Molecular endocrinology of target enzymes in androgen metabolism : implications for prostate cancer
Author: Söderström, Torbjörn
Date: 2001-03-23
Location: Föreläsningssalen C1-87, Norra Hallen 7, plan 8, Huddinge Universitetssjukhus
Time: 9.00
Department: Institutionen för medicinsk laboratorievetenskap och teknik / Department of Laboratory Sciences and Technology
View/ Open:
thesis.pdf (726.1Kb)
Abstract
Genes that are responsible for variations in drug and hormonal responses
are sometimes also associated with the pathophysiology of diseases.
Understanding the aetiology of a disease is often essential for the
design of effective drugs. Androgens are implicated in the development of
prostate cancer and benign prostate hyperplasia (BPI]). This study aimed
at characterising the therapeutic target enzymes steroid 5alpha-reductase
1 and 2 and the steroid metabolising enzyme cytochrome P450 1B I in
relation to prostate cancer in order to gain a better view of the
prostate tumor biology.
The conversion of testosterone to the more potent metabolite dihydrotestosterone by steroid 5alpha-reductase 2 is a key mechanism in the action of androgens in the prostate. The 5alphareductase 2 specific messenger RNA (mRNA) levels were measured in 50 biopsies obtained from 31 Caucasian outpatients, using a solution hybridization method. Significant differences were observed between cancerous and noncancerous tissues. The median 5alpha- reductase 2 mRNA level in noncancerous tissue was 3.4 times higher than in cancerous specimens. 5alpha-reductase 2-specific gene expression and enzyme activity was further measured in 30 prostatic tissue specimens from 15 Caucasian patients. The enzyme activity at pH 5.5 was significantly correlated to the 5alpha-reductase 2-specific mRNA expression as measured by reverse-transcription PCR (RS=0.81). This association makes it possible to predict prostatic 5alpha-reductase 2 activity using core needle biopsies.
In order to elucidate the role of 5alpha-reductase 2 polymorphisms, we performed a population based case control study in 176 Caucasian prostate cancer patients and 161 healthy controls of the importance of the V89L and A49T polymorphisms for the risk of prostate cancer, in relation to age and tumor characteristics. Carriers of the LL genotype were at increased risk of bone metastases at the time of diagnosis compared to the combined groups of individuals with VL or VV genotypes, OR 5.67 (95 % CI 1.44-22.30), when adjusted for age, differentiation grade, T-stage and PSA. Heterozygous prostate cancer cases carrying the AT genotype were significantly younger than cases harboring the AA genotype (mean age 66 vs 71 years).
In the same patient material, the CYP1B1 V432L polymorphism was studied in relation to risk of prostate cancer and tumor characteristics. Carriers of the CYP1B1 432 LL genotype had a higher risk of metastases at the time of diagnosis compared to individuals with VL or VV genotypes, (OR 2.46, 95 % C.I 1.02-5.93) when adjusted for age, differentiation grade, Tstage and PSA. These findings may contribute to further understanding of the etiology of prostate cancer metastases.
The conversion of testosterone to the more potent metabolite dihydrotestosterone by steroid 5alpha-reductase 2 is a key mechanism in the action of androgens in the prostate. The 5alphareductase 2 specific messenger RNA (mRNA) levels were measured in 50 biopsies obtained from 31 Caucasian outpatients, using a solution hybridization method. Significant differences were observed between cancerous and noncancerous tissues. The median 5alpha- reductase 2 mRNA level in noncancerous tissue was 3.4 times higher than in cancerous specimens. 5alpha-reductase 2-specific gene expression and enzyme activity was further measured in 30 prostatic tissue specimens from 15 Caucasian patients. The enzyme activity at pH 5.5 was significantly correlated to the 5alpha-reductase 2-specific mRNA expression as measured by reverse-transcription PCR (RS=0.81). This association makes it possible to predict prostatic 5alpha-reductase 2 activity using core needle biopsies.
In order to elucidate the role of 5alpha-reductase 2 polymorphisms, we performed a population based case control study in 176 Caucasian prostate cancer patients and 161 healthy controls of the importance of the V89L and A49T polymorphisms for the risk of prostate cancer, in relation to age and tumor characteristics. Carriers of the LL genotype were at increased risk of bone metastases at the time of diagnosis compared to the combined groups of individuals with VL or VV genotypes, OR 5.67 (95 % CI 1.44-22.30), when adjusted for age, differentiation grade, T-stage and PSA. Heterozygous prostate cancer cases carrying the AT genotype were significantly younger than cases harboring the AA genotype (mean age 66 vs 71 years).
In the same patient material, the CYP1B1 V432L polymorphism was studied in relation to risk of prostate cancer and tumor characteristics. Carriers of the CYP1B1 432 LL genotype had a higher risk of metastases at the time of diagnosis compared to individuals with VL or VV genotypes, (OR 2.46, 95 % C.I 1.02-5.93) when adjusted for age, differentiation grade, Tstage and PSA. These findings may contribute to further understanding of the etiology of prostate cancer metastases.
List of papers:
I. Bjelfman C, Soderstrom TG, Brekkan E, Norlen BJ, Egevad L, Unge T, Andersson S, Rane A (1997). "Differential gene expression of steroid 5 alpha-reductase 2 in core needle biopsies from malignant and benign prostatic tissue. " J Clin Endocrinol Metab 82(7): 2210-4
Pubmed
II. Soderstrom TG, Bjelfman C, Brekkan E, Ask B, Egevad L, Norlen BJ, Rane A (2001). "Messenger ribonucleic acid levels of steroid 5 alpha-reductase 2 in human prostate predict the enzyme activity. " J Clin Endocrinol Metab 86(2): 855-8
Pubmed
III. Soderstrom T, Wadelius M, Andersson SO, Johansson JE, Johansson S, Granath F, Rane A (2002). "5alpha-reductase 2 polymorphisms as risk factors in prostate cancer. " Pharmacogenetics 12(4): 307-12
Pubmed
IV. Soderstrom TG, Wadelius M, Lundgren S, Andersson SO, Johansson JE, Johansson S, Granath F, Rane A (2001). "Association of CYP1B1 V432L polymorphism with prostate cancer metastases." (Manuscript)
I. Bjelfman C, Soderstrom TG, Brekkan E, Norlen BJ, Egevad L, Unge T, Andersson S, Rane A (1997). "Differential gene expression of steroid 5 alpha-reductase 2 in core needle biopsies from malignant and benign prostatic tissue. " J Clin Endocrinol Metab 82(7): 2210-4
Pubmed
II. Soderstrom TG, Bjelfman C, Brekkan E, Ask B, Egevad L, Norlen BJ, Rane A (2001). "Messenger ribonucleic acid levels of steroid 5 alpha-reductase 2 in human prostate predict the enzyme activity. " J Clin Endocrinol Metab 86(2): 855-8
Pubmed
III. Soderstrom T, Wadelius M, Andersson SO, Johansson JE, Johansson S, Granath F, Rane A (2002). "5alpha-reductase 2 polymorphisms as risk factors in prostate cancer. " Pharmacogenetics 12(4): 307-12
Pubmed
IV. Soderstrom TG, Wadelius M, Lundgren S, Andersson SO, Johansson JE, Johansson S, Granath F, Rane A (2001). "Association of CYP1B1 V432L polymorphism with prostate cancer metastases." (Manuscript)
Issue date: 2001-03-02
Rights:
Publication year: 2001
ISBN: 91-89428-12-9
Statistics
Total Visits
Views | |
---|---|
Molecular ...(legacy) | 567 |
Molecular ... | 103 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Molecular ... | 2 | 0 | 0 | 0 | 0 | 1 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 354 |
thesis.pdf | 278 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 298 |
Sweden | 61 |
China | 56 |
Germany | 48 |
South Korea | 17 |
Denmark | 9 |
Finland | 8 |
United Kingdom | 8 |
Russia | 8 |
Ireland | 7 |
Top cities views
Views | |
---|---|
Sunnyvale | 42 |
Beijing | 22 |
Romeo | 21 |
Kiez | 17 |
Seoul | 16 |
Stockholm | 9 |
Ballerup | 7 |
Hsinchu | 7 |
Dublin | 6 |
London | 6 |