`
`BLOCKADE OF ANDROGENIC STEROID SYNTHESIS FOR TREATING PROSTATE CANCER
` ATTARD
` et al.
`
`The use of C17,20-lyase inhibitors
`in prostate cancer is described by
`authors from Los Angeles. These
`agents suppress the generation of
`testosterone and potentially active
`androgenic precursors, perhaps
`reversing castration resistance.
`Abiraterone is an orally
`bioavailable lyase inhibitor
`structurally related to
`pregnenolone, and is currently
`under clinical assessment.
`
`Another paper is presented by the
`same group of authors in Los
`Angeles addressing some of the
`controversies about the continual
`need for the traditional radical
`open surgical management of RCC,
`and evaluates the oncological
`principles which ensure the
`persistent need for this approach.
`
`Selective blockade of androgenic
`steroid synthesis by novel lyase
`inhibitors as a therapeutic strategy for
`treating metastatic prostate cancer
`
`GERHARDT ATTARD, ARIE S. BELLDEGRUN* and JOHANN S. DE BONO
`Institute for Cancer Research/The Royal Marsden NHS Foundation Trust, Centre for Cancer
`Therapeutics, Sutton, Surrey, UK, and *UCLA David Geffen School of Medicine, Department of
`Urology, Los Angeles, California, USA
`Accepted for publication 21 July 2005
`
`KEYWORDS
`
`castration refractory prostate cancer,
`α
`17
`-hydroxylase, C
`-lyase, CYP450c17,
`17,20
`abiraterone, CB7630
`
`THE NEED FOR NOVEL AGENTS TO TREAT
`PROSTATE CANCER
`
`Prostate cancer is the most common
`malignancy in Western societies and the
`second most common cause of male cancer-
`related death in the UK and USA, accounting
`≈
`for
`12% of all male cancer-related deaths
`[1,2]. When confined to the prostate gland,
`the disease is curable with local therapy
`(radical prostatectomy, external beam
`radiotherapy, brachytherapy or cryotherapy).
`However, despite the use of PSA for screening,
`in 15–33% of men local therapy fails and they
`develop incurable metastatic disease [3,4].
`Activation of the androgen receptor (AR) by
`androgenic steroids including testosterone
`α
`and its more potent 5
`-reduced metabolite,
`α
`5
`-dihydrotestosterone (DHT), regulates the
`transcription of a diverse range of target
`genes involved in prostate cell proliferation,
`differentiation, and apoptosis [5]. Androgen
`deprivation by medical or surgical castration
`remains the mainstay of treatment and
`>
`90% of men with metastatic prostate
`
`cancer initially respond rapidly and
`often dramatically to castration, with
`improvements in bone pain, regression of soft
`tissue metastasis, and steep declines in PSA
`level. However, the duration of response is
`frequently short (12–33 months) and in
`almost all patients is followed by the
`emergence of castration-resistant prostate
`cancer (CRPC) that, untreated, is invariably
`fatal within 9–12 months [3]. Systemic
`chemotherapy with docetaxel for patients
`with CRPC confers a modest survival
`advantage (2–3 months) and is effective
`for palliating symptoms [6], but the
`duration and rate of response is limited.
`Other chemotherapy, e.g. mitoxantrone, has
`not been shown to improve survival but might
`help with symptom control [6]. There is an
`urgent need for new agents that provide
`palliation and improve survival.
`
`Continued androgen-dependent activation of
`a ‘hypersensitive’ AR in castrated patients
`secondary to AR gene amplification [7],
`mutations in the AR gene [5], increased AR
`expression [8], or alterations in AR co-
`repressor/co-activator function [9] appear to
`be important mechanisms of castration
`resistance. These could be reversed by
`suppressing circulating androgens, inhibiting
`the binding of biologically active androgenic
`steroids to the ARs or disrupting AR
`
`©
`
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`2 0 0 5 B J U I N T E R N A T I O N A L | 9 6 , 1 2 4 1 – 1 2 4 6 | doi:10.1111/j.1464-410X.2005.05821.x
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`1 2 4 1
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`WCK1008
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`A T TA R D
`
`E T A L .
`
`generation with drugs such as HSP90
`inhibitors. This review discusses the rationale
`behind using selective lyase inhibitors (e.g.
`abiraterone acetate, also known as CB7630),
`to suppress circulating androgens.
`
`TARGETING THE AR
`
`The benefit of androgen deprivation therapy
`(ADT) was first reported by Huggins and
`Hodges in 1941 [10] when surgical castration
`was found to give symptomatic benefit and in
`some cases, complete responses in metastatic
`prostate cancer. The role of ADT by castration
`has since expanded to the neoadjuvant and,
`more commonly, the adjuvant settings, and to
`patients with a high PSA level but no clinical
`or radiological evidence of metastatic disease
`[3]. Medical castration with LHRH agonists
`(e.g. goserelin and leuprorelin) is often a more
`popular alternative to orchidectomy. These act
`by continuous stimulation of the anterior
`pituitary gland, resulting in inhibition of LH
`secretion and suppression of testicular
`androgen synthesis. Antiandrogens (either
`steroidal, e.g. cyproterone acetate, or
`nonsteroidal, e.g. bicalutamide or flutamide)
`prevent androgen binding to the AR. These
`can be used in combination with LHRH
`analogues to inhibit binding of residual
`androgens to the AR to attempt ‘maximum
`androgen blockade’ [3]. However, this
`combined strategy has not significantly
`prolonged the survival of patients with
`advanced prostate cancer [3]. In addition, up
`to 30% of patients show a decrease in PSA
`level after stopping AR antagonists [11]. This
`can partly be explained by the development
`of AR gene mutations or increased AR
`expression that might cause AR antagonists
`to behave as weak agonists [7,8]. For many
`years, oestrogens, including diethylstilbestrol,
`were the primary medical treatment for
`metastatic prostate cancer, until they were
`superseded by LHRH agonists [3]. Now they
`have a role in treating castrated patients in
`whom castration and antiandrogen therapy
`have failed, but although PSA response rates
`in a series of phase II trials were 21–80%, the
`<
`median response duration is
`6 months
`and the concomitant use of prophylactic
`warfarin has not eliminated the risk of
`thromboembolic events [12].
`
`The presence of AR protein expression and
`significant AR mRNA levels in tumour samples
`from patients with CRPC strongly suggest
`that prostate tumours evolve mechanisms to
`
`1 2 4 2
`
`reactivate AR signalling and AR-responsive
`pathways after ADT [7,13]. This is supported
`by preclinical models, which have suggested
`that, as prostate cancer cells become
`castration resistant (otherwise, but less
`appropriately known as hormone- or
`androgen-resistant), they acquire the ability
`to grow in the presence of low levels of
`androgens (equivalent to castrate), by
`the up-regulation of AR expression [8]. It
`was also reported that, despite castration,
`intraprostatic levels of testosterone and DHT
`in CRPC might remain sufficient to maintain
`tumour growth [14]. The source of these
`androgens is unclear, but altered regulation of
`enzymes involved in the synthesis and
`inactivation of androgens might be one cause
`of their accumulation. In support of this,
`increased expression of enzymes involved in
`androgen synthesis were reported in prostate
`cancer cells acquired from biopsies of CRPC
`[13,15]. These data suggest the possibility of
`endogenous production of steroids by CRPC.
`Overall, these reports indicate that the
`currently used ADTs fail to reverse AR
`signalling in CRPC and support the use of
`novel drugs that target the AR directly or
`indirectly by suppressing the generation of
`ligands.
`
`Plasma testosterone is not completely
`suppressed by castration, in part because of
`peripheral conversion of adrenal androgenic
`steroids to testosterone by 17-ketoreductase
`[3]. Adrenal androgen synthesis can be
`inhibited by targeting the hypothalamo-
`pituitary-adrenal axis or by inhibiting key
`enzymes involved in adrenal steroid
`biosynthesis. Suppression of the
`hypothalamo-pituitary-adrenal axis and
`consequently the generation of adrenal
`androgens by low-dose steroids has not been
`unequivocally shown to occur in patients with
`CRPC, but it could be one explanation for their
`anti-neoplastic activity [16,17]. However,
`ketoconazole, an imidazole antifungal agent
`that weakly and non-selectively inhibits
`several cytochrome P450 enzymes involved in
`adrenal steroid synthesis, induces a transient
`PSA response in 20–30% of patients with
`CRPC [11]. Interestingly, patients who respond
`to ketoconazole and subsequently progress
`show a significant decrease, associated with
`an increase with disease progression of
`adrenal androgens (dehydroepiandrosterone
`(DHEA) and androstenedione) suggesting that
`ketoconazole resistance is caused by adrenal
`androgens [11]. These clinical results lend
`credence to the inhibition of the adrenal
`
`steroid synthesis pathway as a therapeutic
`strategy.
`
`THE ROLE OF CYTOCHROME P450c17 IN
`ANDROGEN BIOSYNTHESIS
`
`The two sites thought to produce most of the
`androgenic steroids in humans are the testis
`and the adrenal cortex. The principal
`enzymatic reaction in steroid biosynthesis
`involves cleavage of a six-carbon group from
`cholesterol by CYP450ssc (desmolase) [18]. A
`series of subsequent reactions catalysed by
`members of the cytochrome P450 family then
`produce the glucocorticoid and
`mineralocorticoid 21-carbon steroid
`hormones vital to human survival (Fig. 1).
`CYP450c17 is a single microsomal enzyme,
`encoded for by the single human CYP17 gene,
`that catalyses the two independently-
`α
`regulated steroids 17
`-hydroxylase and
`C
`-lyase activities needed to produce
`17,20
`the 19-carbon precursors of the sex
`steroids in both the adrenal cortex and the
`α
`testis [18]. The 17
`-hydroxylase activity
`α
`typically converts pregnenolone to 17
`-
`hydroxypregnenolone and progesterone
`α
`to 17
`-hydroxyprogesterone, and the
`α
`C
`-lyase activity converts 17
`-
`17,20
`α
`-
`hydroxypregnenolone to DHEA and 17
`hydroxyprogesterone to androstenedione
`(Fig. 1). The C
`-lyase activity is roughly
`17,20
`50 times more efficient for converting
`α
`17
`-hydroxypregnenolone to DHEA than
`α
`for converting 17
`-hydroxyprogesterone to
`androstenedione [18,19]. The products of
`steroid biosynthesis, androstenedione and
`DHEA, are weak as androgens but in the testis
`can be converted to testosterone by the
`α
`enzyme 17
`-hydroxysteroid dehydrogenase
`[20]. Castration blocks testosterone from this
`source but does not prevent the synthesis of
`adrenal androgens. These androgens might be
`a clinically important source of androgenic
`steroids for activating the AR on prostate
`cancer cells. Steroidogenesis in the human
`adrenal is divided into three morphologically
`and functionally distinct zones. The zona
`glomerulosa, located just below the adrenal
`capsule, does not express CYP450c17 and
`produces the 17-hydroxy 21-carbon steroid
`aldosterone, the principal mineralocorticoid,
`under the regulation of angiotensin II [21].
`The middle layer, the zona fasciculata,
`α
`expresses CYP450c17 and has abundant 17
`-
`hydroxylase but very little C
`-lyase activity,
`17,20
`and produces the 17-hydroxy 21-carbon
`steroid cortisol, the principal glucocorticoid,
`
`©
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` 2 0 0 5 B J U I N T E R N A T I O N A L
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`WCK1008
`Page 2
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`B L O C K A D E O F A N D R O G E N I C S T E R O I D S Y N T H E S I S F O R T R E A T I N G P R O S T A T E C A N C E R
`
`α
`FIG. 1. The impact of abiraterone on the adrenal steroid synthesis pathway. Abiraterone inhibits CYP450c17 17
`
`-lyase activity (crossed out in
`-hydroxylase and C
`17,20
`red) and suppresses androstenedione, DHEA and their androgenic precursors (blue arrows). Suppression of cortisol and its precursors causing a compensatory rise in
`ACTH and excess synthesis of aldosterone and its precursors is predicted (blue arrows).
`
`Cholesterol
`
`desmolase
`
`Adrenal Cortex
`
`Pregnenolone
`
`Progesterone
`
`DOC
`
`Corticosterone
`
`18OH-
`Corticosterone
`
`Aldosterone
`
`3-BHSD-I
`
`17a-hydroxylase
`
`21-hydroxylase
`
`11b-hydroxylase
`
`18-hydroxylase
`
`18-oxidase
`
`17OH-pregnenolone
`
`17OH-progesterone
`
`11-DOC
`
`Cortisol
`
`3-BHSD-I
`
`C17-20 lyase
`
`Peripheral Tissues
`
`
`
`DHEA
`
`Androstenedione
`
`Testosterone
`
`DHT
`
`3-BHSD-I
`
`17-keto-reductase
`
`5a-reductase
`
`under the regulation of adrenocorticotropic
`hormone (ACTH) corticotrophin [21]. The inner
`zona reticularis, which does not become
`morphologically identifiable until the onset of
`adrenarche, expresses CYP450c17 and has
`α
`both 17
`-hydroxylase and C
`-lyase
`17,20
`activities, and thus produces 17-hydroxy
`19-carbon precursors of sex steroids [18,21].
`The C
`-lyase activity of human CYP450c17
`17,20
`is enhanced by serine phosphorylation
`of CYP450c17 and by the presence of
`cytochrome b5. The expression of cytochrome
`b5 increases in the adrenal zona reticularis at
`the onset of adrenarche [18].
`
`Congenital deficiencies in CYP450c17 are a
`rare form of congenital adrenal hyperplasia in
`which not only adrenal but also gonadal
`steroidogenesis is impaired [19]. This results in
`abrogation of gonadal sex steroid production
`and adrenal biosynthesis of cortisol and
`androgens. However, corticosterone synthesis
`is not impaired, and as corticosterone has
`glucocorticoid properties, patients rarely
`manifest symptoms of adrenal insufficiency.
`In fact, rodents lack CYP450c17 and
`use corticosterone as their principal
`glucocorticoid [19]. However, because
`corticosterone is a weaker glucocorticoid than
`
`©
`
` 2 0 0 5 B J U I N T E R N A T I O N A L
`
`cortisol, abnormally high corticosterone
`production is necessary before feedback
`inhibition of pituitary ACTH secretion occurs,
`establishing a new steady state. To produce
`enough corticosterone to compensate for
`the absence of cortisol, more intermediate
`steroids might be generated. These include
`progesterone, 11-deoxycorticosterone (DOC),
`18-hydroxycorticosterone and 19-nor-DOC.
`This ACTH-driven overproduction of
`mineralocorticoids often leads to
`hypertension, a characteristic presenting
`feature of this disease, usually in early
`adulthood [19]. At diagnosis, sexual
`infantilism in 46 XX females and ambiguous
`genitalia in 46 XY males is usually manifest
`and laboratory investigations will often find
`hypokalaemia [19]. An extremely rare disorder
`is isolated C
`-lyase deficiency caused
`17,20
`-
`by mutations that destroy most C
`17,20
`α
`lyase activity but preserve most 17
`-
`hydroxylase activity. Patients do not have
`mineralocorticoid excess but show the
`consequences of absent sex steroids [19],
`so CYP450c17 is a logical target for the
`development of new drugs to treat CRPC.
`The most potent and selective inhibitor of
`CYP450c17 currently in clinical studies is
`abiraterone acetate.
`
`PRECLINICAL DEVELOPMENT OF
`ABIRATERONE ACETATE
`
`The serendipitous discovery that some esters
`of 4-pyridylacetic acid are effective inhibitors
`of the hydroxylase-lyase enzyme in rat testis
`[22] led to the study of a variety of esters of 3-
`α
`and 4-pyridylacetic acid and their
`-alkylated
`α
`derivatives on human testicular 17
`-
`hydroxylase/C
`-lyase [23,24]. The most
`17,20
`α
`-
`potent inhibitors of human testicular 17
`hydroxylase/C
`-lyase had, as a common
`17,20
`structural feature, the 17-(-3-pyridyl)
`substituent that contains nitrogen capable of
`forming a co-ordinate bond with the haem
`iron of the enzyme (Fig. 2) [23,24]. The 3-
`pyridyl substituent results in a several orders
`more potent inhibition of CYP450c17 than
`the 2-pyridyl and 4-pyridyl substituents [23].
`The double bond in the 16,17-position of
`the steroidal skeleton is essential for the
`irreversible inhibition of CYP450c17 [25]. Two
`compounds, CB7598 (abiraterone), which is
`closely related structurally to the natural
`substrate pregnenolone, and CB7627, were
`identified as the most potent, and were
`selected for further development at the
`Institute of Cancer Research in London. With
`<
`a Ki
` of
`1 n
`, both compounds were
`M
`app
`
`1 2 4 3
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`A T TA R D
`
`E T A L .
`
`TABLE 1
`
`Summary of phase I evaluation of abiraterone acetate
`
`Variable
`Number of patients
`Dose levels, mg
`Testosterone level at
`inclusion, nmol/L
`Effect on testosterone (T)
`
`Effect on androstenedione
`Effect on LH
`
`Phase I study patient population
`Single dose in castrate men
`Single dose in intact men
`16
`4
`10, 30, 100, 200, 500
`200, 500
`<
`>
`2
`9
`
`Continuous dosing (12 days) in intact men
`6
`500, 800
`>
`9
`
`Target suppression at
`500 mg
`Same as for T
`Suppressed at inclusion
`
`Suppression with nadir on second
`day, recovery 6–9 days.
`Same as for T
`Maximal rise on third day, recovery
`by 10th day
`
`Suppression with nadir on first to third day and
`sustained for up to 9 days
`Same as for T
`Maximal rise on third day
`
`several times more potent inhibitors of rat
`hydroxylase/lyase activity than ketoconazole
`[23,24]. Unlike CB7627, abiraterone was a
`highly selective inhibitor of CYP450c17 and so
`was chosen as the main candidate for further
`development [24]. However, due to poor
`bioavailability and a susceptibility to
`hydrolysis by esterases, a prodrug for
`abiraterone was sought [26,27]. The amide
`was a several orders less potent inhibitor of
`β
`
`-O-acetate
`hydroxylase/lyase [24] but the 3
`form (abiraterone acetate, CB7630) (Fig. 2)
`
`in vivo was
`was resistant to esterases and
`rapidly deacetylated to abiraterone resulting
`in potent inhibition of CYP450c17 [26,27].
`
`When adult mice given abiraterone acetate or
`ketoconazole i.p. daily for 14 days were
`compared to a control group dosed with
`vehicle alone, abiraterone significantly
`reduced plasma testosterone concentrations
`for at least 24 h despite a four-fold increase
`in LH concentrations [27]. This was associated
`with reduced weights of the ventral prostate
`(48%) and seminal vesicles (87%), compared
`to the controls. The kidneys and testis were
`also reduced in weight by 37% and 62%,
`respectively [27]. There was no weight loss in
`the androgen-dependent organs of the group
`given ketoconazole [27]. There was a marked
`increase in the weight of the adrenal glands in
`the group administered ketoconazole, but no
`change in the control group or in the animals
`dosed with abiraterone, indicating no
`inhibition of corticosterone production by
`abiraterone. Animal toxicology studies found
`no effects on haematological, biochemical or
`renal function variables and only mild
`toxicities. Abiraterone acetate was therefore
`considered safe enough to be studied in
`humans [27].
`
`1 2 4 4
`
`FIG. 2.
`The structure of abiraterone and abiraterone acetate (centre). The effect variations in the orientation
`α
`of the pyridyl substituent have on the potency of 17
`-hydroxylase/C
`-lyase inhibition.
`
`17,20
`
`N
`
`N
`
`N
`
`H O
`
`R O
`
`H O
`
`2-pyridyl
`
`IC50 (nm)
`lyase 76
`hydroxylase 270
`
`3-pyridyl
`
`IC50 (nm)
`lyase 2.9
`hydroxylase 4
`
`4-pyridyl
`
`IC50 (nm)
`lyase 1000
`hydroxylase 4000
`
`
`
`R = H: Abiraterone (CB7598); 17-(3-pyridyl)androsta-5,16-dien-3b -ol
`R = Ac: Abiraterone acetate (CB7630)
`
`CLINICAL EVALUATION OF
`ABIRATERONE ACETATE
`
`A series of three phase I studies were
`performed in men with histologically
`confirmed prostate cancer who had shown a
`biochemical (PSA) relapse after two lines of
`hormone treatment but for whom, at the time
`of participation, no alternative treatment for
`symptomatic or progressive disease was
`considered necessary (Table 1). The first in-
`human study investigated the effect of a
`single dose of abiraterone acetate in castrate
`<
`patients (testosterone confirmed
`2 nmol/L,
`58 ng/mL) with prostate cancer in whom
`treatment with antiandrogens had failed.
`
`Nine patients were treated in groups of three
`at doses of 10, 30 and 100 mg. At these doses,
`the plasma level of abiraterone was below the
`level of detection and there was no consistent
`effect on testosterone [28]. One patient was
`then given 200 mg and six of them 500 mg.
`There were detectable plasma levels of
`>
`200 mg [28].
`abiraterone at doses of
`Abiraterone at 500 mg suppressed
`<
`0.14 nmol/L
`testosterone concentrations, to
`(4 ng/mL), or by 75% when baseline
`>
`0.6 nmol/L (20 ng/
`testosterone levels were
`mL), and androstenedione concentrations.
`Suppression was sustained from the second
`to the fifth day after abiraterone acetate.
`There was no corresponding suppression of
`
`©
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`B L O C K A D E O F A N D R O G E N I C S T E R O I D S Y N T H E S I S F O R T R E A T I N G P R O S T A T E C A N C E R
`
`α
`-hydroxyprogesterone. This first study
`17
`was followed by a second investigating the
`effect of a single dose of abiraterone acetate
`in intact men with prostate cancer who had
`previously been treated with an antiandrogen
`and an LHRH agonist. One patient was given
`200 mg, but the testosterone level was not
`suppressed. Three patients were then given
`500 mg, and in all three there was a reduction
`in testosterone level of more than half from
`baseline. The testosterone nadir was on the
`second day after therapy, with recovery to
`pretreatment levels 6–9 days later. There was
`a corresponding compensatory surge in LH
`levels, maximal on the third day, with recovery
`to pretreatment levels by the 10th day. There
`was no change in cortisol levels in either
`study [28]. The third and last in this series of
`phase I evaluations investigated 12-day
`continuous dosing in intact men with
`prostate cancer who had previously received
`antiandrogens and LHRH agonists. The
`duration of drug treatment was limited by a
`lack of availability of the drug. Three patients
`were given 500 mg daily and another three
`were given 800 mg daily. The testosterone
`level was suppressed after the first day of
`dosing and was sustained for 3 days, and
`then reversed by a rise in LH. The patients
`given 800 mg appeared to show greater
`suppression of testosterone but as in the
`500 mg cohort, the effect of abiraterone was
`insufficient to offset the rise in LH. All six
`patients had a reduced cortisol response to
`ACTH stimulation on the 11th day after
`dosing, suggesting reduced adrenocortical
`reserve. There was a mild reduction in evening
`cortisol levels also in the three patients
`given 800 mg but there were no clinical
`manifestations of adrenocortical insufficiency
`[28]. Pharmacokinetic studies suggested good
`>
`oral bioavailability at doses of
`200 mg.
`The mean (
`) T
` for abiraterone was 2.70
`SD
`max
`(2.71) h with an elimination half-life of 27.6
`(20.17) h, supporting once-daily oral dosing.
`There was an inter-patient 10-fold variation
`in the area under the curve for a given
`dose, making analysis of dose-dependent
`pharmacokinetic relationships difficult.
`Several factors could have caused this wide
`level of variation. As with all oral drugs,
`absorption might have been altered by
`residual food in the stomach despite a 2-h
`fast, by intrinsic inter-individual differences in
`upper gastrointestinal pH, by concomitant
`medication(s) effecting gastric pH, or by
`variable first-pass hepatic metabolism.
`Abiraterone acetate was well tolerated, and
`no serious adverse events or haematological
`
`©
`
` 2 0 0 5 B J U I N T E R N A T I O N A L
`
`or biochemical changes were reported. Mild
`mood variations, flushing attacks, testicular
`discomfort, and headaches were described in
`individual patients [28].
`
`FUTURE DEVELOPMENT OF NOVEL
`LYASE INHIBITORS
`
`Several other derivatives of naturally
`occurring steroidal substrates, including
`pregnane and androstane, are potent
`α
`inhibitors of 17
`-hydroxylase/C
`-lyase
`17,20
`[29,30]. Sa40 (17-(5-pyrimidyl)androsta-5,16-
`β
`diene-3
`-ol) and its 3-acetyl derivative, Sa41,
`
`in vitro
`are three times more potent for
`inhibition of human CYP450c17 than
`abiraterone and abiraterone acetate,
`respectively, but have a poorer
`in vivo rodent
`
`pharmacokinetic profile in
`experiments [29]. Clinical assessment in
`patients is required. L-2 (20-hydroximinio-
`′
`4,16-pregnadien-3-one), L-36 (17-(3
`-
`pyrazolyl)androsta-4,16-dien-3-one) and L-
`′
`39 (17-(5
`-isoxazolyl)androsta-4,16-dien-3-
`one) are steroidal compounds that in addition
`α
`to inhibiting 17
`-hydroxylase/C
`-lyase,
`17,20
`α
`also inhibit 5
`-reductase with a potency
`similar to finasteride [30]. They also interact
`with wild-type AR and the mutated AR on
`cells from the LNCaP cell line [30]. L-36 shows
`an agonistic interaction whereas L-39 is
`
`in vitro LNCaP cell
`antagonistic and inhibits
`growth [30]. L-39 has therefore been
`proposed as a candidate for further
`α
`development. However, the benefit of 5
`-
`reductase inhibitors for treating metastatic
`prostate cancer is unclear [3]. Although
`conversion of testosterone to its more active
`metabolite, DHT, is inhibited, testosterone
`consequently accumulates and can activate
`the AR. Also, interaction with the AR might
`not be desirable as changes in the AR can lead
`to antagonists behaving agonistically [7,8].
`Other nonsteroidal compounds, including TX-
`977 and its two diastereoisomers, reported
`
`in vivo inhibitors of
`to be more potent
`testosterone synthesis, have been associated
`with an increase in weight of the adrenal
`glands in rodent models, suggesting lower
`specificity of lyase inhibition vs glucocorticoid
`synthesis [31]. Abiraterone acetate’s
`selectivity for CYP450c17 and its failure to
`interact with the AR might be preferable for
`treating patients with CRPC. However, at
`present, while the available data are
`encouraging with respect to side-effects
`and endocrine effectiveness with short-term
`dosing, there is no evidence of clinical
`efficacy. A safety and efficacy evaluation of
`
`abiraterone acetate administered daily and
`continuously to castrate men with advanced
`prostate cancer progressing despite hormone
`treatment is planned. Concomitant castration
`is expected to prevent a compensatory LH rise,
`and sustained, profound suppression of
`serum testosterone and androgenic precursor
`levels is predicted. Patients will be closely
`monitored for the development of
`glucocorticoid insufficiency or hypertension.
`Synthesis of corticosterone, a precursor of
`aldosterone and the primary glucocorticoid in
`rodents, will not be inhibited by abiraterone
`and its continued synthesis might prevent
`clinical manifestations of glucocorticoid
`insufficiency. In fact, hypertension due to
`increased ACTH and not glucocorticoid
`insufficiency is described in congenital
`CYP45017c deficiency [19]. The results of
`these studies are keenly awaited.
`
`CONFLICT OF INTEREST
`
`A. Belldegrun: Vice Chairman, Board of
`Directors and Chairman, Scientific Advisory
`Board, Cougar Biotechnology.
`
`REFERENCES
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Cancer Research UK. Mortality
`
`Statistics. Available at http://
`www.cancerresearchuk.org/aboutcancer/
`=
`statistics/mortality?version
`1. Accessed
`July 2005
`Jemal A, Murray T, Samuels A, Ghafoor
`A, Ward E, Thun MJ.
`Cancer statistics,
`
`53: 5–26
`
`CA Cancer J Clin 2003;
`2003.
`Hellerstedt BA, Pienta KJ.
`The current
`state of hormonal therapy for prostate
`
`52:
`
`CA Cancer J Clin 2002;
`cancer.
`154–79
`Han M, Partin AW, Zahurak M,
`Piantadosi S, Epstein JI, Walsh PC.
`Biochemical (prostate specific antigen)
`recurrence probability following radical
`prostatectomy for clinically localized
`
`
`J Urol 2003; 169: 517–23
`
`prostate cancer.
`Buchanan G, Greenberg NM, Scher HI,
`Harris JM, Marshall VR, Tilley WD.
`Collocation of androgen receptor gene
`Clin Cancer
`mutations in prostate cancer.
`
`7: 1273–81
`Res
` 2001;
`Tannock IF, de Wit R, Berry WR
` Docetaxel plus prednisone or
`et al.
`mitoxantrone plus prednisone for
`
`advanced prostate cancer.
`
`351: 1502–12
`2004;
`
`N Engl J Med
`
`1 2 4 5
`
`WCK1008
`Page 5
`
`
`
`A T TA R D
`
`E T A L .
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`7
`
`8
`
`9
`
`10
`
`11
`
`Edwards J, Krishna NS, Grigor KM,
`Bartlett JM.
`Androgen receptor gene
`amplification and protein expression in
`Br J
`hormone refractory prostate cancer.
`
`89: 552–6
`
`Cancer 2003;
`Chen CD, Welsbie DS, Tran C
`
`et al.
`Molecular determinants of resistance to
`
`
`antiandrogen therapy. Nat Med 2004; 10:
`
`
`33–9
`Li P, Yu X, Ge K, Melamed J, Roeder RG,
`Wang Z.
`Heterogeneous expression
`and functions of androgen receptor
`co-factors in primary prostate cancer.
`
`161: 1467–74
`
`Am J Pathol 2002;
`Huggins C, Hodges CV.
`Studies on
`prostatic cancer. I. The effect of
`castration, estrogen and androgen
`injection on serum phosphatases in
`metastatic carcinoma of the prostate.
`
`1: 293–7
`
`Cancer Res 1941;
`Small EJ, Halabi S, Dawson NA
`
`et al.
`Antiandrogen withdrawal alone or in
`combination with ketoconazole in
`androgen-independent prostate cancer
`patients: a phase III trial (CALGB 9583).
`
`22: 1025–33
`
`J Clin Oncol 2004;
`Oh WK.
`The evolving role of estrogen
`Clin Prostate
`therapy in prostate cancer.
`
`1: 81–9
`
`Cancer 2002;
`Holzbeierlein J, Lal P, LaTulippe E
`
`et al.
`Gene expression analysis of human
`prostate carcinoma during hormonal
`therapy identifies androgen-responsive
`genes and mechanisms of therapy
`
`164: 217–
`
`Am J Pathol 2004;
`resistance.
`27
`Mohler JL, Gregory CW, Ford OH 3rd
` The androgen axis in recurrent
`et al.
`
`
`
`440–8
`Castagnetta LA, Carruba G, Traina
`A
`et al. Expression of different 17beta-
`hydroxysteroid dehydrogenase types
`and their activities in human prostate
`cancer cells. Endocrinology 1997; 138:
`4876–82
`16 Khandwala HM, Vassilopoulou-Sellin R,
`Logethetis CJ, Friend KE. Corticosteroid-
`induced inhibition of adrenal androgen
`production in selected patients with
`prostate cancer. Endocr Pract 2001; 7: 11–
`5
`
`12
`
`13
`
`14
`
`15
`
`
`
`prostate cancer. Clin Cancer Res 2004; 10:
`
`17 Akakura K, Suzuki H, Ueda T et al.
`Possible mechanism of dexamethasone
`therapy for prostate cancer: suppression
`of circulating level of interleukin-6.
`Prostate 2003; 56: 106–9
`18 Miller WL, Auchus RJ, Geller DH. The
`regulation of 17,20 lyase activity. Steroids
`1997; 62: 133–42
`19 Auchus RJ. The genetics,
`pathophysiology, and management of
`human deficiencies of P450c17.
`Endocrinol Metab Clin North Am 2001;
`30: 101–19
`20 O’Shaughnessy PJ, Baker PJ, Heikkila
`M, Vainio S, McMahon AP. Localization
`of 17beta-hydroxysteroid dehydrogenase/
`17-ketosteroid reductase isoform
`expression in the developing mouse testis
`– androstenedione is the major androgen
`secreted by fetal/neonatal leydig cells.
`Endocrinology 2000; 141: 2631–7
`21 Dickerman Z, Grant DR, Faiman C,
`Winter JS. Intraadrenal steroid
`concentrations in man: zonal differences
`and developmental changes. J Clin
`Endocrinol Metab 1984; 59: 1031–6
`22 McCague R, Rowlands MG, Barrie SE,
`Houghton J. Inhibition of enzymes of
`estrogen and androgen biosynthesis by
`esters of 4-pyridylacetic acid. J Med Chem
`1990; 33: 3050–5
`23 Rowlands MG, Barrie SE, Chan F et al.
`Esters of 3-pyridylacetic acid that
`combine potent inhibition of 17 alpha-
`hydroxylase/C17,20-lyase (cytochrome
`P45017 alpha) with resistance to
`esterase hydrolysis. J Med Chem 1995;
`38: 4191–7
`24 Potter GA, Barrie SE, Jarman M,
`Rowlands MG. Novel steroidal inhibitors
`of human cytochrome P45017 alpha
`(17 alpha-hydroxylase-C17,20-lyase):
`potential agents for the treatment of
`prostatic cancer. J Med Chem 1995; 38:
`2463–71
`25 Jarman M, Barrie SE, Llera JM. The
`16,17-double bond is needed for
`irreversible inhibition of human
`cytochrome p45017alpha by abiraterone
`(17-(3-pyridyl) androsta-5, 16-dien-
`3beta-ol) and related steroidal inhibitors.
`J Med Chem 1998; 41: 5375–81
`
`26 Chan FC, Potter GA, Barrie SE
`et al. 3- and 4-pyridylalkyl
`adamantanecarboxylates: inhibitors of
`human cytochrome, P450 (17alpha)
`(17alpha-hydroxylase/C17,20-lyase).
`Potential nonsteroidal agents for the
`treatment of prostatic cancer. J Med
`Chem 1996; 39: 3319–23
`27 Barrie SE, Potter GA, Goddard PM,
`Haynes BP, Dowsett M, Jarman M.
`Pharmacology of novel steroidal
`inhibitors of cytochrome P450(17)
`alpha (17 alpha-hydroxylase/C17–20
`lyase). J Steroid Biochem Mol Biol, 1994;
`50: 267–73
`28 O’Donnell A, Judson I, Dowsett M
`et al. Hormonal impact of the 17alpha-
`hydroxylase/C(17,20)–lyase inhibitor
`abiraterone acetate (CB7630) in patients
`with prostate cancer. Br J Cancer 2004;
`90: 2317–25.
`29 Haidar S, Ehmer PB, Barassin S, Batzl-
`Hartmann C, Hartmann RW. Effects of
`novel 17alpha-h