Dutasteride and finasteride have chemopreventive and chemotherapeutic effect on prostate cancer?

Dutasteride and finasteride have chemopreventive and chemotherapeutic effect on prostate cancer?

Marcello Henrique Araujo Da Silva ¹; Caio Lima Correa ²; João Henrique Reis Duque Estrada ².

¹ Master in Science – State University of Rio de Janeiro.

² Graduation students of Medicine of the State University of Rio de Janeiro.

Correspondence to:

Marcello Henrique Araujo Da Silva – Urogenital Research Unit – UERJ

Av. 28 de Setembro, 87, Fundos, Vila Isabel, Rio de Janeiro, RJ, Brazil.

CEP: 20551-030

Phone: +55 21 97419-1464.

E-mail: [email protected]

Abstract about prostate cancer

Prostate cancer shows increasing numbers each year in Brazil. In recent years there has been much discussion about the use of 5-alpha-reductase inhibitors for treatment with prostate cancer. Typically, 5-alpha-reductase inhibitors are prescribed for the treatment of benign prostatic hyperplasia. The best-selling 5-alpha-reductase inhibitors in the world are dutasteride and finasteride. The purpose of this study was to verify whether treatment with dutasteride or finasteride actually works in the treatment of prostate cancer. We conducted a literature review of the last 10 years on the use of dutasteride and finasteride in the treatment of prostate carcinoma, and we used 63 scientific articles indexed in the PubMed research base, published between 2006 and 2016. Further studies should be developed whether the use of 5-alpha reductase inhibitors works for regression of prostate cancer. So we should remember that conventional therapy should not be ruled out. To prevent the appearance of prostate cancer, Cialis is used, it has proven effective treatment with prostate problem.

Keywords: Dutasteride; Finasteride, prostate cancer.

Introduction

Prostate cancer is the second most common type of carcinoma that affects men. One of the safe diagnostic method to prostate cancer is dosing the serum PSA (Prostate Specific Antigen). PSA is produced by prostatic cells, but when they are lised by hyperplastic and carcinogenic processes, antigen extravasations occurs to the blood flow, raising the serum PSA level. A healthy men has up to 2.5 ng/ml of serum PSA. Proportion between 2.5 and 10 ng/ml estimate the risk of cancer by 25%, and request for a fractionated PSA test is already required. If it exceeds 10 ng/ml, the risk rises to 50% 1.

A histopathological scale of prostate cancer, called the Gleason system, was developed to analyze and describe the tumor growth rate. This system has a scale of 1 to 10, with Gleason 1 being the lowest. In Gleason 2 to 4, there is about a 25% chance of cancer spreading out of the prostate in 10 years. In the 5 to 7, this chance of spreading is increased to 50%, with damage to the other organs and decrease of survival rate. At 8 to 10, there is about 75% chance of spreading out. Approximately 70% of prostate biopsies realized are unnecessarily, and often, repeatedly – because of mis-analysis of the PSA’s levels, that is not, even being high, indicative for biopsies2-3.

The angiogenic process in tumorigenesis is of extremely importance for its growth, as well as biochemical changes of membrane. By altering the expression of cell-cell and cell-matrix adhesion proteins and signaling patterns, it allows the establishment of focal adhesions, which increase metastatic capacity 4-6.

Because of the high metabolic rate of tumor cells, there is an increase of oxygen and nutrient supply necessity. Thus, good vascularization, even if chaotic, is essential for accelerated and disorganized growth in carcinogenic processes. The main human angiogenic agent is vascular endothelial growth factor (VEGF). There are several types of VEGF, such as B, C, D and E, with VEGF-A being the most important. This factor has four subtypes derived from alternative splicing, and binds to two types of specific receptor tyrosine kinase, VEGFR1 and VGFR2, important in the angiogenic response, involving proliferation, survival, migration and permeability of angioblasts. Hyper expression of VEGF-A is suggested to be involved with retinopathy, tumor growth and metastasis, arthritis and atherosclerosis 7.

Another agent is the factor induced by hypoxia-1 (HIF-1). This is characterized by being a transcriptional factor sensitive to O2 pressure that can regulate angiogenesis genes, cell proliferation and survival, glucose and iron metabolism, and actions such as metastasis and invasion. The resulting proteins may either raise O2 supply or depress its consumption. Hypoxia is very common inside tumors because of the chaotic organization of tumor cells and abnormal angiogenesis 8.

Currently there are several treatments for prostate cancer, and one of the forms of pharmacological treatment has been gaining visibility in the last 10 years: the use of 5-alpha-reductase enzyme inhibitors, drugs commonly used to treat benign prostatic hyperplasia 9-10.

The 5-alpha-reductase enzyme occurs in three different isoforms in  human body: the type 1 isoform, found in whole body and in a lower concentration in the urogenital system, type 2, found in greater concentration in the urogenital tract and capillary follicles, and type 3, found in the pancreatic islets. Type 1 and type 2 isoforms are the predominant in normal prostatic tissue, in BPH, and in prostate cancer 11.

The two inhibitors of 5-alpha-reductase marketed in Brazil are dutasteride and finasteride. Dutasteride is an inhibitor of the type 1 and type 2 isoforms, whose recommended dose is 0.5 mg / day, with oral bioavailability of 60%, binding to plasma proteins of 99.5%, peak serum concentration in 2-3 hours , half-life of 5 weeks and inhibition of serum concentrations of dihydrotestosterone (DHT) by about 90%. Finasteride is a type 2 isoform inhibitor, whose recommended dose is 5.0 mg / day, with oral bioavailability of 63%, plasma protein binding of 90%, peak serum concentration in 1-2 hours, half-life of 6 hours and inhibition of serum DHT concentrations by about 70% 12-16.

Studies indicate that the use of these drugs decreases VEGF, reducing its expression and the appearance of new vessels in prostate carcinoma, improving the prognosis of the patient. Furthermore, they inhibit the conversion of testosterone to DHT, reducing proliferative and migratory rates and increasing apoptotic by depression of androgenic metabolism, which is already known for its intrinsic correlation in prostate carcinogenesis 17.

Dutasteride reduces the density of arterioles and venules in the prostate as well as the expression of VEGF and HIF-1α in human prostatic tissues 18-20. In prostate carcinoma cultures it has been concluded that dutasteride is effective in inhibiting uncontrolled cell growth and stimulation of apoptosis21-22. In addition, dutasteride affects the metabolism involved in the cytoskeleton and the cell cycle 23.

Dutasteride delays the biochemical progression of prostate cancer in patients with biochemical failure who has undergone aggressive treatment for localized diseases 24; decreases the risk of precursor lesions such as high-grade intraepithelial prostatic neoplasia by 39.2%, but when given 0.5mg / day for 3 years it has not been shown to reduce the detection of prostate cancer 25. Dutasteride also has an effect of prostatic inflammatory attenuation contributing to the improvement of the characteristic urinary symptoms, besides reducing the prostate volume 26. The treatment also reduces the serum PSA level by 38.64%.

Much is said about the efficacy of finasteride (5mg / kg / day) in relation to the carcinoma in question. One study found out that there was a decrease in the relative risk of 24.8% in the prevalence of prostate cancer 29. In another, it has been understood that finasteride decreases the risk of prostate cancer by 25%, and it has increased the effectiveness of the detection, as well as the PSA’s sensitivity  to cancer in general and also to the advanced causes. It also increased the sensitivity of the digital rectal exam, and accuracy in oncological gradation 30.

Finasteride has as one of the main actions the decrease of the volume and prostatic atrophy. It does this by increasing more than twofold when compared to the basal rate, the apoptosis rate of the peripheral and transitional area of the prostate, however, having little effect on the stroma. It is known to decrease PSA twice in epithelial cells, and to have anti-angiogenic, apoptotic function, and also to improve the cancer screening through PSA analyzes, reducing the risk of developing it even with strategies for early detection 31- 38.

One study identified the effects of finasteride on each Gleason level alone. It found that in Gleason 5 there was a 58% reduction in the prevalence of cancer; in Gleason 6, a reduction of 52% and, in Gleason 7, a reduction of 22% 2. Caspase expression, an indicator of apoptosis, is significantly lower in Gleason 4 when compared to 3. Therefore there is a divergence of results in the cases of advanced cancer and the initial ones 39.

Dutasteride is more efficient than finasteride in reducing PSA levels and prostate volume, in addition to better inhibition of androgen receptors 18; 31; 40. However, both are able to bind to androgenic receptors competing with DHT and testosterone by its conformational and chemical similarity, in addition to exerting its known inhibitory function of 5-alpha-reductase.

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By Dr. Ravi Mootha, M.D. On: June 03, 2019 at 08:34:12