Introduction 1 2 3 5 6 12 13 14 16 1 3 17 18 19 30 31 32 33 34 13 Mechanism of action of aromatase inhibitors Aromatase 35 37 1 38 39 40 41 42 43 44 1 38 45 49 14 50 53 14 31 Fig. 1 A E1 E1S E2 T 38  41 54 58 41 54 58 59 60 Aromatase inhibitors 61 62 63 64 2 65 66 67 68 69 Fig. 2 4-OHA 66  70 ® 71 70 72 73 2 66 74 75 76 Letrozole pharmacodynamics and pharmacokinetics Potency 3 77 70 Fig. 3 77  31 4 31 1 31 71 75 78 82 Fig. 4 31  Table 1 77 Aromatase inhibitor 50 Human placental microsomes Particulate fractions of human breast cancer Rat ovarian microsomes MCF-7Ca cancer cells JEG-3 cancer cells CHO cells Hamster ovarian tissue Human breast Letrozole  2 (1)      0.8 (1) Anastrozole  8 (0.25)      15 (0.053) Exemestane  15 (0.13)      5 (0.16) 4-OHA  30 (0.07)      30 (0.027) AG  20,000 (0.0001)      10,000 (0.0008) Letrozole 11 (1)   0.07 (1) 0.07 (1)  20 (1) 0.8 (1) Anastrozole 23 (0.48)   0.82 (0.085) 0.99 (0.071)  600 (0.033) 14 (0.057) Fadrozole 5 (2.2)   0.05 (1.4) 0.07 (1.0)  30 (0.67) 1 (0.80) 4-OHA 62 (0.18)        AG 1900 (0.0058)        Letrozole 1.02 (1)   0.35 (1.0) 0.45 (1)   0.14 (1) Anastrozole 5.35 (0.19)   3.62 (0.097) 5.66 (0.080)   17.17 (0.0082) 4-OHA    0.59 (0.59) 1.6 (0.28)   0.72 (0.19) Letrozole   7 (1)      Anastrozole   25 (0.28)      Fadrozole   7 (1)      Letrozole      1.4 (0)   Anastrozole      27 (0.052)   4-OHA      60 (0.023)   AG      5500 (0.00025)   4-OHA AG 50 71 50 71 75 83 P P P 84 78 85 90 Selectivity 77 71 78 71 86 91 93 86 Anti-tumor activity in vivo 77 78 94 95 50 61 96 97 94 98 99 99 100 100 80 101 101 P 102 102 103 104 Pharmacokinetics of letrozole 105 107 108 109 1/2 1/2 109 110 1/2 111 Clinical development of letrozole 92 112 113 97 101 114 118 99 102 119 P 120 121 121 122 123 124 125 Conclusions Letrozole is a highly potent and selective AI that inhibits the enzyme activity of intracellular aromatase at the major sites where it is found, resulting in almost complete suppression of whole body aromatization. By effectively blocking estrogen synthesis, letrozole inhibits the growth or induces the regression of hormone-responsive breast tumors in vivo. Estrogen is implicated as a major risk factor in the majority of breast cancers; therefore, use of the most potent AI is a logical treatment strategy. 118 123 In conclusion, experimental data indicating that letrozole efficiently inhibits aromatase activity have been confirmed clinically, leading to approved indications across the spectrum of breast cancer. The broad range of indications for letrozole in unique clinical settings is reshaping the management of hormone-sensitive breast cancer.