Endocrine therapy breast cancer, based on ideas about the hormone-the tumor localization, despite the obvious success, associated with the use of anti-estrogens, until recently, could not satisfactorily resolve the problem of treatment of locally advanced (inoperable) and in particular with metastatic forms of the disease. The use of tamoxifen with the aim of adjuvant hormonal therapy, or at common forms of tumors significantly improve the results of treatment of breast cancer in the first case, at the expense of reduction of the frequency and the delay of recurrence after surgical interventions with the increase of the overall five-and ten-year survival rate, in the second - by achieving palliative objective effects with the improvement of the quality of life of patients with women, mostly located in menopausal period (over the age of 50-55 years old .) Apart from the practical value of the results of a wide use of tamoxifen (and recently, new anti-estrogens, in particular, farestona with similar effect), the fact is many times greater it efficiency with a high content of estrogenoretseptorov (more than 10 f. mol / mg protein) or progesterone receptors in tumor compared to the ER (-) neoplasms testifies to the potential of "eliminating" the influence of estrogen as a way of suppressing the growth of breast cancer.

The mechanism of such action of tamoxifen and other similar drugs is in blocking the binding of 3H-estradiol with estrogenoretseptorami of the tumor cells (competitive antagonism), translocation of the complex "tamoxifen-receptor of the cytoplasm in its kernel with the suppression of DNA synthesis and, as a consequence, the loss of stimulating action of estrogen on the growth of breast cancer.

However, the observed often the original refractory to hormone replacement therapy "first-line" tamoxifen (farestonom and other antiestrogenami) or progression of breast cancer after the application of the above-mentioned funds from the "peripheral" blocking of estrogen levels in the tumor forced to seek another option to reduce or suppress the effects of estrogen in the tumor - reduction of their products.

This effect is possible with the application of the so-called aromatase inhibitors, a key enzyme conversion PP.19-androgens in the aromatic C18 estrogenic steroids in the peripheral tissues and, what is very important, tumor tissues.

Aromatase is a complex of cytochrome P450 - gemoproteina and flavoprotein (никотинамидадениндинуклеотиддифосфат - cytochrome P450 reductase) with the function of the regulation of transformation of androstenedione in the estrogen.

In physiological conditions as a result of the process of aromatization of this androstenedione enzyme in peripheral tissues produces about 100 ng estrone per day, which is sufficient to maintain concentrations of estradiol in the blood at the level of 10-20 ng / ml. The aromatase is not involved in the production of corticosteroids and androgens and mineralocorticoids, which allows to avoid undesirable multilateral hormonal influences, in addition to suppress the production of estrogen, but only with the help of highly specific her inhibitors.
Aromatase inhibitors may be attached to a catalytic part of the enzyme. Usually they have a structure of steroids are analogues of androgens, the irreversibility of different actions and can cause a number of adverse reactions and affecting the steroid receptors. Suppression of activity of aromatase agents, interacting with the cytochrome P450-part of the enzyme system (as a rule, non-steroidal structure of the group of imidazoles, triazoles and analogues aminoglutethimide), is reversible. In connection with the peculiarities of biochemical mechanisms of action that is aromatase inhibitors of the second of the above-mentioned types first of all have found application in the clinic.

In fact the only drug inhibitor of aromatase, the first generation of broadly used in hormone replacement therapy common breast cancer, was aminoglutethimide (orimeten, Mam, etc.), Proposed earlier as an anticonvulsant funds, and in the treatment of disseminated breast cancer (due to the use of observed side effects) - in the form of equivalent ablative of procedure of the removal of the adrenal glands, ie a kind of "chemical adrenalektomii". Much later it was found that the main effect of aminoglutethimide is caused by suppression of activity of aromatase.

As the experience of the application of aminoglutethimide in hormone replacement therapy "second line" of patients with breast cancer, resistant to tamoxifen or with the progression after a period of effective treatment of the anti-estrogen, the drug again lead to regression of tumor lesions in about 20-30% of the cases, but with serious side-effects. Even the reduction of the daily dose aminoglutethimide up to 500 mg (instead of the initially recommended dose of 1000 mg / day) is not spared from the need to carry out the treatment of the drug, together with hydrocortisone or very significant doses of cortisone ( cortisol acetate) to prevent the development of adrenal insufficiency. Other side effects aminoglutethimide, despite the concurrent use of hydrocortisone (cortisol acetate), limiting its application, such as general weakness, drowsiness, lethargy (up to 23%), skin rash (6%), vomiting, nausea, etc., Stimulated the search for a more specific and safety of aromatase inhibitors as a means of hormone replacement therapy common breast cancer "second line" in postmenopausal women with unknown or positive receptors of estrogen and progesterone.

Among non-steroidal aromatase inhibitors of the last generation, synthesized with the aim of replacing aminoglutethimide and extant practice, such as formestane, anastrozole (arimedeks) vorozol and letrozole (Femara), the last was made on the experimental data and results of application in the clinic.

Experimental and clinical preconditions of use of the letrozole in hormone replacement therapy common breast cancer

Letrozole (Letrozole), which is a synthetic derivative of benzidriltriazola [4,4 '- (1H-1, 2,4,-triazole-1ilmetilen) bisbenzonitril]

, The ability to inhibit aromatase human in vitro in 150-250 times more aminoglutethimide, 19 times more active than anastrozole (arimedeks) and in two times in relation to vorozolu. Dose of letrozole, make the same suppress aromatase in vivo, in 10 000 times less than the aminoglutethimide. These in vitro studies show that letrozole unlike many of aromatase inhibitors and, in particular, aminoglutethimide, does not affect the synthesis of other hormones, in addition to estrogen, and is highly specific in relation to the enzyme. Concentration of letrozole, causing, for example, the suppression of the production of progesterone, corticosterone, and aldosterone, at least 10 000 times more than necessary for therapeutic level of reduction of estrogen. Therefore, already on the basis of the experimental data, we can assume that letrozole should be different from the aminoglutethimide lower toxicity.
High selectivity of letrozole in relation to suppress aromatase activity is also confirmed by clinical, endocrinological research, have established that not a single dose of the drug inside the dose of 0.1-2.5 mg no use of it for three months at doses of 0.1-5 mg / day does not cause any significant changes in the level of LH, FSH, aldosterone, androstenedione and adrenal response to the introduction of adrenocorticotropic hormone for women in menopause.

Letrozole quickly absorbed by ingestion. The maximum concentration of the drug in the blood already in 1-1,5 hours after a single intake of the dose of 2.5 mg (as subsequently found - optimal therapeutic). Decrease in the level of estrogen in the blood (serum estradiol, estrone and estrone sulfate) and in the urine is registered already through 8 h and reaches maximum values ​​(a drop of 95% of the background and in some cases - to undetectable concentrations) after two weeks of daily use of the drug in the dose. Reduced estrogen levels, as shown in experimental models (hormone-dependent and induced diletilbenzantratsenom breast cancer in mice and rats), accompanied by a reduction in the volume of tumors in animals on the 68-92% with minimum doses of letrozole from 5 up to 250 mcg / day, respectively. The antitumor effect (reduction of the size of the tumour) have letrozole is more pronounced than the anastrozole (92% vs. 65% reduction; p <0.05) and tamoxifen (76% vs 36%; p <0.05).

An important feature of letrozole, largely explaining its advantages in the experimental and, as will be further shown when compared with aromatase inhibitors of the first and second generations in clinical conditions is the ability to inhibit the activity of this enzyme in tumor tissue and vnegonadnyh sources of production of estrogen. To understand the clinical significance of this phenomenon in relation to hormone replacement therapy letrozole breast cancer in women in menopause you should keep in mind the following facts.

1. If the main source of estrogen in premenopausal are the ovaries, the human ovarian postmenopausal mechanism of the production of these female sex hormones is practically absent or in connection with his sharp weakening may not be taken into account. In postmenopause the ovaries and adrenal cortex secrete androgens A19, which in the peripheral tissues (skin, subcutaneous fat, muscles, liver and in the tissues) under the influence of aromatase turn into C18-estrogena;

2. Estrogen levels in tumors in breast cancer in women in menopause in 10-20 times higher than in plasma, which testifies to the local (in situ) education estrogen aromatase enzyme, the increased activity of which is determined by roughly two-thirds of cases of carcinoma of these compared with the content of the enzyme in the normal tissues of the breast;

3. The regression of the cancer of mammary gland as a result of the treatment of aromatase inhibitors is only observed in tumors with increased its activity.