Figure 5.

In vivo sensitisation to oxaliplatin antitumour activity by inhibition of MRP2 with myricetin. Nude mice (NIH-III) were implanted subcutaneously with HepG2 cells, which showed MRP2-mediated deficits in oxaliplatin accumulation in vitro. Tumour bearing mice (8 per group) were then treated with oxaliplatin (3 mg/kg ip), myricetin (25 mg/kg iv) or matching drug vehicle, alone or in combination once weekly for five weeks starting when tumours measured approximately 200 mm³. Arrowheads are the time of treatment. Experimental endpoints measured during and after treatment included body weight (A), tumour volume (B), time for tumours to quadruple in volume from baseline (C), and time to euthanasia from the start of treatment (D). Asterisks shown in panel B are P values (***P < 0.002; ****P < 0.0001) for differences between the oxaliplatin alone and oxaliplatin plus myricetin treatment groups at each time point from Bonferroni post-tests that followed Two-way Repeated Measures ANOVA. P values shown in panels C and D are for comparisons of all treatment groups. Oxaliplatin reduced body weight but had no antitumour activity when given alone. When combined with myricetin, oxaliplatin slowed tumour growth and extended the survival of animals with little or no increase in toxicity.