Effects of Δ⁹-tetrahydrocannabinol on irinotecan-induced clinical effects in rats

Because of the great interest for research on the potential use of cannabis preparations as co-medication for alleviation of toxic effects in cancer management, we investigated the influence of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) to modulate irinotecan (CPT-11)-induced toxicity. Male Wistar rats were treated either with a single irinotecan intraperitoneal dose, 100 mg/kg body-weight (b.w.), or with irinotecan in combination with THC (7 mg/kg b.w., p.o., administered repeatedly for 1, 3 and 7 days). Serial blood samples were obtained up to seven days after dosing and were analyzed for complete blood count and biochemical parameters (liver enzymes, creatinine, inflammatory markers, and lipid status). Serial urine samples were collected in the first 24 h to monitor the time-course of THC metabolite 11-nor-9-carboxy-Δ⁹-THC (THC-COOH) excretion with concomitant irinotecan treatment or without. Both irinotecan and irinotecan + Δ⁹-THC administration caused moderate leukopenia but a greater decrease in leukocyte count was observed in the irinotecan + Δ⁹-THC treated compared to the single irinotecan suggesting higher cytotoxic effects in combined treatment. Irinotecan treatment induced elevation of aspartate aminotransferase (AST) in rats without diarrheal symptoms and without an increase in circulating pro-inflammatory mediators. Interestingly, the elevation of AST was not observed in the irinotecan + Δ⁹-THC group. The median creatinine-corrected urinary THC-COOH concentration was higher in the irinotecan + THC group compared to the THC-only group in a time-dependent manner, suggesting a possible early interaction between cannabinoids and irinotecan. Further studies are needed to investigate the role of cannabinoids particularly on hematological toxicity, irinotecan metabolism and their role as a possible modifiable factor among irinotecan-treated hosts.