Association between exposure to topical tacrolimus or pimecrolimus and cancers.

BACKGROUND: The Food and Drug Administration has issued a public health advisory regarding cancer risk from topical calcineurin inhibitors. OBJECTIVE: To compare the rates of cancer among patients with common dermatologic conditions who were exposed or not exposed to topical calcineurin inhibitors. METHODS: A retrospective cohort observational study used data from an integrated healthcare delivery system on 953,064 subjects with diagnoses of atopic dermatitis or eczema between 2001 and December 2004. The main endpoint was initial cancer diagnosis. Chart review was performed to confirm cancer diagnosis in the subjects exposed to topical calcineurin inhibitors when any particular cancer rate was at least 3 times higher than that in unexposed subjects. Data were analyzed using the Cox proportional hazards model. RESULTS: Age- and sex-adjusted hazard ratios for all cancers were 0.93 (95% CI 0.81 to 1.07; p = 0.306) for tacrolimus-exposed versus -unexposed subjects and 1.15 (95% CI 0.99 to 1.31; p = 0.054) for pimecrolimus-exposed versus -unexposed subjects. T-cell lymphoma was the only cancer associated with a significantly increased risk among subjects exposed to tacrolimus (HR = 5.04, 95% CI 2.39 to 10.63; p < 0.001) or pimecrolimus (HR = 3.76, 95% CI 1.71 to 8.28; p = 0.010). Subsequent chart review of subjects in the exposed group with T-cell lymphoma found that 4 of 16 had skin lesions that were suspected to be the early lesions of T-cell lymphoma prior to exposure to tacrolimus or pimecrolimus. After these 4 cases were excluded, the age and sex hazard ratio for T-cell lymphoma was 5.44 (95% CI 2.51 to 11.79; p < 0.001) for tacrolimus and 2.32 (95% CI 0.89 to 6.07; p = 0.086) for pimecrolimus. There was no statistically significantly increased risk for other subgroups of cancer, including melanoma. CONCLUSIONS: Exposure to topical tacrolimus or pimecrolimus was not associated with an increase in the overall cancer rate. Use of topical tacrolimus may be associated with an increased risk of T-cell lymphoma.

Identifying efficacious approaches to chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a mouse model of transplacental carcinogenesis.

The carcinogenic potential of dibenzo[a,l]pyrene (DBP) has been well characterized in numerous animal models. We have previously documented that a single dose of 15 mg/Kg DBP to pregnant mice late in gestation (GD 17) produces an aggressive T-cell lymphoma as well as lung and liver cancer in offspring. The current study examines the chemopreventative properties of chlorophyllin (CHL) and chlorophyll (Chl) in this transplacental carcinogenesis model. Pregnant B6129SF1 females, bred to 129S1/SvIm males, received purified diets incorporated with either 2000 p.p.m. CHL, 2000 p.p.m. Chl or 10% freeze-dried spinach beginning at gestation day 9. Lymphoma-dependent mortality was not significantly altered by maternal consumption of any of the diet and little effect on lung tumor burden in mice surviving to 10 months of age was observed. However, coadministration of CHL at 380 mg/Kg with DBP by gavage (molar ratio of 10:1, CHL:DBP) provided significant protection against DBP-initiated carcinogenesis. Offspring born to dams receiving CHL co-gavaged with DBP exhibited markedly less lymphoma-dependent mortality (P < 0.001). The degree of protection by CHL, compared with controls dosed with DBP in tricaprylin (TCP) as the vehicle, was less marked, but still significant. Coadministration of CHL (TCP as vehicle) also reduced lung tumor multiplicity in mice by approximately 50% and this was observed throughout the study (P < 0.005). This is the first demonstration that CHL can provide potent chemoprotection in a transplacental carcinogenesis model and support a mechanism involving complex-mediated reduction of carcinogen uptake.