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Abstract: PO1877

Cisplatin-Induced AKI Cancer Mouse Model Refinement

Session Information

Category: Onco-Nephrology

  • 1500 Onco-Nephrology

Authors

  • Thompson, Lauren E., University of Colorado Health, Aurora, Colorado, United States
  • McGinnis, Courtney D., University of Colorado Health, Aurora, Colorado, United States
  • Edelstein, Charles L., University of Colorado Health, Aurora, Colorado, United States
  • Joy, Melanie S., University of Colorado Health, Aurora, Colorado, United States
Background

Cisplatin (CIS), a common chemotherapeutic, causes acute kidney injury (AKI) in up to one-third of patients. Traditional mouse models use healthy mice and a single, lethal dose of CIS (20-30 mg/kg). This model does not accurately reflect the clinical use of CIS where cancer patients receive 25-100 mg/m2 once every 3-4 weeks. There is a need for a multi-dose mouse cancer model of CIS-AKI that more closely reflects CIS clinical use.

Methods

C57BL/6 male mice (8 weeks old; n=45) were injected in the right flank with murine lung cancer cells (CMT167; 0-1,500,00 cells). Subcutaneous solid tumors were allowed to grow for ~2 weeks until digital caliper measurement confirmed they were ≥50 mm3. Mice were then dosed with CIS (0, 12.5, 15 mg/kg) or vehicle (saline) 1x/week for up to 4 weeks. Mice were evaluated for outcomes of general health (body weight), survival, cancer progression (tumor volume), and kidney injury (SCr, BUN, KIM-1). Assessments were performed ≥1x/week until sacrifice after 1-4 weeks of CIS treatment. Analyses for differences from baseline to sacrifice based on both cancer cells injected and CIS dose were assessed by 2-way ANOVA with a Tukey-Kramer post-hoc test. p<0.05 was considered statistically significant.

Results

Groups injected with >1 million CMT167 cells experienced the greatest decline in survival due to rapid tumor growth and ulceration (0% at 8 d). Cancer-free mice treated with CIS also experienced poor survival due to dehydration and weight loss (60% at 15 d). Mice injected with 50,000 CMT167 cells had the best survival (100% at 13 d). Body weight was significantly decreased as CIS dose increased (p=1.9*10-8) and increased as number of CMT167 cells increased (p=5.5*10-8). Tumor volume was significantly increased as number of CMT167 cells increased (p=5.1*10-5) and somewhat decreased as CIS dose increased (p=0.092). CIS dose did not significantly impact BUN or SCr levels but an increase in KIM-1 was somewhat associated with an increased CIS dose (p=0.105; 12.5 vs 15 mg/kg CIS p=0.191). There were no significant differences in body weight, tumor volume, or survival between the 12.5 and 15 mg/kg CIS treated mice.

Conclusion

The results indicate that the ideal CMT167 mouse cancer model of CIS-AKI should use 50,000 CMT167 cells and 15 mg/kg CIS. This model can be used to better understand CIS-AKI and to test potential protective compounds.

Funding

  • Other NIH Support