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.