Blockade of testicular and adrenal androgens in prostate cancer treatment.
Prostate cancer is the most hormone sensitive of all cancers. However, any hormonal therapeutic strategy must take into account the fact that two almost equivalent sources of androgens act in the prostate, namely testosterone of testicular origin, and the locally produced androgens testosterone and dihydrotestosterone (DHT) derived from dehydroepiandrosterone of adrenal origin. Combined androgen blockade--medical or surgical castration plus a pure antiandrogen--would, therefore, be the logical first-line treatment for prostate cancer, although castration or an antiandrogen alone is still chosen in the majority of cases. Although long-term control, or even cure, is possible when combined androgen blockade is used when the tumor is localized, resistance to treatment invariably develops in patients when start of treatment is delayed until the disease has become metastatic. This observation can be explained either by elevated levels of the androgen receptor, which can increase the response to low levels of androgens and also modify the response to antiandrogens; or by local biosynthesis of androgens. Research to identify new and more potent antiandrogens, as well as blockers of peripheral and adrenal androgen biosynthesis--such as abiraterone--could be of great importance.
Research Center in Molecular Endocrinology, Oncology and Human Genomics, Laval University, Laurier Boulevard, Quebec City, QC G1V 4G2, Canada. flabrie@attglobal.net
Fernand
F
Labrie
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D000726:Androgen Antagonists; D000728:Androgens
Lancet. 2000 Apr 29;355(9214):1491-8
10801170
Urol Oncol. 2009 May-Jun;27(3):251-7
19414113
J Clin Oncol. 2009 Aug 10;27(23):3742-8
19470933
J Urol. 2007 Oct;178(4 Pt 1):1282-8; discussion 1288-9
17698092
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):vii-ix
18471779
Mol Cell Endocrinol. 1991 Jul;78(3):C113-8
1838082
Cancer Res. 2004 Jan 15;64(2):765-71
14744796
Cancer Res. 2006 Mar 1;66(5):2815-25
16510604
J Urol. 2006 Dec;176(6 Pt 2):S47-9
17084166
Endocr Relat Cancer. 2009 Dec;16(4):1139-55
19608712
N Engl J Med. 1995 May 25;332(21):1393-8
7723794
Jpn J Clin Oncol. 2004 Jan;34(1):20-8
15020659
Eur J Cancer Clin Oncol. 1985 Apr;21(4):453-8
4007016
J Clin Oncol. 2006 Jul 1;24(19):3089-94
16809734
Endocrinology. 2010 Aug;151(8):3514-20
20534728
Lancet. 2010 Apr 24;375(9724):1437-46
20398925
J Natl Cancer Inst. 1988 Sep 21;80(14):1138-47
3411627
Eur J Cancer Clin Oncol. 1988 Apr;24(4):659-66
3289945
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):259-70
18471784
Endocr Rev. 2005 May;26(3):361-79
15867098
Urology. 1997 Jan;49(1):71-8
9000189
Cancer Sci. 2006 Apr;97(4):243-7
16630114
J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):8-15
17611102
Endocrinology. 1999 Mar;140(3):1481-91
10067877
J Steroid Biochem Mol Biol. 2006 Jun;99(4-5):182-8
16621522
Urol Clin North Am. 1997 May;24(2):421-31
9126240
Cancer Res. 1997 Jan 15;57(2):314-9
9000575
Cancer. 1971 Aug;28(2):322-8
5566355
Clin Cancer Res. 2004 Nov 1;10(21):7121-6
15534082
Cancer Res. 2007 May 15;67(10):5033-41
17510436
J Urol. 1993 Mar;149(3):607-9
7679759
Nat Genet. 1995 Apr;9(4):401-6
7795646
N Engl J Med. 1989 Aug 17;321(7):419-24
2503724
Cancer Res. 2001 Apr 1;61(7):2892-8
11306464
BJU Int. 2006 Sep;98(3):573-9
16925756
Br J Urol. 1993 Nov;72(5 Pt 1):629-34
10071551
Urology. 2002 Jul;60(1):115-9
12100935
Urology. 1997 Apr;49(4):580-6; discussion 586-9
9111629
Int J Urol. 2006 Dec;13(12):1494-500
17118024
Clin Invest Med. 1982;5(4):267-75
6819101
J Urol. 2008 Oct;180(4):1438-43; discussion 1443-4
18710743
Nat Clin Pract Urol. 2009 Feb;6(2):76-85
19198621
Prostate Cancer Prostatic Dis. 1999 Jan;2(1):4-8
12496859
Nat Med. 2004 Jan;10(1):33-9
14702632
Prostate Cancer Prostatic Dis. 2009;12(3):241-6
19597531
Br J Urol. 1993 Nov;72(5 Pt 1):662-3
10071562
J Natl Cancer Inst. 1999 Nov 3;91(21):1869-76
10547394
J Urol. 1981 Sep;126(3):372-5
7277602
N Engl J Med. 1998 Oct 8;339(15):1036-42
9761805
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):207-21
18471780
Int J Urol. 2004 May;11(5):304-9
15147546
Cancer. 1984 Apr 1;53(7):1447-50
6697289
Endocr Relat Cancer. 2005 Mar;12(1):101-7
15788642
Endocrinology. 1988 Sep;123(3):1412-7
2969802
J Natl Cancer Inst. 2003 Jul 2;95(13):981-9
12837834
BJU Int. 2007 Jul;100 Suppl 2:48-51
17594360
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):373-88
18471793
Endocrinology. 1989 Jun;124(6):2745-54
2524377
Important Adv Oncol. 1985;:193-217
3916740
J Cell Biochem. 2004 Feb 15;91(3):483-90
14755679
Int J Urol. 2004 Apr;11(4):218-24
15028100
J Clin Oncol. 2010 Mar 20;28(9):1489-95
20159823
J Clin Oncol. 2005 Nov 10;23(32):8253-61
16278481
N Engl J Med. 2004 Oct 7;351(15):1488-90
15470210
J Steroid Biochem. 1989 May;32(5):695-8
2525654
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):303-15
18471788
Br J Cancer. 2004 Jun 14;90(12):2317-25
15150570
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):223-8
18471781
J Clin Oncol. 2008 Oct 1;26(28):4563-71
18645193
J Urol. 1993 Jan;149(1):77-82; discussion 83
7678043
N Engl J Med. 2010 Jul 29;363(5):411-22
20818862
J Steroid Biochem Mol Biol. 2009 Jan;113(1-2):52-6
19073258
Br J Urol. 1988 Apr;61(4):341-6
3289676
Adv Protein Chem. 2001;56:293-368
11329857
Mol Endocrinol. 1993 Dec;7(12):1541-50
8145761
Circulation. 2010 Feb 16;121(6):833-40
20124128
J Urol. 1996 Feb;155(2):620-3
8558675
Urology. 1997 Aug;50(2):309-13
9255312
Best Pract Res Clin Endocrinol Metab. 2008 Apr;22(2):293-302
18471787
J Clin Endocrinol Metab. 1986 Nov;63(5):1145-50
3489728
Prostate. 1986;8(3):293-300
3703748
Eur Urol. 1998;33(2):144-51
9519355
Endocrinology. 1969 Dec;85(6):1000-3
4242276
Science. 2009 May 8;324(5928):787-90
19359544
Cancer. 1996 Mar 1;77(5):934-40
8608487