KR20010001654A - Methods for Gene Treatment of Benign Prostatic Hyperplasia and its medical agent - Google Patents

Abstract

PURPOSE: A method and genetic therapeutic agent for curing BPH(Benign Prostatic Hyperplasia) is provided to dramatically inhibit the growth of the prostatic gland texture by giving medication to the prostatic gland texture with an adenovirus vector(Ad/OC/HSV-TK) including an HSV-TK(herpes simplex virus- thymidine kinase) gene and an osteocalcin promoter. CONSTITUTION: A method for curing a benign prostatic hyperplasia is a TUMAP(TransUrethral Molecular Ablation of Prostate) giving a genetic therapeutic agent to the prostatic gland texture using an ultrasound, wherein the genetic therapeutic agent includes an adenovirus vector(Ad/OC/HSV-TK) and a genetic therapeutic agent causing an apoptosis. The method for curing the benign prostatic hyperplasia is a TRMAP(TransRectal Molecular Ablation of Prostate) giving the genetic therapeutic agent to the prosatic gland texture using the ultrasound.

Description

Gene therapy for the treatment of enlarged prostate and its method {Methods for Gene Treatment of Benign Prostatic Hyperplasia and its medical agent}

The present invention relates to a gene therapy agent for the treatment of enlarged prostate and a method of treatment thereof.

In general, the prostate gland is the organ that produces the prostate fluid that becomes part of the semen to nourish and activate the sperm and protect against urinary tract infections. It is located just below the bladder and surrounds the urethra, which is the passage through which urine flows out of the bladder. do.

Benign Prostatic Hyperplasia (BPH) is a disease in which the prostate gland is abnormally enlarged, and especially after the 40s and 50s, the prostate enlarges, causing urinary tract to interfere with urine flow, thereby causing various urination disorders. If this is explained in more detail as follows.

Symptoms of urination abnormalities not only do not hold urine well, the urine stem is thin and weak, even if you try to urinate for a long time, or even after the urine remains (urine remains in the bladder) gradually urinate This stretched belly hurts, and also because the urine is often seen affects the kidneys, there is a problem that eventually leads to chronic kidney failure due to a decrease in kidney function.

In addition, the stagnant urine as described above has a problem that can easily cause complications, such as inflammation, stones by providing a good condition for the growth of bacteria in the prostate and urethra.

On the other hand, according to the recently released statistics of the prostate hypertrophy, as of 1995, 2,657,000 elderly people over 65 years of age accounted for 5.9% of the population. This is an increase of 2.1% of the total population, up 1.2 million from 1980's 1456,000 (3.8%). In addition, the average life expectancy of Koreans was 73.5 years in 1995 (male 69.5 years, female 77.4 years), which was 4.5 years longer than in 1985. Due to the rapid increase in elderly population, social interest in the welfare, health and quality of life of the elderly is increasing, and prostate hyperplasia is also due to the increase of elderly population, the increase of interest by information media, and the improvement of medical opportunities. That number is on the rise. In fact, statistics from the Korea Medical Insurance Association and Korea Medical Insurance Management Corporation increased 4.6 times compared to 10 years ago. According to the Korea Urology Association, 1,530 patients with prostate hyperplasia admitted to national training hospitals were in 1985 and 4166 in 1995. 2.7 times increased. The prostate hyperplasia is a benign tumor, and the cause and pathology of the disease have not yet been clearly identified. However, it is hypothesized that the male hormone called DHT is excessively produced due to age and the prostate enlarges.

These prostate hyperplasias are largely divided into surgical therapy, low-invasive treatment and drug therapy. Surgical treatment includes transurethral prostatectomy, laparotomy, and prostatectomy. Vascularization, laser prostatectomy, radiofrequency ablation, thermotherapy, hyperthermia, etc., pharmacotherapy, alpha-adrenergic receptor blockers, 5 alpha-reductase inhibitors that reduce the size of the prostate 5 alpha-receptor blockers and other common plant extracts to relax muscles surrounding the prostate.

However, surgical treatment has serious complications such as erectile dysfunction, retrograde ejaculation, urethral stenosis, urinary incontinence, and bleeding after surgery, and drug therapy also has side effects such as cardiovascular and central nervous system side effects, decreased libido, and decreased erection. In addition, there is a problem that can not expect a long-term treatment effect in addition to only a temporary symptom improvement effect in terms of treatment effect, which will be described in more detail as follows.

Transurethral resection of prostate (TURP) is a treatment that removes the prostate gland after dissecting a prosthesis with a resection loop and removes the prostate tissue. General anesthesia is essential, and patients with congenital diseases that cannot be anesthetized cannot undergo surgery. In particular, given that the majority of patients with prostatic hyperplasia are old, there is a problem that a large number of patients with prostatic hyperplasia are exposed to the risk of or during anesthesia.

In addition, after the operation, the catheter should be inserted for 5 days or more, and blood transfusion due to bleeding is required, and if the operation time is prolonged, complications such as nausea, vomiting, high blood pressure, and confusion are expected. In addition, a large number of erectile dysfunctions occur after surgery (about 10-20%), and sexual dysfunction of retrograde ejaculation, in which ejaculatory fluid is not ejected to the outside, as well as urinary incontinence and urethral narrowing due to urethral damage. Will be.

Transureth needle ablation (TUNA) is a method of applying high fever to the prostate using radiofrequency waves, and bleeding is less than that of TURP, but for a long time after the procedure While catheter attraction is essential, according to the enlarged area of the prostate gland, especially prostate hyperplasia close to the bladder neck is not only curable but also has a clinically ineffective therapeutic effect.

An object of the present invention is to solve the above-mentioned conventional problems, and in particular, to provide a gene therapy agent for the treatment of enlarged prostate and prostatic hyperplasia that can selectively remove prostate cancer cells associated with the enlarged prostate .

In addition, another object of the present invention is to provide a treatment method for the treatment of enlarged prostate gland which can be easily performed in the outpatient without side effects such as pain, bleeding, etc., and can selectively remove only prostatic hypertrophy tissue.

In order to achieve the above object, the therapeutic method for the treatment of prostate hyperplasia of the present invention is toxic thymidine kinase (TK: thymidine) in combination with acyclovir (ACV: acyclovir) using the osteocalcin gene expressed in benign prostatic hypertrophy tissue. It is characterized in that the Ad / OC / HSV-TK consisting of a recombinant adenovirus (Ad) vector including an OCase (osteocalcin promotor) that induces kinase.

In addition, the therapeutic method for the treatment of enlarged prostate of the present invention is characterized in that the gene therapy agent of the enlarged prostate gland is administered directly to the tumor of the enlarged prostate through the urethra and the rectum.

Figure 1 shows the recombination process of the present invention OC / HSV-TK.

Figure 2 shows the restriction map of the present invention Ad / OC / HSV-TK.

Figure 3 is an exemplary view showing a prostate hypertrophy treatment process of the present invention Ad / OC / HSV-TK.

Figure 4 is a conceptual diagram showing the principle of treatment of enlarged prostate of the present invention Ad / OC / HSV-TK.

Figure 5 is an exemplary view showing an embodiment of the present invention transurethral prostate molecule removal.

Figure 6 is an exemplary view showing an embodiment of the present invention transectal prostate molecular removal.

Figure 7 shows the apoptotic bodies in the prostatic glandular lumen of the prostate tissue after treatment of the present invention.

Figure 8 shows the cell death after treatment in other prostate tissue.

9 shows lymphocyte infiltration and progenitor cells of the prostate into prostate epithelial cells after treatment.

Hereinafter, with reference to the embodiment according to the technical idea of the gene therapy agent and the method for the treatment of the present invention configured as described above prostate hyperplasia will be described in detail. Figure 1 shows the recombination process of the present invention OC / HSV-TK, Figure 2 shows a restriction map of the present invention Ad / OC / HSV-TK, Figure 3 is the present invention of Ad / OC / HSV-TK Figure 4 is an exemplary view showing the treatment process, Figure 4 is a conceptual diagram showing the treatment principle of the present invention Ad / OC / HSV-TK, Figure 5 is an exemplary view showing an embodiment of the present invention, the urethral prostate molecular removal procedure, Figure 6 Exemplary diagram showing an embodiment of the present invention for the removal of transectal prostate molecules.

Gene therapy for the treatment of enlarged prostate of the present invention adenovirus vector comprising a herpes simplex virus thymidine kinase (HSV-TK) gene and OC promoter (osteocalcin promoter) to induce necrosis or apoptosis of prostate tissue (Ad / OC / HSV-TK), which will be described in more detail as follows.

The gene therapy agent for the treatment of prostate hyperplasia of the present invention is not only the adenovirus vector (Ad / OC / HSV-TK) gene therapy agent but also an OC promoter (osteocalcin promoter) in place of the herpes simplex virus thymidine kinase (HSV-TK) and Adenovirus vectors comprising a recombinant gene OC-p53, OC-CD, or PSA-p53, PSA-CD, PSA-HSA-TK, PSA-TNF, together with a Prostate Specific Antigen (PSA) gene, and Retrovirus vectors are used. In addition, non-viral vectors such as liposomes are used. In this case, the TNF is a tumor necrosis factor, CD is cytosine deaminase, HSA is human serum albumin, and p53 is a tumor suppressor gene.

In addition, the therapeutic method for the treatment of enlarged prostate of the present invention, as shown in Figure 5, by inserting the urethral bladder through the urethra simply and accurately the gene for causing the gene therapy or apoptosis (apoptosis) in the prostate tissue Transurethral Molecular Ablation of Prostate (TUMAP).

In addition, another prostatic hypertrophy treatment method of the present invention, as shown in Figure 6, by administering the gene therapy or apoptosis (apoptosis) to the prostate tissue using a rectal ultrasound through the rectum simply and accurately Transrectal Molecular Ablation of Prostate (TRMAP).

The following is more specifically described through the following embodiments of the present invention configured as described above. These examples are intended to illustrate the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1:

Recombinant Process of Ad / OC / HSV-TK

Recombination of the adenovirus vector (Ad / OC / HSV-TK) comprising the herpes simplex virus thymidine kinase (HSV-TK) gene and an OC promoter (os / calcium) is shown in FIG. ElSPl is digested with Hind III and treated with alkaline phosphatase. A portion of a Hind III digested 3.1 kb containing 1.3 kb OC promoter and 1.8 kb herpes simplex virus thymidine kinase (HSV-TK) therapeutic gene was coupled to p ?? ElSPl adenovirus vector using T4 ligase. . The p ?? ElSPl-Ad / OC / HSV-TK expression clone thus synthesized was centrifuged with CsCl ₂ , and then 5 μg of N- [1- (2,3 dioleoylosyl) propyl in 293 cells with pJM17. ] -N, N, N- trimethylammoniunnethyl sufate-mediated transfection method is used for cotransfection. Meanwhile, the 293 cell line is a human embryonic kidney cell line, which is stably converted to sheared adenovirus type 5 DNA to compensate for the deletion of the viral genome of a replication-deficient recombinant virus in which the Ela coding sequence has been removed, thereby recombining in culture conditions. Allow the virus to multiply. A culture of 293 cells showing complete cytopathic effect is collected and centrifuged for 10 minutes at a gravity of 1000 × g. Pooled supernatants are stored as primary viral stock at -80 ° C. The virus stock was again amplified in 293 cells, and the Ad / OC / HSV-TK clone was selected as a platelet purification method. One of the virus clones is collected again after 36-40 hours after amplification in the 293 cells, and pelletized to dissolve in phosphate buffered saline (PBS) solution to remove cell byproducts. . Virus present in the cell lysate is purified by CsCl ₂ gradient centrifugation. The concentrated virus is stored at −80 ° C. via dialysis, and the viral titer is determined by platelet assay. At this time, the base sequence of the Ad / OC / HSV-TK, as shown in Figure 3, AD5 is 1-367, HSV-TK is 368-2205, OC is 2206-3581, AD5 is 3581- 35923.

At this time, the OC promoter used in the present invention is a tissue-specific promoter primarily acting in osteoblasts, and in particular, bone metastasis of prostate cancer is an osteoblast type. Very high herpes simplex virus thymidine kinase (HSV-TK) following treatment with adenovirus vectors containing herpes simplex virus thymidine kinase (HSV-TK) induced by the OC promoter. Can represent potency. In particular, very high herpes simplex virus thymidine kinase (HSV-TK) following treatment with adenovirus vectors, including herpes simplex virus thymidine kinase (HSV-TK), which is induced by OC promoters in benign prostatic hypertrophy tissues. Prodrugs were identified by the use of an OC promoter, a prostate tissue-specific promoter that induces a herpes simplex virus thymidine kinase (HSV-TK), which confirms the titer and inhibits the proliferation of prostatic hypertrophy cells. After adding acyclovir (ACV), a prodrug, it inhibits DNA proliferation of prostatic hypertrophy cells and induces apoptosis, thereby enabling non-invasive molecular prostatectomy to treat patients with prostatic hyperplasia.

Example 2:

Transurethral Prostate Molecular Removal (TUMAP)

(1) Transrectal prostate examination, transrectal ultrasonography of the prostate, prostate specific antigen level and video-urethral cystoscopy to identify lesions of enlarged prostate The patient's prostate size, anatomy, anatomical abnormalities such as prostate cancer and lumbar stenosis are checked.

(2) The patient with confirmed prostatic hyperplasia is laid in a comfortable position on the urethra cystoscope table for urethral insertion.

(3) A local anesthetic synovial fluid (lidocain jelly) is administered to the urethra of the patient lying on the urethral bladder table.

(4) After inserting the urethroscope into the urinary tract of the synovial drug-administered patient, the prostate hypertrophy tissue was directly confirmed, and the anatomical structure of the prostate hyperplasia confirmed by the transectal ultrasonography as well as the vertices of the gene therapy product. See. At this time, the urethral prostate injector is directly inserted into the enlarged prostate tissue through a predetermined side hole of the urethoscope.

(5) The appropriate dose of gene therapy for prostatic hypertrophy molecular removal through the video augmentation system is 5 × 10 ¹⁰ plaque forming units (pfus) for Ad / OC / HSV-TK. As soon as the gene therapy agent melts at -80 ℃, the maximum volume of 0.3cc injection solution is made of phosphate buffered saline (PBS) or normal saline. Administration is by direct injection. If necessary, in addition to the medial prostatic hyperplasia of the bladder neck, an additional injection is given.

(6) Patients who have undergone prostatic hyperplasia receive acyclovir (ACV) from the day before the procedure to 7 days after the procedure. The acyclovir (ACV: acyclovir) is administered in the form of an oral tablet 200mg / Tab five times a day (5 tablets) for 21 days, patients can be taken orally without any discomfort. At this time, the acyclovir (ACV) is reduced to a dose of 75% when the number of absolute granulocytes (1000 / mm ³⁾ or platelets (platelets) is less than 100,000 / mm ³ in the blood test do.

(7) All patients will receive oral broad-spectrum antibiotics simultaneously before and after treatment for 3 days to prevent infection after urethral treatment.

Example 3:

Rectal Prostate Molecular Removal (TRMAP)

(1) Transrectal prostate examination, transrectal ultrasonography of the prostate, prostate specific antigen level and video-urethral cystoscopy to identify lesions of enlarged prostate The patient's prostate size, anatomy, anatomical abnormalities such as prostate cancer and lumbar stenosis are checked.

(2) The patient is placed left and right on the treatment table so that the rectal ultrasonography can be inserted into the rectum of the patient whose prostate hyperplasia has been identified.

(3) The prosthetic prosthetic injector is attached to the transesophageal ultrasonography and is injected directly into the prostate area of the patient lying on the treatment table with a gene therapy agent for precise prostate molecular removal under ultrasound guidance. At this time, the proper dose of the gene therapy product is 5 × 10 ¹⁰ plaque forming units (pfus) for Ad / OC / HSV-TK. A maximum volume of 0.3cc injection solution is made with phosphate buffered saline (PBS) or normal saline, and injected directly into six prostate sites, 3 places on one side of the prostate. If necessary, in addition to the medial prostatic hyperplasia of the bladder neck, an additional injection is given.

(4) Patients who have undergone prostatic hyperplasia receive acyclovir (ACV) from the day before the procedure to 7 days after the procedure. The acyclovir (ACV: acyclovir) is administered in the form of an oral tablet 200mg / Tab five times a day (5 tablets) for 21 days, patients can be taken orally without any discomfort. At this time, the acyclovir (ACV) is reduced to a dose of 75% when the number of absolute granulocytes (1000 / mm ³⁾ or platelets (platelets) is less than 100,000 / mm ³ in the blood test do.

(5) All patients will receive oral broad-spectrum antibiotics simultaneously before and after treatment for 3 days to prevent infection after urethral treatment.

Herpes simplex virus thymidine kinase (HSV-TK) present in high concentrations in cells of prostatic hypertrophy tissue by Ad / OC / HSV-TK administered directly to the prostate region of a patient with enlarged prostate by such a treatment method, 3 and 4, unlike cellular thymidine kinase, several, including guanosine analogue (ACV: acyclovir), other than thymidine Analogs (or homologues) can be phosphorylated, in particular acyclovir (ACV) in prostatic hypertrophic cells to the triphosphate form. At this time, triphosphated acyclovir (ACV: acyclovir) enters prostate hypertrophy cells instead of guanosine triphosphate during DNA synthesis, thereby inhibiting DNA synthesis of cells and killing prostatic hypertrophy cells, thereby treating prostatic hypertrophy. Have. In other words, the herpes simplex virus thymidine kinase (HSV-TK) phosphorylates acyclovir (ACV), a nucleoside analog (or homologue) analogue in prostate cells, at least 1000 times more than thymidine kinase in normal cells. Phosphorylated tricyclophosphorylation (ACV: acyclovir) can cause chain termination during prostatic hypertrophy DNA synthesis, which can kill prostatic hypertrophy cells. same.

After injection of the Ad / OC / HSV-TK therapeutic agent, if only about 10% of the prostatic hypertrophy cells are infected with the therapeutic agent, the treatment mechanism as shown in FIG. The prostate hypertrophy cells into which the herpes simplex virus thymidine kinase (HSV-TK) suicide-causing gene has been transferred, as well as the surrounding prostate hypertrophy cells which do not have this gene, die. That is, when acyclovir (ACV) is administered, the apoptotic vesicles generated in the prostatic hypertrophy cells into which the therapeutic agent of the present invention has been introduced have the surrounding herpes simplex virus thymidine kinase (HSV-TK) gene. Ingested by the missing prostate cells, the surrounding untreated cells also die. In addition, triphosphatated acyclovir (ACV) is introduced into the surrounding prostatic hypertrophy cells through a gap junction of prostatic hypertrophy cells to necrotic the prostatic hypertrophy cells to treat prostatic hyperplasia double. At this time, when the prostatic hypertrophy cells die, macrophage (macrophage), lymphocytes (lymhocyte) associated with the immune function is involved to induce immune function against prostatic hypertrophy cells, as well as simple herpes virus Timmy in blood vessels between the prostatic hypertrophy tissue Dean kinase (HSV-TK) suicide-causing genes have been introduced to damage the blood vessels of enlarged prostate tissues, which can lead to more effective prostatic hypertrophy treatment.

Biological test example:

In adult male rats (sprague-Dawley species), the herpes simplex virus thymidine kinase (HSV-TK) gene was administered directly, and gencyclovir (GCV) was administered twice daily for 20 days at 20 mg / kg of Kg. Conduct the experiment. The experiment was divided into 2 × 10 ⁹ pfu and 1 × 10 ⁹ pfu dosed Ad / OC / HSV-TK-administered groups, and the gene therapy agent was directly administered to the prostate tissue under microscopy. Subjects were divided into 1) normal control group, 2) gencyclovir (GCV) control group, 3) Ad / OC / HSV-TK control group, and 4) Ad / OC / HSV-TK + gencyclovir (GCV) gene therapy group. Observation of cytopathological changes such as cell cycle changes of prostate tissues, measurement of changes in weight (volume) of prostate tissues, and urinary kinetic tests after treatment were used to observe changes in urination function in rats. Done.

Biological test results:

As a result of the experiment, the prostate weight (volume) in the Ad / OC / HSV-TK + gencyclovir (GCV) treatment group was normal in phosphate buffered saline (PBS), as shown in Table 1 below. Biostatistic compared to prostate weight of control group (0.85 ± 0.05) as well as prostate weight of the Gencyclovir (GCV) control group (0.89 ± 0.06) and prostate weight of Ad / OC / HSV-TK control group (0.76 ± 0.04) As a very significant low figure. In particular, the high-dose ^{(2 × 10 9 pfu) Ad} / OC / HSV-TK / GCV Ad / OC / HSV-TK / from GCV treatment group, 0.49 in the group with prostate weight of 0.43 ± 0.02 low doses (1 × 10 ⁹ pfu) of It is lower than the prostate weight of ± 0.05.

In addition, cytopathology, as shown in Fig. 7 to 9, a large number of apoptosis of epithelial cells was observed in the Ad / OC / HSV-TK + gencyclovir (GCV) treatment group, lymphocytes Necrosis of prostate cells was observed with the appearance of. At this time, no urodynamic changes were observed in all treated rats.

Efficacy of Ad / OC / HSV-TK / GCV Therapy on Prostatic Hypertrophy in Biological Experiments Treatment period Treatment Sample Number of rats Prostate Weight (gm) Rat weight (gm) Day 0 - 3 0.48 ± 0.04 229 ± 10.9 50th day PBS 5 0.85 ± 0.05 353 ± 27.8 GCV 5 0.89 ± 0.06 345 ± 18.8 Ad / OC / HSV-TK 5 0.76 ± 0.04 345 ± 14.3 Ad / OC / HSV-TK / GCV (1 × 10 ⁹ pfu) 7 0.49 ± 0.05 349 ± 30.0 Ad / OC / HSV-TK / GCV (2 × 10 ⁹ pfu) 4 0.43 ± 0.02 350 ± 15.7

(Weight is the mean ± standard error.)

Meanwhile, the gencyclovir (GCV) is structurally different from acyclovir (ACV) due to the addition of a hydroxymethyl group, and due to this chain difference, acyclovir (ACV) Acyclovir is administered orally, intravenously, or topically to humans, whereas gencyclovir (GCV) is administered only by intravenous injection. In addition, both acyclovir (ACV) and gencyclovir (GCV) are commonly used in clinical practice for herpes virus infection, where acyclovir (ACV) has Because of its usability, it is used in in vitro and in vivo studies, whereas gencyclovir (GCV) is used for the activity analysis of TK.

As described above, the gene therapy agent for the treatment of prostatic hyperplasia of the present invention selectively inhibits the growth of benign prostate tissue in vivo and induces necrosis, which is very effective and stable to treat prostatic hyperplasia. Will be.

In addition, the gene therapy method for the treatment of prostatic hyperplasia of the present invention is a pain within a short period of time by simply and accurately administering the gene therapy agent as well as other gene therapy agents that may cause necrosis or apoptosis of prostate tissues directly and easily. And without the side effects such as bleeding will be effective to treat prostatic hyperplasia.

Claims (15)

Gene therapy for the treatment of prostate hyperplasia comprising the nucleotide sequence shown in the sequence listing. The method of claim 1, Adenovirus recombination vector (Ad / OC / HSV-TK) or retroviral recombination vector (Re / OC / HSV-TK) containing herpes simplex virus thymidine kinase gene and osteocalcin promoter. Gene therapy for the treatment. The method according to claim 1 or 2, Adenovirus genetic vector (Ad / PSA / HSV-TK) or retrovirus genetic vector (Re / PSA / HSV-TK) comprising the herpes simplex virus thymidine kinase gene and a prostate specific antigen promoter Gene therapy for the treatment of enlarged prostate. The method according to claim 1 or 2, Gene therapy for the treatment of prostatic hyperplasia, characterized in that the adenovirus recombination vector (Ad / OC / CD) or retro-virus recombination vector (Re / OC / CD) comprising the osteocalcin promoter and cytosine deaminoase . The method according to claim 3 or 4, Adenovirus recombination vector (Ad / PSA / CD) or retroviral recombination vector (Re / PSA / CD) comprising the prostate specific antigen promoter and cytosine deaminoase for the treatment of enlarged prostate Gene therapy. The method according to claim 1 or 4, Gene therapy for the treatment of enlarged prostate gland characterized in that the herpes simplex virus thymidine kinase gene and a liposome non-viral vector containing an osteocalcin promoter (Liposome / OC / HSV-TK). The method according to claim 1, wherein Gene therapy for the treatment of enlarged prostate gland characterized in that the herpes simplex virus thymidine kinase gene and a prostate specific antigen promoter (Liposome / HSA / HSV-TK). The method according to claim 1 or 4, Gene therapy for the treatment of prostatic hyperplasia, characterized in that the liposome non-viral vector (Liposome / OC / CD) comprising the osteocalcin promoter and cytosine deaminoase. The method of claim 5, Gene therapy for the treatment of enlarged prostate, characterized in that the prostate specific antigen promoter and liposome non-viral vector (Liposome / PSA / CD) comprising a cytosine deaminoase. The method according to claim 1 or 2, Gene therapy for the treatment of prostatic hyperplasia, characterized in that the liposome non-viral vector (Liposome / OC / p53) comprising the osteocalcin promoter and p53 tumor suppressor gene. The method of claim 5, Gene therapy for the treatment of prostatic hyperplasia, characterized in that the prostate specific antigen promoter and liposome non-viral vector (Liposome / PSA / p53) comprising a p53 tumor suppressor gene. In the method of treating prostatic hyperplasia, Treatment method for the treatment of enlarged prostate gland, characterized in that the urethral bladder is inserted through the urethra and simply and precisely administered a therapeutic agent to the prostate tissue (TUMAP). The method of claim 12, A therapeutic method for the treatment of enlarged prostate gland, characterized by administering a therapeutic agent by inserting the urethral prostate injector directly into the enlarged prostate tissue. In the method of treating prostatic hyperplasia, Treatment method for the treatment of prostatic hyperplasia, characterized in that the use of transrectal ultrasound through the rectum to simply and accurately administer the therapeutic agent to the prostate tissue. The method of claim 14, A method for the treatment of enlarged prostate, characterized in that to administer a therapeutic agent by inserting a prosthetic prostate injector directly into the prostatic hypertrophy tissue.