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Antisense gene therapy using anti-k-ras and antitelomerase oligonucleotides in colorectal cancer
S Lledó1, R Alfonso, S F Aliño
1Department of General and Digestive Surgery, Hospital Clínico Universitario, Universidad de Valencia, Valencia, Spain. cirugia@telefonica.net
Aim:
To test the efficacy of anti-k-ras and antitelomerase oligonucleotides for disabling colorectal cancer cell growth.
Material And Methods:
An established human colorectal cancer cell line (SW 480, ATTC) was used. Oligodeoxiribonucleotides (ODNs) have a phosphorotioate modification to ensure intracellular intake. We used an antitelomerase ODN (Telp5) and two anti-k-ras ODNs (AS-KRAS and ISIS). AS-KRAS is designed to join the k-ras oncogene s exon 1. ISIS links to the terminal transcription unit 5 of k-ras. Telp5 joins the template region of the hTR telomerase subunit. ODNs have been tested in different concentrations (1, 5, 10, 20 micromolar). Cell viability has been tested at 48 and 72 hours. Statistical analysis and graphic design were made with the statistical package "Analyzing Data with GraphPad Prism-1999", GraphPad Sofware Inc., San Diego CA. We used the Student's t test for statistical analysis.
Results:
The lowest dose (1 microM) was not effective. Using the highest dose (20 microM for 48 hours) of combined AS-KRAS and Telp5 cell viability decreased to 99.67%. The rest of results varied depending on ODN type, dose, and exposure time.
Conclusions:
Tested antisense ODNs stop colorectal cancer cell growth, and a combination of anti-telomerase and anti-k-ras is the most useful treatment. Efficacy is best with a higher dose and longer treatment period.
Insights
Antisense oligonucleotides targeting telomerase and k-ras oncogenes effectively inhibit colorectal cancer cell growth. Combining anti-telomerase (Telp5) and anti-k-ras (AS-KRAS, ISIS) oligonucleotides shows the most promise for cancer treatment.
Area of Science:
- Molecular Biology
- Oncology
- Biotechnology
Background:
- Colorectal cancer (CRC) remains a significant health concern globally.
- Targeting key oncogenes and telomerase offers potential therapeutic strategies for CRC.
- Antisense oligonucleotides (ODNs) represent a promising class of targeted therapies.
Purpose of the Study:
- To evaluate the efficacy of anti-k-ras and anti-telomerase oligonucleotides in inhibiting colorectal cancer cell proliferation.
- To determine the optimal conditions for ODN treatment, including dosage and duration.
Main Methods:
- Utilized a human colorectal cancer cell line (SW 480).
- Employed phosphorotioate-modified oligodeoxynucleotides (ODNs): anti-telomerase (Telp5) and anti-k-ras (AS-KRAS, ISIS).
- Assessed cell viability at various ODN concentrations (1-20 micromolar) and time points (48, 72 hours) using statistical analysis.
Main Results:
- Low ODN concentrations (1 micromolar) showed limited efficacy.
- High concentrations (20 micromolar) of combined AS-KRAS and Telp5 ODNs for 48 hours resulted in 99.67% reduction in cell viability.
- Efficacy varied based on ODN type, concentration, and exposure duration.
Conclusions:
- Antisense ODNs targeting k-ras and telomerase demonstrate significant potential in halting colorectal cancer cell growth.
- Combination therapy with anti-telomerase and anti-k-ras ODNs appears most effective.
- Higher ODN doses and longer treatment periods enhance therapeutic efficacy.
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