Aromatase-Inhibiting Anticancer Drugs Discussion - Essay Example

The aromatase-inhibiting (AI) drugs target the aromatase enzyme in the human body. Most of the development and use of these drugs have been for cancers of the breast, as well as a selection of other cancers, found to express aromatase enzyme activity. Aromatase synthesizes estrogens. Estrogens play a key role in the development and growth of breast tumors. Hence, estrogen is a key target in breast cancer drug developments. In order to understand the rationale, structure and mechanisms of AI drugs, it is necessary to provide an overview of the structure, function, and tissue locations of the aromatase enzyme. The paper will, then, continue with a discussion of the molecular structures, binding methods, and corresponding effects of the aromatase inhibitors (AIs). The structure, function and binding interactions of the aromatase enzyme are still being investigated. Aromatase is a rate limiting enzyme in estrogen biosynthesis (Hong et al. 2009). It belongs to the monooxygenase family (particularly, the cytochrome P450 family) of enzymes and catalyzes the biosynthesis of oestrogen (specifically, oestrone) from androstenedione, involving a unique sequence of three reactions that require O2 molecules to produce an aromatic ring structure within the oestrogen molecule. The binding fit of androstenedione to aromatase is tight because the aromatase enzyme is not one of the promiscuous enzymes — which have looser fits for the various substrate structures they bind (Waterman, 2009). To conduct reactions, aromatase requires a partner enzyme, NADPH-cytochrome P450 reductase (Hong et al. 2009). High levels of aromatase enzyme expression and correspond oestrogen in tissues play a key role in augmented tumor growth. Blocking this biosynthesis pathway is the rationale behind the development of AIs (Pant & Dutta, 2008). The reason that most of the development and use of AI drugs have been for cancers of the breast is that most breast cancer cases have up to ten times the amount of oestrogen found in the average circulatory system. It is important to note that aromatase activity (and the formation of oestrone) is more pronounced in postmenopausal women, which is why most AIs are commonly used for postmenopausal women with breast cancer (Waterman, 2009). The aromatase enzyme has also been identified in endocrine tissues (such as ovary, uterus, prostate, and bone) and cancer associated with these tissues. Interestingly, the enzyme has also been found to be expressed in non-endocrine tissues, such as liver, lung, and colon cancers (Hong & Chen, 2006). In cancer treatments, AI drugs are often used in combination with the drug Tamoxifen, which blocks oestrogen activity, as opposed to synthesis (Waterman, 2009). The AIs, currently in use by the medical community, are defined as the third generation AIs. The older drugs include testolactone and aminoglutethimide –first generation drugs –, and formestane and fadrozole – second generation drugs (Ponzone et al. 2008). The older drugs have been less specific in binding to aromatase, and their binding to other P450 enzymes is what causes significant side effects (Chen et al. 2007). The newer drugs were developed in the 1990s and include exemestane (Aromasin), anastrozole (Arimidex), and letrozole (Femara). Natural aromatase-inhibiting compounds have also been found, including flavones and coumarins (Hong & Chen, 2006). Exemestane is a steroidal (or type I) compound, while the latter two are non-steroidal (or type II) AIs. The three drug structures vary from each other but they have the same effect, as well as similar patterns of adverse events (Jänickle, 2008). Figure 1 shows the basic structure of these three AIs. As can be seen, the natural substrate of aromatase, androstenedione, is a 4 ringed streroidal structure; Type I AIs are derivatives of androstenedione (also having an analogues 4 ringed steroidal structure), while type II AIs are derivatives of phenobarbitone (Ponzone et al. 2008). The substrate-like type I AI, exemestane, binds covalently, as a pseudo-substrate, resulting in an irreversible inactivation of aromatase. Type II compounds bind reversible to aromatase (Ponzone et al. 2008). It is more practical to discuss the details of the two AI types separately. Type I exemestane is a mechanism-based inhibitor (MBI). There are several MBIs, but only examestane is FDA-approved for clinical use (Hong & Chen, 2006). The MBIs have been classified into groups based on which carbon atoms have been substituted compared to androstenedione: MDL18,962 is classified as a “C-10 substituted androstendione”; formestane as a “4-substituted androstenedione”; androst-4-ene-3, 6, 17-trione and 6 alpha-bromoandrostenedione as “6-substituted androstenedione”; 7α-APTADD and exemestane as “substituted androsta-1, 4-diene-3, 17-diones”; and 1,4,6-androstatriene-3 and 17-dione as “substituted androsta-1, 4, 6-diene-3, 17-diones”. The molecular structures of AIs are understood. However, since the structure and binding of aromatase is still being studied, the molecular basis for the activity of MBIs are not fully understood yet (Hong et al. 2009). The discussion on molecular activity of MBIs is focused on exemestane (Hong et al. 2007). Although the activity of steroid analogues is not yet fully understood, their clinical outcome effects are found to be promising; it is recognized that MBIs are generally highly selective and less toxic (Hong & Chen, 2006). Mechanism-based reflects that exemestane requires the catalytic activity of aromatase in order to inhibit aromatase. Exemestane inhibits aromatase in a time-dependent manner. In the case of human placental aromatase, exemestane causes a time-dependent inactivation of the enzyme with a half-life of 13.9 minutes (Hong & Chen, 2006). More recently, examestane has been found to have a function in the degradation of the aromatase enzyme, in addition to inactivation. Again, a complete understanding of this function has not been attained yet. Upon binding, examestane is converted to reactive intermediates by aromatase in a series of redox reactions; the process is thought to involve the hydroxylation of the C-19 group in exemestance by the heme group in aromatase. The reactive intermediated are only produced in the presence of a redox partner, NADPH-P450 reductase, and its cofactor, NADPH. These intermediates bind irreversibly and the result is a suicide inhibition of the aromatase enzyme (Hong et al. 2007). Anastrozole and letrozole are the type II FDA-approved AIs. They are non-steroidal derivates that have a triazole functional group that interacts with a heme prosthetic group in aromatase. Hong et al. (2009) have published recent information about the aromatase structure with a key objective of examining the interaction of the enzyme with various substrates and AIs. The authors also explain that it has been easier to establish the binding nature of the steroidal AI, exemestane, than it has to determine the binding nature of the non-steroidal AIs. However, there is general agreement that the triazole nitrogen (N-4) is the key to heme iron interaction. The authors provide a new binding model of anastrozole to aromatase, which serves as a model for all of the triazole derived AIs (Hong et al. 2009). These type II AIs are competitive inhibitors of the androstenedione substrate (Hong & Chen, 2006). Competitive inhibition is reversible based on the concentrations of competing substrates and their analogous inhibitors. It is well understood that breast cancer patients need to be aromatase-positive and estrogen receptor (ER)-receptor positive in order to respond to AI drug treatments (Chen et al. 2007). However, some aromatase and ER-receptor positive patients, undergoing AI treatments, are found to be unresponsive to the inhibiting effects of AI drugs. The exact reasons for AI resistance are not fully understood. There are two types of AI (or endocrine therapy) resistance: De novo/intrinsic resistance and acquired resistance. De novo/intrinsic resistance refers to cases when patients have a lack of response to initial exposure to the drug treatments, while acquired resistance refers to a developed resistance to the drug therapy after an initial response the drugs (Chen et al. 2007). Aside from the AI resistant cases, AI drug developments have a promising future (Waterman, 2009). The newer generation drugs are biochemically more potent and selective than the older versions of AI drugs. They have better clinical outcomes compared with tamoxifen and there is no question about their superior efficiency and tolerability in postmenopausal breast cancer patients (Ponzone et al. 2008). Although there is no ambiguity that AIs are effective, there is unclear data about the efficacy of steroidal versus non-steroidal AIs, so there is ambiguity about which AIs should be used for patients (Jänickle, 2008; Ponzone et al. 2008). Figure 1: Structures of the natural aromatase substrate, androstenedione, and its product, estrone, and the third generation aromatase inhibitors, exemestane, letrozole, and anastrozole (Hong et al. 2007). References Chen, S., Masri, S., Hong, Y., Wang, X., Phung, S., Yuan, Y.C., Wu, X. (2007) New experimental models for aromatase inhibitor resistance. The Journal of Steroid Biochemistry and Molecular Biology[online], 106, 8-15, Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743954/?tool=pubmed [Accessed 14th October 2009]. Dutta, U., & Pant, K. (2007) Aromatase Inhibitors: Past, Present and Future in Breast Cancer Therapy. Medical Oncology[online], 25, 113-124, Available from: http://www.springerlink.com/content/3851305670u771t7/ [Accessed 14th October 2009]. Hong, Y., & Chen, S. (2006) Aromatase Inhibitors. Annals of the New York Academy of Sciences[online], 1089, 237-251, Available from: http://www3.interscience.wiley.com [Accessed 14th October 2009]. Hong, Y., Li, H., Yuan, Y.-C., & Chen, S. (2009) Molecular Characterization of Aromatase. Annals of the New York Academy of Sciences[online], 1155, 112-120, Available from: http://www3.interscience.wiley.com [Accessed 14th October 2009]. Hong, Y., Yu, B., Sherman, M., Yuan Y.-C., Zhou, D., Chen, S. (2007) Molecular Basis for the Aromatization Reaction and Exemestane-Mediated Irreversible Inhibition of Human Aromatase. Mol Endocrinol, 21, 401-414, Available from: http://mend.endojournals.org/cgi/content/full/21/2/401[Accessed 14th October 2009]. Jänickle, F. (2008) The similarities of aromatase inhibitors outweigh the differences. [Article]. Anti Cancer Drugs[online] March, 19, S7-S9, Available from: http://ovidsp.ovid.com/ [Accessed 14th October 2009]. Ponzone, R., Mininanni, P., Cassina, E., Pastorino, F., & Sismondi, P. (2008) Aromatase inhibitors for breast cancer: different structures, same effects? 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