous solubility of the drug 3, 18…”

Section: Introductionmentioning

confidence: 99%

A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II

Chee

Yalowich

Bodner

et al. 2010

Bioorganic & Medicinal Chemistry

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Etoposide is a widely used anticancer drug that targets topoisomerase II, an essential nuclear enzyme. However, despite the fact that it has been in use and studied for more than 30 years the specific site on the enzyme to which it binds is unknown. In order to identify the etoposide binding site(s) on topoisomerase II, a diazirine-based photoaffinity etoposide analog probe has been synthesized and its photoreactivity and biological activities have been characterized. Upon UV irradiation, the diazirine probe rapidly produced a highly reactive carbene species that formed covalent adducts containing stable carbon-based bonds indicating that it should also be able to form stable covalent adducts with amino acid residues on topoisomerase II. The human leukemia K562 cell growth and topoisomerase II inhibitory properties of the diazirine probe suggest that it targets topoisomerase II in a manner similar to etoposide. The diazirine probe was also shown to act as a topoisomerase II poison through its ability to cause topoisomerase IIα-mediated double-strand cleavage of DNA. Additionally, the diazirine probe significantly increased protein-DNA covalent complex formation upon photoirradiation of diazirine probe-treated K562 cells, as compared to etoposide-treated cells. This result suggests that the photoactivated probe forms a covalent adduct with topoisomerase IIα. In conclusion, the present characterization of the chemical, biochemical, and biological properties of the newly synthesized diazirine-based photoaffinity etoposide analog indicates that use of a proteomics mass spectrometry approach will be a tractable strategy for future identification of the etoposide binding site(s) on topoisomerase II through covalent labeling of amino acid residues.

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“…Essential steps in the isolation procedure are CH2C12 and XAD-4 extraction and XAD-8 cc followed by Si gel chromatography, using two different mobile phases. The isolated 5-methoxypodophyllotoxin [1] was very pure (>99%) and possessed the desired stereochemical configuration, namely (-)-5methoxypodophyllotoxin [1], The in vitro cytotoxicity of 5-methoxypodophyllotoxin [1] against EAT and HeLa cells was determined and compared with those of podophyllotoxin [3], etoposide [4], teniposide [51, and 5-methoxypodophyllotoxin-4-P-Dglucoside [6], It appeared that 5-methoxypodophyllotoxin [1] has about the same cytotoxic potency as podophyllotoxin [31-Etoposide [4] and teniposide [5] are clinically applied semi-synthetic cytostatics, chemically prepared from the natural lignan, podophyllotoxin [3] (1-3). The total chemical synthesis of [3] is complicated because of the presence of four chiral centers, a rigid trans-lactone, and an axially locked 1-aryl substituent (4).…”

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confidence: 99%

Isolation, Purification, and Cytotoxicity of 5-Methoxypodophyllotoxin, a Lignan from a Root Culture of Linum flavum

Uden

Woerdenbag²,

Homan³

et al. 1992

J. Nat. Prod.

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A method has been developed for the large scale isolation of 5-methoxypodophyllotoxin [1] from a high-producing root culture derived from Linum flavum. A closely related lignan, 5'-demethoxy-5-methoxypodophyllotoxin [2], was also present in the root culture and was the cause of the main isolation difficulties. Essential steps in the isolation procedure are CH2Cl2 and XAD-4 extraction and XAD-8 cc followed by Si gel chromatography, using two different mobile phases. The isolated 5-methoxypodophyllotoxin [1] was very pure (greater than 99%) and possessed the desired stereochemical configuration, namely (-)-5-methoxypodophyllotoxin [1]. The in vitro cytotoxicity of 5-methoxypodophyllotoxin [1] against EAT and HeLa cells was determined and compared with those of podophyllotoxin [3], etoposide (VP-16-213) [4], teniposide (VM-26) [5], and 5-methoxypodophyllotoxin-4-beta-D-glucoside [6]. It appeared that 5-methoxypodophyllotoxin [1] has about the same cytotoxic potency as podophyllotoxin [3].

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Etoposide and teniposide

Cited by 56 publications

References 65 publications

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II

Isolation, Purification, and Cytotoxicity of 5-Methoxypodophyllotoxin, a Lignan from a Root Culture of Linum flavum

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