The Journal of Urology
Volume 172, Issue 6, Part 1 , Pages 2483-2484, December 2004

RE: INFLAMMATION AS A TARGET FOR PROSTATE CANCER CHEMOPREVENTION: PATHOLOGICAL AND LABORATORY RATIONALE

Department of Urology; New York Presbyterian/Weill Cornell Medical College; 115 E. 61st St., 11th Floor; New York, New York 10021

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To the Editor 

Prostate cancer has minimal steroid 5α-reductase (5αR) activity in low grade disease (Gleason 2 to 6) and no activity in high grade disease (Gleason 7 to 10).1 Finasteride blocks steroid 5αR. One of the conclusions of the Prostate Cancer Prevention Trial was “…[finasteride] increased the risk of high-grade prostate cancer (Gleason Grade 7, 8, 9, 10).”2

Dietary fats decrease the activity of 5αR and the conversion of testosterone (T) to dihydrotestosterone (DHT).3 Fair demonstrated in the LNCaP prostate cancer nude mouse model that decreasing fat from 40% to 2.8% stops the growth of implanted lymph node positive cancer (LNCaP-5αR positive).4 Blocking fatty acid synthetase (FAS) in the nude mouse model halts the growth of PC-3 (FAS+++) more than LNCaP (FAS+), and is reversed by palmitate, the end product of FAS and the most potent fatty acid inhibitor of 5αR3.3, 5

Japanese men have low DHT and low 5αR. The Japanese incidental (autopsy) prostate cancer rate is the same as that for United States males and high risk black males but the clinical prostate cancer rate is low for Japanese men in Japan. In first generation Japanese men in the United States with a high fat, Western diet prostate cancer death rate increased from 1.7 to 12.9 per 100,000, the same rate as in Western males.6, 7 Obesity (body mass index [BMI] 30 or greater) was an independent predictor of higher Gleason grade cancer (p <0.001) and was associated with a higher risk of biochemical recurrence after radical prostatectomy (p = 0.027). Black men had higher BMIs (p <0.001) and higher recurrence rates (p <0.003) compared with white men.8 Epidemiological studies show a direct correlation of dietary fat to clinical prostate cancer deaths (40 different countries from low risk Asia to moderate risk Latin America to high risk United States and Europe).7

The incidental (autopsy) prostate cancer rate is the same in low risk (Asian) and high risk (black) men. The difference in clinical prostate cancer rates can be explained by the genetic variation in 5αR activity (as well as diet).6 One amino acid substitution at V89L in the SR5A2 gene coding for 5αR decreases 5αR activity. Such mutations are found predominantly in black men.9 Luo et al found “consistently decreased expression of SRD5A2 was observed in 25 prostate cancer samples when compared to 25 matched normal samples and nine [benign prostatic hyperplasia] samples.”1

Finasteride blocks steroid 5αR and the conversion of T to DHT. Blocking the conversion of T to DHT increases cellular T, decreases cellular DHT and increases cellular estrogen (E).10 These changes in cellular E/DHT affect the autocrine factors in prostate epithelial cells such as androgen receptor, caspase 3, etc and the paracrine factors in prostate stromal cells such as tumor growth factor, vascular endothelial growth factor, etc. These changes secondary to low 5αR activity explain many of the observations concerning androgen receptors, growth factors, and E stimulated “inflammatory proliferation” of prostate epithelial cells at the primary site of origin of prostate cancer.11, 12, 13 The posterior lateral lobe of the prostate is the site of origin of 95% of the prostate cancers, develops from the urogenital sinus with the confluence of wolffian (testosterone) and mullerian (estrogen) elements, and has estrogen receptors that have been imprinted during the embryogenesis of the prostate.

In obesity the adipose tissue has aromatase that produces increased serum E, which down-regulates the hypothalamic-pituitary-gonadal axis and decreases serum T. Blocking the steroid aromatase conversion of T to E with anastrozole decreased serum estradiol in obese (BMI greater than 35) infertile men from 46.0 to 28.9 pg/ml (p <0.001), and increased serum testosterone from 295 to 445 mg/dl without increasing bone turnover or osteoporosis of estrogen deprivation.14, 15

Blocking the steroid aromatase conversion of T to E avoids the weak agonist effects of estrogen receptor blockers such as tamoxifen (endometrial cancer [male breast cancer?] and thromboembolism).12, 16 Blocking the steroid aromatase conversion of T to E by anastrozole may prevent the promotion of high grade prostate cancer resulting from the low steroid 5αR activity secondary to genetic, epigenetic, dietary, pharmacological or environmental factors.

Respectfully,

W. Reid Pitts, Jr.

Department of Urology

New York Presbyterian/Weill Cornell Medical College

115 E. 61st St., 11th Floor

New York, New York 10021

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REFERENCES 

  1. Luo J , Dunn TA , Ewing CM , Walsh PC , Isaacs WB . Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate cancer . Prostate . 2003;57:134
  2. Thompson IM , Goodman PJ , Tangen CM , Lucia MS , Miller GJ , Ford LG , et al.   The influence of finasteride on the development of prostate cancer . N Engl J Med . 2003;349:215
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  7. Carroll KK , Khor HT . Dietary fat in relation to tumorigenesis . Prog Biochem Pharmacol . 1975;10:308
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  9. Reichardt JK , Makridakis N , Henderson BE , Yu MC , Pike MC , Ross RK . Genetic variability of the human SRD5AZ gene: implications for prostate cancer risk . Cancer Res . 1995;55:3973
  10. Lemack GE , Poppas DP , Vaughan ED . Urologic causes of gynecomastia: approach to diagnosis and management . Urology . 1995;45:313
  11. de Marzo AM , Marchi VL , Epstein JI , Nelson WG . Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis . Am J Pathol . 1999;155:1985
  12. Coffey DS . Similarities of prostate and breast cancer: evolution, diet, and estrogens . Urology . 2001;57(suppl):31
  13. Chang SM , Chung LW . Interaction between prostatic fibroblast and epithelial cells in culture: role of androgen . Endocrinology . 1989;125:2719
  14. Raman JD , Schlegel PN . Aromatase inhibitors for male infertility . J Urol . 2002;167:624
  15. Scherr D , Pitts WR , Vaughan ED . Diethylstilbestrol revisited: androgen deprivation, osteoporosis and prostate cancer . J Urol . 2002;167:535
  16. Steiner MS , Raghow S , Neubauer BL . Selective estrogen receptor modulators for the chemoprevention of prostate cancer . Urology . 2001;57(suppl):68

 J Urol, part 2, 171: S30–S35, 2004

PII: S0022-5347(05)61446-2

doi:10.1097/01.ju.0000144062.31241.c3

Refers to article:

  • Inflammation as a Target for Prostate Cancer Chemoprevention: Pathological and Laboratory Rationale

    M. SCOTT LUCIA, KATHLEEN C. TORKKO
    The Journal of Urology February 2004 (Vol. 171, Issue 2, Supplement, Pages S30-S35)

The Journal of Urology
Volume 172, Issue 6, Part 1 , Pages 2483-2484, December 2004

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