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Drug repositioning in chemoprevention of colorectal cancer

Zhang, Naiqi LU (2023) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Background
Colorectal cancer (CRC) ranks as the third most frequently occurring cancer and the second leading cause of cancer-related deaths worldwide. In response to the high demand for an effective prevention strategy, chemoprevention, using medications to block the pathogenetic pathways of disease, might be an attractive strategy to offer a more effective option at a low cost. Therefore, we aimed to assess the potential beneficial effects of already-approved drugs on the chemoprevention of CRC, especially in high-risk groups.
Methods
Papers I, II, and III were population-based cohort studies. By accessing several nationwide Swedish registers, we identified individuals who had ever been previously prescribed melatonin... (More)
Background
Colorectal cancer (CRC) ranks as the third most frequently occurring cancer and the second leading cause of cancer-related deaths worldwide. In response to the high demand for an effective prevention strategy, chemoprevention, using medications to block the pathogenetic pathways of disease, might be an attractive strategy to offer a more effective option at a low cost. Therefore, we aimed to assess the potential beneficial effects of already-approved drugs on the chemoprevention of CRC, especially in high-risk groups.
Methods
Papers I, II, and III were population-based cohort studies. By accessing several nationwide Swedish registers, we identified individuals who had ever been previously prescribed melatonin (Paper I), proguanil/atovaquone (Paper II), and selective serotonin reuptake inhibitor (SSRI, Paper III), respectively, and matched them with comparisons who did not use the drugs based on age and sex. The Cox regression model was used to calculate hazard ratios (HRs) and 95% CI confidence intervals (CIs). Paper IV was a nested case-control study exploring the combined effect of SSRIs and aspirin against CRC. We identified CRC cases and randomly matched them to controls conditional on birth year and sex using incidence-density sampling. The conditional logistic regression model was used to calculate odds ratios (ORs) and 95% CIs.
Results
We found that uses of melatonin (Paper I), proguanil/atovaquone (Paper II), and SSRIs (Paper III) were all associated with a reduced CRC risk, with adjusted HRs and 95% CIs, 0.82 (0.72-0.92), 0.76 (0.62-0.93) and 0.77 (0.70-0.85), respectively. Tests for trends showed significant dose-response correlations (P <0.001). The decrease in CRC risk was independent of tumor location and stage at diagnosis. In Paper IV, both aspirin and SSRIs monotherapy were negatively associated with CRC risk, but the combined use of aspirin and SSRIs was associated with an even lower CRC risk (adjusted OR, 0.77, 95% CI, 0.67-0.89) than aspirin monotherapy (adjusted OR, 0.91, 95% CI, 0.87-0.97) or SSR monotherapy (adjusted OR, 0.93, 95% CI, 0.86-1.00). A significant interaction was observed at the additive scale (P <0.001).
Conclusion
We identified several potential chemopreventive agents against CRC. Our findings call for further studies to confirm the underlying mechanisms and the plausibility of clinical recommendations.

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author
supervisor
opponent
  • Professor Pottegård, Anton, Department of Public Health at the University of Southern Denmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Drug repositioning, Colorectal cancer (CRC), Pharmacoepidemiology, Chemoprevention, Melatonin, Proguanil, Atovaquone, Selective serotonin reuptake inhibitor (SSRI)
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2023:65
pages
87 pages
publisher
Lund University, Faculty of Medicine
defense location
Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
defense date
2023-11-29 13:30:00
ISSN
1652-8220
ISBN
978-91-8021-405-6
language
English
LU publication?
yes
id
101a23f6-07e8-4a75-b23b-fc36c3c2029b
date added to LUP
2023-11-07 15:45:16
date last changed
2023-11-10 07:56:24
@phdthesis{101a23f6-07e8-4a75-b23b-fc36c3c2029b,
  abstract     = {{Background<br/>Colorectal cancer (CRC) ranks as the third most frequently occurring cancer and the second leading cause of cancer-related deaths worldwide. In response to the high demand for an effective prevention strategy, chemoprevention, using medications to block the pathogenetic pathways of disease, might be an attractive strategy to offer a more effective option at a low cost. Therefore, we aimed to assess the potential beneficial effects of already-approved drugs on the chemoprevention of CRC, especially in high-risk groups. <br/>Methods<br/>Papers I, II, and III were population-based cohort studies.  By accessing several nationwide Swedish registers, we identified individuals who had ever been previously prescribed melatonin (Paper I), proguanil/atovaquone (Paper II), and selective serotonin reuptake inhibitor (SSRI, Paper III), respectively, and matched them with comparisons who did not use the drugs based on age and sex. The Cox regression model was used to calculate hazard ratios (HRs) and 95% CI confidence intervals (CIs). Paper IV was a nested case-control study exploring the combined effect of SSRIs and aspirin against CRC. We identified CRC cases and randomly matched them to controls conditional on birth year and sex using incidence-density sampling. The conditional logistic regression model was used to calculate odds ratios (ORs) and 95% CIs.<br/>Results<br/>We found that uses of melatonin (Paper I), proguanil/atovaquone (Paper II), and SSRIs (Paper III) were all associated with a reduced CRC risk, with adjusted HRs and 95% CIs, 0.82 (0.72-0.92), 0.76 (0.62-0.93) and 0.77 (0.70-0.85), respectively. Tests for trends showed significant dose-response correlations (P &lt;0.001). The decrease in CRC risk was independent of tumor location and stage at diagnosis. In Paper IV, both aspirin and SSRIs monotherapy were negatively associated with CRC risk, but the combined use of aspirin and SSRIs was associated with an even lower CRC risk (adjusted OR, 0.77, 95% CI, 0.67-0.89) than aspirin monotherapy (adjusted OR, 0.91, 95% CI, 0.87-0.97) or SSR monotherapy (adjusted OR, 0.93, 95% CI, 0.86-1.00). A significant interaction was observed at the additive scale (P &lt;0.001). <br/>Conclusion<br/>We identified several potential chemopreventive agents against CRC. Our findings call for further studies to confirm the underlying mechanisms and the plausibility of clinical recommendations.  <br/><br/>}},
  author       = {{Zhang, Naiqi}},
  isbn         = {{978-91-8021-405-6}},
  issn         = {{1652-8220}},
  keywords     = {{Drug repositioning; Colorectal cancer (CRC); Pharmacoepidemiology; Chemoprevention; Melatonin; Proguanil; Atovaquone; Selective serotonin reuptake inhibitor (SSRI)}},
  language     = {{eng}},
  number       = {{2023:65}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Drug repositioning in chemoprevention of colorectal cancer}},
  url          = {{https://lup.lub.lu.se/search/files/164508697/Naiqi_Zhang_-_WEBB_supplementary_materials.pdf}},
  year         = {{2023}},
}