Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer

Utsugi, Teruhiro; Shibata, Jiro; Sugimoto, Yoshikazu; Aoyagi, Kumio; Wierzba, Konstanty; Kobunai, Takashi; Terada, T.; Oh‐hara, Tomoko; Tsuruo, Takashi; Yamada, Yuji

doi:10.1016/s0169-5002(97)89549-9

Cited by 21 publications

References 15 publications

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Biotechnological aspects of the production of the anticancer drug podophyllotoxin

Farkya

Bisaria

Srivastava

2004

Appl Microbiol Biotechnol

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The natural lignan podophyllotoxin, a dimerized product of two phenylpropanoid moieties which occurs in a few plant species, is a pharmacologically important compound for its anticancer activities. It is used as a precursor for the chemical synthesis of the anticancer drugs etoposide, teniposide and etopophose. The availability of this lignan is becoming increasingly limited because of the scarce occurrence of its natural sources and also because synthetic approaches for its production are still commercially unacceptable. Biotechnological production using cell culture may be considered as an alternative source. Selection of the best performing cell line, its maintenance and stabilization are necessary prerequisites for its production in bioreactors and subsequent scale-up of the cultivation process to the industrial level. Scale-up of growth and product yield depends on a multitude of factors, such as growth medium, physicochemical conditions, seed inoculum, type of reactor and processing conditions. The composition of the growth medium, elicitors and precursors, etc. can markedly influence the production. Optimum levels of parameters that facilitate high growth and product response in cell suspensions of Podophyllum hexandrum have already been determined by statistical design. P. hexandrum cells have successfully been cultivated in a 3-l stirred-tank bioreactor under low shear conditions in batch and fed-batch modes of operation. The batch kinetic data were used to identify the mathematical model which was then used to develop nutrient-feeding strategies for fed-batch cultivation to prolong the productive log phase of cultivation. An improvement in the production of podophyllotoxin to 48.8 mg l(-1) in a cell culture of P. hexandrum was achieved, with a corresponding volumetric productivity of 0.80 mg l(-1) day(-1), when the reactor was operated in continuous cell-retention mode. Efforts are being made to further enhance its production levels by the development of hairy root culture or by varying the channeling of precursors towards the desired biosynthetic pathway by molecular approaches.

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Biotechnological aspects of the production of the anticancer drug podophyllotoxin

Farkya

Bisaria

Srivastava

2004

Appl Microbiol Biotechnol

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Natural products as leads to anticancer drugs

2007

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Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as "lead" compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

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Anti Cancer: DNA Topoisomerase Inhibitors

Denny¹

2013

Reference Module in Chemistry, Molecular Sciences and Chemical Engineering

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Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer

Cited by 21 publications

References 15 publications

Biotechnological aspects of the production of the anticancer drug podophyllotoxin

Biotechnological aspects of the production of the anticancer drug podophyllotoxin

Natural products as leads to anticancer drugs

Anti Cancer: DNA Topoisomerase Inhibitors

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