ArticleInvestigational new drugs2004
A novel mammalian cell-based approach for the discovery of anticancer drugs with reduced cytotoxicity on non-dividing cells.
Article in Investigational new drugs, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- Use of Bacteriocins and Bacteriocinogenic Beneficial Organisms in Food Products: Benefits, Challenges, Concerns.Foods (Basel, Switzerland) · 2022Review
- Nerve Growth Factor (NGF)-Receptor Survival Axis in Head and Neck Squamous Cell Carcinoma.International journal of molecular sciences · 2018Article
- Synthetic Gene Expression Circuits for Designing Precision Tools in Oncology.Frontiers in cell and developmental biology · 2017Review
- Mammalian synthetic biology: emerging medical applications.Journal of the Royal Society, Interface · 2015Review
- Synthetic biology for therapeutic applications.Molecular pharmaceutics · 2015Review
- A designer cell-based histamine-specific human allergy profiler.Nature communications · 2014Article
- Synthetic approaches to study transcriptional networks and noise in mammalian systems.IET systems biology · 2013Article
- Emerging biomedical applications of synthetic biology.Nature reviews. Genetics · 2011Review
- The impact of synthetic biology on drug discovery.Drug discovery today · 2009Review
- A novel mammalian expression system derived from components coordinating nicotine degradation in arthrobacter nicotinovorans pAO1.Nucleic acids research · 2005Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A key asset of cytotoxic drugs in cancer therapeutics is their ability to discriminate between proliferating and mitotically inert cells and eliminate preferentially neoplastic ones. We have designed a high throughput-compatible mammalian cell-based assay for the discovery of cytotoxic drugs, which selectively kill proliferation-competent target cells. This cytotoxic drug discovery assay is based on a transgenic CHO-K1-derived cell line engineered for a conditional G1-specific growth arrest following tetracycline-responsive overexpression of the human cyclin-dependent kinase inhibitor p27(Kip1). The CHO-derived cell line CHO-p27(Kip1) shows wild type proliferation rates and can be expanded in the presence of tetracycline antibiotics when p27(Kip1) expression is repressed. Upon withdrawal of regulating antibiotics CHO-p27(Kip1) differentiates into a 1:1 mixed population consisting of two different proliferation phenotypes: (i) a G1-arrested cell population induced by heterologous expression of p27(Kip1) which mimics mitotically inactive terminally differentiated cells and (ii) a proliferation-competent cell population which eliminated the p27(Kip1) expression unit and imitates neoplastic cell characteristics. Addition of chemical or metabolic libraries to CHO-p27(Kip1) populations cultivated in tetracycline-free medium followed by scoring for cell viability will reveal cytotoxic drug candidates associated with a high viability ratio of proliferation-competent/arrested populations. We have validated the cell-based cytotoxic drug discovery assay using the clinically licensed cancer drugs mitomycin C, doxorubicin, etoposide and 5-fluorouracil. Comparative proof-of-concept studies showed that these top-prescribed cancer therapeutics preferentially eliminate proliferating cells while showing less interference with the viability of G1-arrested cell populations. These results demonstrate the CHO-p27(Kip1)-based cytotoxic drug finder technology is ready-to-apply for high throughput screenings of chemical as well as metabolic libraries to discover novel cancer therapeutics which show reduced cytotoxicity on terminally differentiated cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.