[Steroid and xenobiotic receptor (SXR), multidrug resistance gene (MDR1) and GSTs, SULTs and CYP polymorphism expression in invasive bladder cancer, analysis of their expression and correlation with other prognostic factors].
BACKGROUND
Steroid and Xenobiotic Receptor (SXR) has demonstrated its activation by numerous drugs, including cytochrome P450 potent inducers like rifampicina or cotrimazol. The role of SXR is well known, and lies regulating in a positive manner cytochrome P450 3A4 (CYP3A4) transcription and the multidrug resistance gene (MDR1), it's considered a key in the xenobiotic detoxification mechanism, being involved in all phases of the detoxification process. Enzymes involved in Policyclic Aromatic hidrocarbures (PAH) metabolism and degradation are polymorphic in humans, including glutation S-transferases (GSTs), N-acetiltransferases (NATs), sulfotransferases (SULTs)1A1 and cytochrome p450 (CYP)1B1.


OBJECTIVE
The objectives we've planned are: 1. Analyze the expression of the transcription factor SXR and MDR1 in bladder by means of RT-PCR real time, both in normal bladder and in tumoral bladder. 2. Analyze the relation between clinical and pathological factors with the expression of SXR and MDR1. 3. Analyze the expression of the polymorphims CYP1B1, GSTM1 GSTT1 and SULT1A1 and their correlation with different clinic-pathological and molecular factors.


METHODS
In a prospective way the size of the sample was estimated. In 67 patients from two institutions (Hospital Universitario Miguel Servet (49 HUMS) and Clinica Universitaria de Navarra (18 CUN)), diagnosed of invasive bladder cancer and treated by means of radical cystectomy, were determined the expression of both SXR and MDR1 by means of real time PCR, as well as the polymorphisms CYP1B1, GSTM1 GSTT1 y SULT1A1 by means of RFLP (Restriction fragment length polymorphism). Correlations with other prognostic factors by contingency tables were performed.


RESULTS
Average follow up was 23.7 months with a median of 28.26 months. Of the 67 patients studied, 31 patients (46.3) presented disease progression, in form of local recurrence or in distant metastasis or both. With a average time to progression of 12.4 months and a median of 10 months, with a range of 1.1 month to 31.9 month. 36 patients (53.7%) did not have any evidence of disease progression during follow up. The Steroid and Xenobiotic Receptor as well as the Multidrug Resistance Gene (MDR1) are expressed in both normal bladder (0.94DeltaCt y 0.94DeltaCt) and tumoral bladder in the cystectomy specimen (1.09 DeltaCt y 0.45 DeltaCt). We've analyzed their expression in a quantitative manner and in a qualitative manner. The expression of SXR correlates with the presence of ca. in situ (p=0.024), vasculo-lymphatic invasion (p=0.05) mean while MDR1 correlates with presence of vasculo-lymphatic invasion (p=0.05) Both factors are correlate between each others (p=0.011). Polymorphisms: CYP1B1, GSTM1, GSTT1 and SULT1A1, are expressed in these patients but their expression doesn't correlates with any prognostic factor


CONCLUSIONS
Both SXR and MDR1 are expressed in normal bladder as well as in tumoral bladder. And their expression correlates with different prognostic factors with influence in the survival described in the literature.
Rioja Zuazu
J
J
Departamento de Urología, Clínica Universitaria, Universidad de Navarra, Pamplona. jriojazu@gmail.com
Bandrés Elizalde
E
E
Rosell Costa
D
D
Rincón Mayans
A
A
Zudaire Bergera
J
J
Gil Sanz
M J
MJ
Rioja Sanz
L A
LA
García Foncillas
J
J
Berián Polo
J M
JM
D000368:Aged; D000369:Aged, 80 and over; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D011379:Prognosis; D011446:Prospective Studies; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D015238:Sulfotransferases