The Coffey Lecture: Steroidogenic enzyme inhibitors and hormone dependent cancer

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Urologic Oncology (Impact Factor: 2.77). 01/2009; 27(1):53-63. DOI: 10.1016/j.urolonc.2008.07.036
Source: PubMed


To improve treatment for patients with breast and prostate cancer.
A number of novel inhibitors of steroidogenic enzymes have been developed. Their biological effects have been evaluated in a variety of preclinical models. Aromatase (estrogen synthetase) inhibitors have now been extensively tested in clinical trials in breast cancer patients. Inhibitors of 17alpha-hydroxylase/lyase have also been studied in preclinical models and are beginning trials in prostate cancer patients.
The enzyme aromatase (CYP19) has proven to be an important therapeutic target. Inhibitors of aromatase (AIs) are showing greater benefit than antiestrogens in the treatment of breast cancer. Although effective in other conditions in both women and men, AIs have not been useful in benign prostatic hypertrophy or prostate cancer. However inhibitors of 17alphahydroxylase/lyase (CYP17) to block synthesis of androgens may be effective for prostate cancer. Recent clinical trials with abiraterone and preclinical studies with other novel CYP17 inhibitors, which also interact with the androgen receptor and cause its down-regulation, could provide a new approach for treating this disease. In further studies, we optimized treatment with aromatase inhibitors and antiestrogens utilizing an intratumoral aromatase xenograft model. AIs were more effective and sustained growth inhibition was longer than antiestrogens. However, inevitably tumors eventually began to grow despite continued treatment. Analysis of breast tumors from mice treated with letrozole revealed up-regulation of HER-2 and MAP Kinase signaling proteins and down-regulation of the estrogen receptor. Our studies showed that tumors adapt to AI treatment by activating alternate signaling pathways, thus enabling them to proliferate in the absence of estrogen. When mice bearing resistant tumors were treated with trastuzumab, the anti-HER-2 antibody (herceptin), HER-2 was decreased in the tumor but the estrogen receptor and aromatase were restored. Tumor growth was significantly inhibited by treatment with trastuzumab in addition to letrozole.
Aromatase inhibitors are proving to be an effective new class of agents for the treatment of breast cancer. Compounds inhibiting 17alphahydroxylase/lyase have potential for the treatment of prostate cancer. Our results suggest that strategies to overcome resistance to these types of agents can restore sensitivity of the tumors to hormone therapy.

Download full-text


Available from: Vincent Njar, Aug 14, 2014
    • "The peripheral synthesis rate of steroid hormones is controlled by the local expression of enzymes which synthesize the estrogens and androgens from adrenal derived precursors (Labrie et al. 2000). Aberrant expression of enzymes involved in local steroidogenic pathway may lead to the formation of an abnormal intracellular steroids level and to uncontrolled cells proliferation (Brodie et al. 2009). Some evidence suggest, that changes in the expression of genes encoding steroidogenic enzymes could have a significant meaning in the etiology of hormone dependent tumors, including breast (Sasano et al. 2006), endometrial (Sasano et al. 2000), ovarian (Mungenast and Thalhammerand 2014), prostate (Gianfrilli et al. 2014) as well as in the other tumors not directly related with reproductive features like lung (Drzewiecka et al. 2015), thyroid (Rahbari et al. 2010), colon (Lin and Giovannucci 2010), central nervous system ( Park et al. 2010), or gastric (Nakamura et al. 2006; Frycz et al. 2015). "

    No preview · Article · Dec 2015 · Biochemistry and Cell Biology
  • Source
    • "Because approximately 75% of postmenopausal breast cancer is estrogen-receptive positive [23], inhibition of aromatase activity is an important strategy to reduce the growth-stimulatory effects of estrogens in estrogen-dependent breast cancer [24] [25]. Because of the importance of aromatase activity to the growth of breast and other hormone-dependent tumors, and the established protective effect of retinoids, in the present study we examined the effect of naturally occurring retinoids on aromatase activity and expression in vitro. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aromatase converts androgens into estrogens and is thought to supply a local source of estrogen that facilitates the growth of hormone-responsive tumor cells. Inhibition of aromatase is therefore an important chemopreventive strategy. We investigated the effect of retinol and selected retinoids on the activity and expression of aromatase in two human carcinoma cell lines in vitro. Retinol (ROH) and all-trans retinoic acid (ATRA) significantly inhibited aromatase activity in a concentration-dependent manner in microsomes isolated from JEG-3 human placental carcinoma cells, whereas 9-cis and 13-cis retinoic acid had significant inhibitory activity only at the highest concentrations tested. Similar results were observed in an assay of cellular aromatase activity in MCF-7 human breast cancer cells. Enzyme kinetic studies by double-reciprocal plot demonstrated that ROH inhibited microsomal aromatase activity in a mixed manner. In addition, ROH suppressed both the basal and cAMP-induced expression of aromatase mRNA in MCF-7 cells and inhibited transcription controlled by a cAMP-responsive element. These results suggest that aromatase activity and expression are a molecular target of ROH and chemopreventive retinoids, an activity that may underlie, in part, their inhibitory effects on hormone-dependent cancer.
    Full-text · Article · Jun 2011 · The Journal of nutritional biochemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: A quadrupole lens system which can be integrated into the Trinitron gun system is proposed. The system's main feature is that the quadrupole lens is located inside the main lens. The advantages of this system are: the construction is simple, with a single quadrupole lens for three beams, and the quadrupole effect is not affected by the spherical aberration of the main lens. As geometric and astigmatic defocusing is cancelled by applying dynamic focusing, high uniform resolution has been realized over the entire screen
    No preview · Conference Paper · Nov 1988
Show more