Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the long-term safety and efficacy of Ad-OC-TK (recombinant adenoviral vector carrying an osteocalcin promoter-driven herpes simplex virus thymidine kinase gene) plus VAL (valacyclovir) gene therapy for hormone-refractory prostate cancer. Ad-OC-TK/VAL therapy is the first in vivo adenovirus-mediated gene therapy to be used to treat metastatic prostate cancer, including bone metastasis. Six patients were enrolled in this trial, and two doses of Ad-OC-TK (2.5 x 10(9) or 2.5 x 10(10) plaque-forming units) were injected into locally recurrent tumor or bone metastasis on day 1 and day 8. Patients were also given VAL (3 g/day) for 21 days. Safety and efficacy were evaluated for at least 8 months in each patient. All patients tolerated this therapy with no serious adverse events. One prostate-specific antigen (PSA) response (from 318.3 to 4.9 ng/ml) was observed with a time to PSA progression (TTP) of 12 months. Docetaxel (30 mg/m2 per week) and estramustine (560 mg/day) combination chemotherapy (DE) was given to three docetaxel-naive patients on PSA failure after gene therapy. All three patients had a PSA response to DE therapy with 21, 7, and 4 months of TTP. These results suggest that additional trials are warranted.
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PMID:Long-term outcome of phase I/II clinical trial of Ad-OC-TK/VAL gene therapy for hormone-refractory metastatic prostate cancer. 1802 Oct 19

Many cancers can cause disability and pain by invading nerves. In particular, prostate carcinoma has a high propensity for neural invasion (NI) at an early stage. Attempted surgical treatment of tumors with NI often leads to erectile dysfunction and deteriorated quality of life. Therefore, there is a need for novel modalities that will selectively target cancer cells while preserving neural function. Herpes simplex viruses (HSVs) have a natural trophism for peripheral nerves. We hypothesized that oncolytic therapy using HSV engineered to minimize neurotoxicity would be appropriate for this clinical setting. Attenuated HSV (NV1023) injected to sciatic nerves of nude mice had no toxic effect on nerve function (n=30). NV1023 had significant oncolytic effect on prostate carcinoma cells (PC3, DU145, and LNCap) in vitro. An in vivo model of NI was established by implanting prostate carcinoma cells in the sciatic nerves of nude mice. Mice were treated with NV1023 or saline 7 days after establishment of tumors. Significant reduction in tumor size and inhibition of NI was found 6-8 wk after treatment (P<0.005). All animals treated with saline developed complete paralysis <5 wk post-treatment, whereas most NV1023-treated animals had preserved nerve function >12 wk after treatment (P<0.0001). We conclude that oncolytic therapy effectively treats prostate carcinomas with NI in an in vivo murine model while preserving neural function. These findings may hold significant clinical implications for patients with prostate cancer or other neurotrophic tumors.
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PMID:Attenuated multimutated herpes simplex virus-1 effectively treats prostate carcinomas with neural invasion while preserving nerve function. 1823 72

Effective treatment for recurrent, disseminated prostate cancer is notably limited. We have developed adenoviral vectors with a prostate-specific two-step transcriptional amplification (TSTA) system that would express therapeutic genes at a robust level to target metastatic disease. The TSTA system employs the prostate-specific antigen (PSA) promoter/enhancer to drive a potent synthetic activator, which in turn activates the expression of the therapeutic gene. In this study, we explored different configurations of this bipartite system and discovered that physical separation of the two TSTA components into E1 and E3 regions of adenovirus was able to enhance androgen regulation and cell-discriminatory expression. The TSTA vectors that express imaging reporter genes were assessed by noninvasive imaging technologies in animal models. The improved selectivity of the E1E3 configured vector was reflected in silenced ectopic expression in the lung. Significantly, the enhanced specificity of the E1E3 vector enabled the detection of lung metastasis of prostate cancer. An E1E3 TSTA vector that expresses the herpes simplex virus thymidine kinase gene can effectively direct positron emission tomography (PET) imaging of the tumor. The prostate-targeted gene delivery vectors with robust and cell-specific expression capability will advance the development of safe and effective imaging guided therapy for recurrent metastatic stages of prostate cancer.
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PMID:Configurations of a two-tiered amplified gene expression system in adenoviral vectors designed to improve the specificity of in vivo prostate cancer imaging. 1830 74

Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.
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PMID:Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter. 1877 2

Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47Delta synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47Delta could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47Delta, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47Delta, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47Delta may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo.
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PMID:Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells. 1919 21

Tumor-selective replication-competent viral vectors, such as oncolytic herpes simplex virus (HSV) type I (HSV-1), represent an attractive strategy for tumor-based therapies because these viruses can replicate and spread in situ exhibiting cytopathic effects through direct oncolytic activity. These lytic viruses offer a distinct advantage over other forms of cancer therapies in that they are self-perpetuating and can spread not only in the tumor itself, but also to distant micrometastases. Translational studies aimed at identifying novel virotherapies for human cancers are incumbent upon the appropriate experimental models. While animal models are the preferred choice for efficacy studies of HSV virotherapy, we have developed a novel complementary approach toward assessing the effectiveness of oncolytic HSV therapy in both brain and prostate cancers. This experimental model takes advantage of previously published work in which human prostate cancer biopsies and rodent brain slices can be easily maintained ex vivo. The advantage of these systems is that the three-dimensional structure remains intact. Thus, all of the factors that may affect viral entry and replication, such as cell-cell and cell-matrix interactions, and interstitial fluid within this three-dimensional milieu remain preserved. Moreover, with respect to the brain, this system offers the advantage of direct access to brain cells, such as microglia and astrocytes, and circumvents the problems associated with the presence of the blood-brain barrier.
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PMID:Analysis of HSV oncolytic virotherapy in organotypic cultures. 1956 96

Oncolytic herpes simplex viruses type 1 (oHSVs) such as G47Delta and G207 are genetically engineered for selective replication competence in cancer cells. Several factors can influence the overall effectiveness of oHSV tropism, including HSV-1 receptor expression, extracellular matrix milieu and cellular permissiveness. We have taken advantage of human prostate organ cultures derived from radical prostatectomies to investigate oHSV tropism. In this study, we show that both G47Delta and G207 specifically replicate in epithelial cells of the prostatic glands but not in the surrounding stroma. In contrast, both the epithelial and stromal cell compartments were readily infected by wild-type HSV-1. Analysis of oHSV replication in prostate surgical specimens 3 days post infection showed that G47Delta generated approximately 30-fold more viral progeny than did G207. This correlated with the enhanced expression of G47Delta-derived glycoprotein gB protein levels as compared with G207. In benign prostate tissues, G207 and G47Delta titers were notably reduced, whereas strain F titers were maintained at similar levels compared with prostate cancer specimens. Overall, our results show that these oncolytic herpes vectors show both target specificity and replication competence in human prostate cancer specimens and point to the utility of using human prostate organ cultures in assessing oHSV tropism and cellular specificity.
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PMID:Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures. 1969 98

Studies of self-reported sexually transmitted infections (STI) suggesting an association with prostate cancer may reflect underreporting of such infections among nondiseased subjects. To reduce such bias, we studied archived sera in a cohort of U.S. military personnel known to have high rates of both STIs and prostate cancer. Using a nested case-control design, serum samples from 534 men who served on active duty between September 1, 1993 and September 1, 2003 were examined. Controls were individually matched to cases based on date of serum collection, date of birth, branch of service, military rank, marital status, and race. Each of the 267 case-control pairs had two serum samples: a recent serum sample, taken approximately 1 year before the case's prostate cancer diagnosis, and an earlier serum sample, taken approximately 8 years before diagnosis. Each serum specimen was studied for antibodies against human papillomavirus, herpes simplex virus-2 (HSV-2), and Chlamydia trachomatis. Logistic regression accounted for matching and potential confounding factors. Study data indicated no association between prostate cancer and serologic evidence of infections just before the reference date. However, a statistically significant association between prostate cancer and serologic evidence of HSV-2 infection was detected in the earlier sample (odds ratio, 1.60; 95% confidence interval, 1.05-2.44). The strength of this association increased when analyses were restricted to sera collected at least 60 months before diagnosis (odds ratio, 2.04; 95% confidence interval, 1.26-3.29; 204 pairs). If this association is causal, then our findings would suggest a long latency period for prostate cancer development after HSV-2 infection.
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PMID:Sexually transmitted infections and prostate cancer among men in the U.S. military. 1975 45

The use of replication-competent viruses that can selectively replicate in and destroy neoplastic cells is an attractive strategy for treating cancer. Various oncolytic viruses have been taken to clinical trials since a recombinant virus was first applied to cancer patients a decade ago. The concept of the therapy is simple: infectious virus kills the host cancer cells in the course of viral replication. It is important, however, that the virus does not harm the surrounding normal tissue. Oncolytic viruses can be classified largely into two groups: DNA viruses genetically engineered to achieve cancer specificity (e.g. adenovirus, herpes simplex virus and vaccinia) and RNA viruses of which human is not the natural host (e.g. Newcastle disease virus and reovirus). Prostate cancer has always been one of the major targets of oncolytic virus therapy development. The result of six clinical trials for prostate cancer has been published and several trials are now going on. Forty-eight of 83 (58%) patients evaluated in the phase I studies demonstrated a >25% decrease in serum prostate-specific antigen level without evidence of severe toxicities. The result shows the oncolytic virus therapy is promising toward clinical application. Here, we review the recent advances in the field and summarize the results from clinical trials.
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PMID:Oncolytic virus therapy for prostate cancer. 1983 25

Prostate cancer is one of the most prevalent cancers in men. Replication-competent oncolytic herpes simplex virus (oHSV) vectors are a powerful antitumor therapy that can exert at least two effects: direct cytocidal activity that selectively kills cancer cells and induction of antitumor immunity. In addition, oHSV vectors can also function as a platform to deliver transgenes of interest. In these studies, we have examined the expression of a xenogeneic homologue of the prostate cancer antigen, prostatic acid phosphatase (PAP), with the goal of enhancing virotherapy against PAP-expressing tumors. PAP has already been used for cancer vaccination in patients with prostate cancer. Here we show that treatment with oHSV bPDelta6 expressing xenogeneic human PAP (hPAP) significantly reduces tumor growth and increases survival of C57/BL6 mice bearing mouse TRAMP-C2 prostate tumors, whereas expression of syngeneic mouse PAP (mPAP) from the same oHSV vector did not enhance antitumor activity. Treatment of mice bearing metastatic TRAMP-C2 lung tumors with oHSV-expressing hPAP resulted in fewer tumor nodules. To our knowledge, this is the first report of oncolytic viruses being used to express xenoantigens. These data lend support to the concept of combining oncolytic and immunogenic therapies as a way to improve therapy of metastatic prostate cancer.
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PMID:Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer. 2022 Jul 84


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