Experimental studies of the therapeutic and toxic effects of FOLFIRI chemotherapy in colon cancer

• Author / Creator

  Ali, Gauhar

• Introduction:
  Chemotherapy is an essential component of cancer treatment and can be effective in controlling tumor growth and increasing the likelihood of remission accompanied with increased survival. However, chemotherapy is associated with substantial acute and long-lasting toxicity which have detrimental effects on an individual’s quality of life. The therapeutic and toxic effects of chemotherapy regimens is constantly under investigation so as to maximize anti-tumor activity whilst minimizing treatment-associated toxicity.

  Several cancer therapies induce muscle fibre atrophy; this treatment-associated wasting is not well understood and has been investigated for single agents in experimental studies in healthy animals. Therapy-induced muscle atrophy has not been investigated within the complex interplay among tumor, chemotherapy regimen and treatment response. Possible interactions between cancer and treatment in development of muscle wasting remain uncharacterized. The complement system is an inflammatory component of immune responses which may contribute to treatment-associated muscle wasting.

  Methods:
  A preclinical model with Fischer 344 rats bearing the Ward colon adenocarcinoma were treated with FOLFIRI (irinotecan/5-fluorouracil) at a dose and schedule which recapitulates treatment response and toxicity that align with human patient experience. HEALTHY controls were compared with TUMOR rats and TUMOR+FOLFIRI rats given 2 weekly cycles of FOLFIRI (n=8/group). Gastrocnemius muscle fibre cross sectional area (CSA) was assessed as an index of atrophy. mRNA sequencing of gastrocnemius was performed. Differential gene expression (DE) was assessed (fold-change≥1.5; p-value<0.05) and Ingenuity Pathway Analysis (IPA) used for functional annotation of DE mRNAs.

  In a second study, rats were randomized to receive an orally active, small molecular weight inhibitor of the complement system at the start of FOLFIRI treatment; treatment-associated toxicity was assessed via changes in body weight and food intake and tumor response was assessed through tumor measurements.

  Results:
  Compared with HEALTHY, TUMOR growth (0.57±0.1% of body weight) resulted in a -22.2% (p<0.05) reduction in gastrocnemius mean fiber CSA. FOLFIRI shrank the tumor (-89%) and induced further -22% reduction in muscle fibre CSA. Muscles of TUMOR vs HEALTHY showed 1283 DE transcripts and 43 DE canonical pathways(p<0.05). TUMOR+FOLFIRI expanded DE to 2095 transcripts and 72 canonical pathways (p<0.05). The top 4 pathways associated with TUMOR were (p<0.01) Adipogenesis, EIF2 Signaling, Transcriptional Regulatory Network in Embryonic Stem Cells, and Actin Cytoskeleton Signaling; in TUMOR+FOLFIRI they were (p<0.001) Protein Ubiquitination, EIF2 Signaling, Hepatic Fibrosis / Stellate Cell Activation and ATM Signaling.

  Complement inhibitor appeared safe, showing no effect on rat body weight or food intake; colon tumor shrunk rapidly in the presence of this agent and histological examination showed that tumor was eliminated with only residual secondary lymphoid reaction present at tumor site.

  Conclusions:
  Tumor and FOLFIRI resulted in progressive atrophy and changes in skeletal muscle transcriptome. FOLFIRI specifically exacerbates a catabolic transcriptional program, in spite of robust tumor response. Complement inhibitor potentiated tumor response to FOLFIRI and this requires further investigation.

• Subjects / Keywords

  • colon cancer
  • chemotherapy
  • FOLFIRI
  • irinotecan (CPT-11)
  • 5-fluorouracil (5-FU)
  • skeletal muscle
  • muscle atrophy
  • complement system

• Graduation date

  Spring 2023

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-menn-ap67

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.