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Related Concept Videos

Telomeres and Telomerase02:41

Telomeres and Telomerase

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In eukaryotic DNA replication, a single-stranded DNA fragment remains at the end of a chromosome after the removal of the final primer. This section of DNA cannot be replicated in the same manner as the rest of the strand because there is no 3’ end to which the newly synthesized DNA can attach. This non-replicated fragment results in gradual loss of the chromosomal DNA during each cell duplication. Additionally, it can induce a DNA damage response by enzymes that recognize single-stranded...
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Targeted Cancer Therapies02:57

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
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Targeting telomerase with radiolabeled inhibitors.

Philip A Waghorn1, Mark R Jackson1, Veronique Gouverneur2

  • 1CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK.

European Journal of Medicinal Chemistry
|September 23, 2016
PubMed
Summary

Telomerase inhibition combined with radionuclide therapy shows promise for cancer treatment. Synthesized 123I-labeled telomerase inhibitors demonstrated efficacy in reducing cancer cell survival, enhancing radiosensitivity.

Keywords:
Iodine-123Targeted radionuclide therapyTelomeraseTelomerase inhibitors

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Area of Science:

  • Oncology
  • Radiochemistry
  • Molecular Biology

Background:

  • Telomerase is highly expressed in ~85% of cancers but absent in most normal cells, making it a key cancer therapy target.
  • Direct telomerase inhibition alone is insufficient due to a lag period before growth arrest.
  • Telomerase inhibition can enhance cancer cell radiosensitivity, suggesting a combined therapy approach.

Purpose of the Study:

  • To investigate the simultaneous inhibition of telomerase and targeted radionuclide therapy delivery.
  • To synthesize and evaluate 123I-radiolabeled telomerase inhibitors for cancer cell survival effects.

Main Methods:

  • Synthesis of 123I-radiolabeled telomerase inhibitors.
  • In vitro evaluation of telomerase inhibition using IC50 determination.
  • Assessment of cancer cell survival using clonogenic assays in a telomerase-positive cell line (MDA-MB-435).

Main Results:

  • An 123I-labeled analogue of MST-312 (123I-MST-312) was synthesized, showing telomerase inhibition with an IC50 of 1.58 microM.
  • Clonogenic assays demonstrated a dose-dependent effect of 123I-MST-312 on cancer cell survival.
  • The study confirmed the potential of combining telomerase inhibition with radionuclide therapy.

Conclusions:

  • 123I-MST-312 effectively inhibits telomerase and reduces cancer cell survival in vitro.
  • This study supports the strategy of simultaneous telomerase inhibition and targeted radionuclide therapy for enhanced cancer treatment.
  • Further research into 123I-labeled telomerase inhibitors could lead to novel cancer therapeutic agents.