Sex differences in improved efficacy of doxorubicin chemotherapy in Cbr1+/− mice

The anthracycline chemotherapeutic agent doxorubicin is converted by the enzyme carbonyl reductase 1 (CBR1) into its cardiotoxic metabolite doxorubicinol. Cbr1+/- mice have been shown to be protected from doxorubicin-induced cardiotoxicity, and the inhibition of CBR1 activity may be a useful means of ameliorating the side effects of doxorubicin in patients undergoing chemotherapy. Because reduced conversion to doxorubicinol increases circulating levels of the more effective parent drug doxorubicin, it was hypothesized that therapeutic efficacy against tumors might also be enhanced. Cbr1+/- mice were bred to mice transgenic for the polyomavirus middle T antigen (PyVT) to create offspring with palpable mammary tumors. Latency to initial tumor formation was similar in Cbr1+/- and Cbr1+/+ animals. Tumor regression was improved in Cbr1+/- animals, but only in male mice. Western blotting showed a marked sex difference in protein levels, with a much higher expression of Cbr1 in the female kidney and liver. Thus, the combined effects of a naturally low expression and the heterozygous Cbr1 null allele seem to have enhanced tumor regression in Cbr1+/- males. Future efforts to design a clinical CBR1 inhibitor to protect patients from the cardiac side effects of doxorubicin treatment should evaluate the effect of sex on anticancer efficacy.