Classical cadherins type I 21 Ecadherin

The tight association of individual cells at junctional organelles and the polarized distribution of cytoplasmic and cell surface-components are the primary characteristics of normal epithelial tissues. As a result of this adhesion, normal epithelial cells are less mobile as compared to either cells of mesenchymal origin or to cancer cells of epithelial origin. Normal epithelial cells also have the ability to form selective permeability barriers, and to exhibit vectorial transport in tissues....

References

Garraway, The genomic landscape of prostate cancer. Front En-docrinol (Lausanne), 2012. 3 p. 69. 2 You, J.S. and P.A. Jones, Cancer genetics and epigenetics two sides of the same coin Cancer Cell, 2012. 22(1) p. 9-20. 3 Feil, R., Epigenetics, an emerging discipline with broad implications. C R Biol, 2008. 331(11) p. 837-43. 4 Wilson, V.L., P.A. Jones, and R.L. Momparler, Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2'-deoxycytidine as a possible...

A

CT-guided percutaneous transgluteal biopsy of the prostate. Two needles are inserted at different angles to ensure adequate sampling of both sides of the prostate (Reprinted from American Journal of Roentgenology, Volume 166 Issue 6, Papanicolaou N, Eisenberg PJ, Silverman SG, McNicholas MM, Althausen AF. 1996, 1332-1334, with permission from The American Roentgen Ray Society). Papanicolaou et al. 19 described this technique in 10 patients with a mean age of 67 years and mean PSA of...

Acute and late adverse events

Acute and late adverse events of conventional EBRT EBRT delivered with conventional techniques is fairly well tolerated, although grade 2 or higher acute rectal morbidity (discomfort, tenesmus, diarrhea) or urinary symptoms (frequency, nocturia, urgency, dysuria) requiring medication occur in approximately 60 of patients. Symptoms usually appear during the third week of treatment and resolve within days to weeks after treatment is completed. The incidence of late complications that...

Conclusion

The present review has revealed that our understanding of the role played by the personal beliefs of men regarding their LPCa and its treatment is still limited. The existing evidence has been dominated by qualitative methods, cross-sectional designs and the use of non-validated instruments. However, it is also clear from existing findings that the adoption of the SRM and NCF, with their associated validated instruments, could provide a greater understanding of the factors that influence...

Cytotoxic agents

Cytotoxic chemotherapy has had an established role for many cancer types for many decades with the ability to eradicate some cancers, prevent relapse from micrometastatic disease in others and offer life prolonging or palliative benefit in other cancers. With respect to prostate cancer, a role for cytotoxic chemotherapy in the treatment of metastatic castrate refractory prostate cancer (CRPC) was first established using mitoxantrone in 1996, when it was shown to provide effective palliation of...

Discussion

In many patients with prostate cancer, androgen deprivation therapy is administered over prolonged periods of time. The benefits of long-term AS in patients with advanced disease are well established, nevertheless, because this therapy has potential long-term side effects strategies should be applied that manage or prevent long-term complications 50 . One such strategy is IAS, in which patients receive regular cycles of AS, the duration of which is usually determined by PSA levels 51 . Canadian...

Expression data analysis and putative mechanisms of TrxG function in malignant progression

As summarized in previous sections, epigenetic gene regulation plays a crucial role in PCa. In particular, HPTMs mediated by TrxG genes are emerging as novel drivers of tumor progression, or as mediators of tumor suppressive functions. Although these genes have been extensively investigated in hematological neoplasms, their roles in solid tumors such as PCa have not been completely elucidated. As demonstrated for other epigenetic players, it is likely that The functioin of TrxG members is...

Incidence and mortality

In Table 1 absolute numbers and age-standardized rates of incidence and mortality are presented for selected regions and countries 1 . In 2008 it was estimated that nearly every seventh case of male malignoma was prostate cancer (899 thousand new cases, 13.6 of the total). Therefore, in men prostate cancer was the second most diagnosed cancer after lung cancer. Approximately three quarters of these cases were diagnosed in more developed countries. The highest incidence rates were measured in...

Hyaluronic acid

The Hyaluronic acid (HA) is a polysaccharide normally found in human tissues as a component of the connective tissue. Normally, it plays a vital role on the skin and in the synovial fluid of the joints. It is normally degradable by the normal enzymatic system in relative short time. However, to make it last for months when used for the treatment of skin wrinkles and osteoarthritis, the compound is modified making it stable for duration close to 1 year before it is reabsorbed by the body. Only...

Integrins as therapeutic targets

As previously discussed, integrins have been shown to mediate tumour progression, tumour cell metastasis and EMT in both in vitro and in vivo models. Thus, these preclinical studies have suggested that integrins could be a novel therapeutic target to prevent cancer progression, including prostate cancer. Currently, studies have been focused on targeting integrin avp3 in breast cancer, ovarian cancer and prostate cancer. Integrin avp3 is likely to be a good cancer angiogenesis target because it...

Integrins in Prostate Cancer Invasion and Metastasis

Paulynn Chin Suyin, Joanne Louise Dickinson and Adele Frances Holloway Additional information is available at the end of the chapter http dx.doi.org 10.5772 53482 Prostate cancer is the most commonly diagnosed cancer in men and is the second leading cause of cancer deaths in men after non-melanoma skin cancer. According to the United States National Cancer Institute, it was estimated that almost 241 740 men would be diagnosed with prostate cancer in the United States alone in 2012 and more than...

Introduction

For several years, prostate cancer (PCa) has been considered a genetic disease, driven by somatic mutations occurring at critical oncogenic or tumor suppressive loci 1 . This view has changed over the last decades, thanks to mounting evidence on the role of epigenet-ics in PCa initiation and progression 2 . The term epigenetics derives from a Greek word, and literally means above the gene. In molecular biology, this definition includes all heritable gene expression patterns, which are not...

Materials and methods

In a cross-sectional audit study, serum testosterone level was determined in all patients on 3-month LHRH formulations, treated in out-patient clinic in two months period. Blood samples were taken immediately before the next injection. Only patients, who previously received more than one injection and with previous injection exactly 3 months or less before examination were eligible. Three preparations were found to be used Diphereline (triptorelin 11.25 mg), Eligard (modern leuprolide...

Matrix metalloproteinases 61 Structural motifs

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that consist of more than 21 human MMPs. MMPs are divided into eight distinct structural groups, five of which are secreted and three of which are membrane-localized MMPs, MT-MMPs (Table 1). The existence of multiple MMPs suggests that each MMP subfamily has a specific function that is cell-type specific. Understanding the structural composition of each of the MMP subfamilies may provide some insight into their...

MicroRNAmediated regulation of PCSCs

For the identification of novel PC therapeutic targets it is important to evaluate functional genes that are related with CSCs self-renewal and survival abilities. The experiences with PC therapy showed that PC recurs frequently meaning that chemotherapy, radiotherapy, androgen-ablation therapy, and radical prostatectomy are not sufficient enough to eliminate TICs or metastatic cells. PCSCs are androgen independent and therapy resistant cells. Thus, generating novel therapies that specifically...

Natural Compounds Antioxidant and Antiandrogens in the Prevention of Prostate Cancer In vivo Evidences from Murine

Rossano Lattanzio, Alessia Lamolinara, Mauro Piantelli and Manuela lezzi Additional information is available at the end of the chapter http dx.doi.org 10.5772 45948 Prostate cancer (PCa)is the most frequent malignant neoplasia in men. The number of cases has continuously increased over the past decades, partly due to the higher life expectancy. Additional factors are the high caloric diet and lack of physical exercise, typically seen in the Western countries. Notably, up to 40 of cancer...

Natural history of prostate cancer

Although the natural history of prostate cancer (PCa) has not been fully elucidated, it is thought to arise from damaged prostate epithelium and progressively develop over many decades 27 . Prostate disease is heterogeneous and multifocal, further complicating the understanding of its progression. Based on autopsy studies, about one-third of men over the age of 50 years display histological evidence of PCa. However, a majority of these cases remain clinically insignificant, underscoring the...

Ncadherin

N-cadherin is a member of the classical Cadherin family of transmembrane glycoproteins involved in homotypic cell adhesion (Takeichi, 1995). The extracellular domain of N-cadherin consists of five cadherin domains with residues that allow homophilic binding in the first extracellular domain (ECD) (Shan et al., 1999 Koch et al., 1999).In neuronal cells, N-cadherin is involved in the control of axonal growth, synapse formation and synaptic plasticity (Matsunaga et al., 1988 Riehl et al., 1996...

New therapeutics settings in the treatment of castration resistant prostate cancer

Being able to predict which patients will develop metastasis and death with rising PSA levels after treatment with androgen ablation is essential for deciding therpeutic interventions and gauging prognosis. The major biologic processes under therpeutic investigation in prostate cancer involve growth and survival, chemotherapy and hormone therapy resistance, ex-tragonadal androgen production, modulation of the androgen receptor, angiogenesis, the bone interface, immune surveillance and escape,...

Normal and pathological processes involving MMP expression

MMPs are involved in normal embryonic development (Alexander et al., 1996b Lelongt et al., 1997), renal organogenesis (Lelongt et al., 1997), and invasion and metastasis of cancer (Stetler-Stevenson et al., 1993). There are several examples of normal embryonic development that require MMP expression, including trophoblast implantation, embryonic growth, and tissue morphogenesis. In addition, MMPs are required for normal wound repair. As part of the wound repair process, development of new...

PSA in the era of biologic and targeted therapy

A wealth of data establishes PSA as a marker of tumor aggressiveness, tumor stage, drug response and survival. Controversy and concern persists regarding PSA's role as a marker of disease stabilization and response induced by cytostatic and immunotherapies when compared to cytolytic therapies. An evaluation of the difficulties surrounding PSA interpretation has been addressed 42 . Two vaccine trials, Sipuleucel-T (Provenge) 43, 44, 45 and the TRICOM PROSTVAC 46, 47 demonstrated a significant...

Roles of integrins in cancer progression

While integrins mediate cell attachment, ligation of integrins by the ECM proteins induces cell migration by generating the traction required for invasion. In cancer, expression of in-tegrins that are involved in cell adhesion are frequently altered, leading to cell proliferation, migration and metastasis. Previous studies in which integrin expression levels were correlated to the different stages of human tumours and the pathological outcomes (metastasis, recurrence, survival), implicated a...

Stromal AR inhibits cancer epithelial cells

We have observed and previously demonstrated by co-culture experiments using well characterized stromal cell lines, both in vitro and in vivo that, in the presence of androgen, stromal cells expressing AR decrease the growth and invasive ability of prostate cancer epithelial cells. It was hypothesized that this distinct effect of AR in stromal cells is due to the involvement of paracrine factors mechanisms regulated by both the epithelial and stromal cells. The analysis was established 21 by...

YY1 as a transcription factor

The YY1 protein consists of 414 amino acids and multiple functional domains (Figure 1). As a transcription factor, YY1 is capable of directly binding to DNA through the zing-finger domains at its C-terminus. YY1 recognizes and binds its DNA consensus sites with a core sequence of either CCAT or ACAT, and these consensus elements have been identified in over 7 of vertebrate genes, underscoring the importance of YY1 in gene regulation 3 . Figure 1. The Domain Structure of the YY1 Protein YY1 is...

The androgen receptor and CaP progression

The development and progression of prostate cancer (CaP) is largely dependent on the dysregulation of the androgen androgen receptor (AR) signaling pathway though, the mechanism of CaP progression remains elusive. Initial treatments for CaP included prostatectomy or radiation to destroy cancerous cells 1 . However, these treatments were not curative and more often than not there were recurrences and metastases of the cancer. Mainstay treatments that target the androgen AR pathway through...

The prostate cancer microenvironment

The morphology of a tumor may also influence in the biological responses of cancer cells to a specific therapy. Although most of the reports in cancer therapy utilize monolayer cultures, multicellular aggregates (spheres) are probably more important because reflects the three-dimensional structure for a real-time model representing a tumor, allowing to study the interaction of tumor cells with the microenvironment 105 . The fact that spheroids mimic the tumor microenvironment is also an...

Treatment sideeffects and their psychological impact

Men confronted with this treatment decision often need to take into consideration a range of factors, including the potential physical side effects of treatments and their psychological, social and emotional consequences. For example, patients being treated with radical therapies can experience severe side-effects, such as urinary incontinence (UI) and erectile dysfunction (ED), as a result of treatment. UI symptoms can persist years after treatment 8 and this can have an impact on all aspects...

Vaccinesbased immunotherapy

Sipuleucel-T is an active cellular immunotherapy consisting of autologous peripheral-blood mononuclear cells, including antigen-presenting cells (APCs), which have been activated ex vivo with a recombinant fusion protein known as PA2024, composed of prostatic acid phos-phatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF). In the first two randomized trials, sipuleucel-T, the primary endpoint was not accomplished since these studies did not show a significant effect...

Mechanisms involved in the development and progression of the disease

To understand prostatic growth in diseased states, it is important to understand the hormonal influences at play in normal prostate development and function. Testosterone is the primary circulating androgen in men. Within the prostate, testosterone is converted to a more potent androgen dihydrotestosterone (DHT) by the action of intracellular 5a-reductase enzymes 6 . Circulating DHT levels are low (1 10) when compared with testosterone, whereas in the prostate, this ratio is reversed, making...

Castrate testosterone values in different prostate cancer studies

Serum testosterone value around 1.735 nmol l or 50 ng dl as castrate level for the purpose of hormonal treatment of prostate cancer was used already in 1970'ties 2 . Later, some LHRH formulations were designed to achieve serum testosterone below this value in 95 of treated patients. It was accepted as standard value in guidelines 50 . Guidelines have at present gone even a step further and stated testosterone levels above 50 ng dl to be in-sufficient and additional hormonal manipulation to be...

Colorectal cancer47 010

Number of publications in the PubMed with keywords related to cancer PCa is the most common solid cancer in men worldwide and is the most common of all cancers in the North America. In an epidemiological study was reported that the estimated PCa incidence rates remain most elevated in North America, Oceania, and Western and Northern Europe. Mortality rates tend to be higher in less developed regions of the world including parts of South America, the Caribbean, and sub-Saharan Africa....

Problems with direct testosterone immunoassays

Large differences were reported from measurements of the same serum sample with chemi-luminescent assays from different manufacturers 39,40 . Direct RIA techniques were not better 41 . In the low range (values of interest for castration control in patients with prostate cancer), which was close to range of female testosterone levels, direct assays gave results more than 20 different from the gold standard 41 . Abbot Architect assay was also reported to give consistently up to 20 higher results...

AR in CaP progression

The efficacy of many CaP treatments is often temporary, as CaP cells often become refractory to hormone ablation therapies. The current therapeutics are largely targeted towards the inhibition of AR activation, such as anti-androgens, chemical castration (treatment with gonadotropin releasing hormone (GnRH) super agonists to inhibit testosterone secretion from the testes), or surgery (orchidectomy) 7 . AI-CaP or castration resistant CaP is thought to occur due to the androgen deprivation...

An advanced understanding of cancer biology comes of age 41 Specific targeting of DNA repair mechanisms

In recent years one successful targeted approach has been to exploit the vulnerability of tumors with an impaired DNA damage repair mechanism by inhibiting a second DNA repair pathway and as such commit the cancer cell to die. This concept of synthetic lethality has been most successfully demonstrated in patients bearing tumors with BRCA-1 -2 mutations where homologous recombination (HR) mechanisms are already known to be inadequate. This hypothesis has reactivated the development of poly...

Treating prostate cancer with PARP1 inhibitors

Recently, the augmented immunodetection of PARP-1 was associated with prostate cancer progression and prediction of biochemical recurrence 138 . Preclinical data also indicated that PARP inhibitors might sensitize cancer cells and potentiate the effects of radiotherapy and chemotherapy. Interesting, inhibition or depletion of PARP-1 by antisense RNA 139 , chemical inhibitors 140-142 , or by the expression of dominant negative mutants (4-5), promotes genomic instability 143 , as revealed by...

YY1 studies in the clinical applications of prostate cancer

Many biological functions of YY1 implicate its oncogenic role in human cancers. Further corroborating these observations is the frequent overexpression of YY1 in cancer cells, including prostate tumors 123 . These oncogenic properties confer YY1 with great potential as a therapeutic target in prostate cancer treatment. YY1 antagonizes p53 function through multiple mechanisms, including facilitating Mdm2-mediated p53 ubiquitination and degradation, inhibiting p53-mediated transcription, blocking...

Conclusions

Serum testosterone levels provide objectivity for proper prostate cancer disease states characterization. Testosterone level before treatment may add to prognosis. More importantly, testosterone levels during treatment become main issue in individual's prostate cancer treatment decisions, as soon as increasing PSA levels indicate failure of primary local treatment. Apparent difference between guidelines (which ask for 20ng dl) and practice in serum testosterone values of hormonally treated...

A systematic review of the literature

An initial scope for existing literature reviews in prostate cancer research yielded two reviews 25, 26 . The more recent review 26 was conducted five years ago and restricted its search period to a 14 year time span, used a small number of literature databases and only searched for original, peer-reviewed studies to explore broadly the personal (not just beliefs specifically) and external factors pertaining to the decision-making process of patients. It concluded that there is a general lack...

PSADT as a surrogate for drug activity

PSA is one of the major androgen receptor-dependent target genes 27 , and clinical monitoring is used to detect early stage disease as well as the emergence of recurrent tumor after therapy 28, 29, 30 and changes mirror changes in tumor bulk and indicate response to drugs. The graphic representation of PSA-DT is illustrated and its formula is given in Figure 4 26 . Kelloff et al. 31 , reviewed the use of PSA-DT as a surrogate for tumor response to drugs in patients with prostate cancer. They...

Alterations in signaling pathways of PCSCs

Alterations in the signaling pathways are probably one of the reasons why cancer stem cells gain a tumorigenic potential. Thus, disclosing the signaling pathways' expressional regulations might provide potential therapeutic targets. The WNT, JAK STAT, NF-kB, NOTCH, and PI3K AKT mTOR signaling pathways were found to be the regulators of CSC biology in prostate tissue and therefore are candidate targets. The idea of inhibiting signaling that induces proliferation and survival could mean an...

Considerations about the various prostate cancer treatments and their associated side effects

A number of side effects are associated with the various treatments available for PCa. As it was presented before, associated side effects include ED and UI amongst others, and a number of palliative care treatments and exercises have been proposed to counteract these effects 24, 52, 53 A very important and unquestionable point is that pelvic floor muscle exercises are relevant to the treatment of ED in patients with PCa that will be submitted to RP. Most physiotherapy treatments for ED focus...

Recommendation for health care

It is clear that the use of patients' beliefs in their decisions on a treatment modality has led them to base their decisions on misconceptions rather than on evidential information. HCPs may need to challenge misinformed beliefs held by patients to help them make more informed decisions regarding their treatment. In order to make more conclusive recommendations for health care practice, further research is required to establish the extent to which personal beliefs alter treatment selection.

Reasons for testosterone measurement in prostate cancer

Testosterone measurement in prostate cancer patients has more than 40 years history 2 . Confirmation of castrate testosterone level is necessary before identifying prostate cancer as castration resistant. Castrate states are at present defined as serum testosterone level below 20 ng dl ( 0.69 nmol l) or below 50 ng dl ( 1.73 nmol l) 3 , but it was not always this way and different testosterone measurement methods have important implications. Need for controlling quality of chemical castration...

Other targets

Is a small molecular kinase inhibitor of Src family kinases (SFK), being studied for prostate cancer because Src signaling is involved in androgen-induced proliferation. In a phase II trial in chemotherapy-nai've patients with metastatic CRPC, dasatinib 100 mg orally twice daily) showed lack of progression in 43 of patients at week 12 and in 19 in patients at week 24. It also revealed a decrease in the markers of bone metabolism (N-telopeptide and bone alkaline phosphatase) A...

Nomenclature

SEER Surveillance, Epidemiology and End Results Program of the National Cancer Institute of the USA NCHS National Center for Health Statistics RKI-Robert Koch Institut MCR Munich Cancer Registry PSA Prostate specific antigen RPE Radical prostatectomy XRT Radiation therapy HIFU High-intensity focused ultrasound Hormone Hormon therapy TUR Transurethral resection of the prostate AS Active surveillance WW Watchful waiting ASR (W) Age-standardised rate, using the proposed world standard population...

MFV as potential candidate in PCa

Together with criticism of XMRV as potential candidate for CFS, we presented data in July 2010 1 related to a novel viral candidate for both PCa and CFS Micro-Foci inducing Virus or MFV. While the more specific aspects related to CFS association are presented elsewhere 1 , MFV properties which link this virus to PCa will be here described. 3.1. Cancer Cluster Genetic Data Micro-Foci inducing Virus was initially discovered in a paediatric tumor diagnoses-association generally defined as...

Clinical phase II studies of IAS

Comparison of therapeutic efficacies of IAS and CAS Following apparently successful pilot studies, a number of phase II IAS trials were conducted (Table 1) 16 . Since the end points of most phase II studies were safety and feasibility of IAS, survival data were not reported in general. Out of the 19 studies reviewed by Abra-hamsson only five involved more than 100 patients (102, 103, 146, 250 and 566 patients, respectively) and the other smaller studies employed a mean number of 52...

The incidence of genetic PTEN alteration

The deletions involving the chromosome 10q, which hosts the PTEN locus, 10q23, in CaP is a frequently observed phenomenon. Modifications to PTEN in various stages of CaP have been characterized to include both homozygous and hemizygous deletions, as well as inactivating mutations. Although the incidence and the modes of these alterations have been inconsistent across studies, the severity of PTEN loss seems to correlate with disease progression 119 . Whereas locally confined CaP presents...

The importance of the early diagnosis of the prostate cancer

The early diagnosis of PCa has been facilitated by the determination of the prostate specific antigen (PSA), rectal touch and ultrasonography, which has subsequently led to a high cure rate in the early stages (stage I II) of the disease. However, it is important to have in mind, that these current diagnostic techniques have not, in several cases, sufficient specificity and sensitivity to determine the stage and aggressiveness of the PCa and to identify appropriate treatment 2, 6, 35-37 ....

PSA Velocity PSAV

PSA-V is the rate of change in serum PSA over time. PSA-V 1 2 ((PSA2-PSA1 t1 in years) + (PSA3 - PSA2 t2 in years)), where PSA1 is the first, PSA2 the second and PSA3 the third PSA measurement. Time represents the interval (in years) between PSA measurements. It is recommended that three PSA measurements obtained over 24 months yields optimal accuracy. A PSA-V exceeding 0.75 ng ml year is highly predictive of prostate cancer. PSA-V is more useful than PSA doubling time (PSA-DT) in the...

Treatment techniques

Preplanned transperineal implantation techniques First of all, TRUS imaging is obtained before planned procedure to assess the prostate volume. A computerized plan is generated from the ultrasound images, producing isodose distributions and the ideal location of seeds within the gland to deliver the prescription dose to the prostate. Several days to weeks later, the implantation procedure is performed. Needles are then placed under ultrasonographic guidance through a perineal template...

Oncogene addiction pathways

The development of drugs targeting tumours driven by so-called 'oncogene addictions' has lead to some success. Examples include imatinib targeting the bcr-abl translocation in CML and mutated c-kit in GIST, trastuzumab and laptinib in HER-2 positive breast cancers BRAF inhibitors in melanomas with BRAF mutations. Molecular studies in prostate cancer have to date identified mutations of this type in less than 20 of all sporadically occurring prostate cancers. Analysis of a cohort of 206 prostate...

Why Psasgr is more useful than PSADT

As noted in Figure 10, when SGR is fast and increases 1 from 4 to 5 day, the doubling time changes 1.3-fold from 4 to 3 days (a slight change). However, when the SGR is slower and increases 1 from 1 2 d, doubling time changes four-fold from 69 to 17 days (a large change). A DT of 1-day does not represent the same growth rate when the tumor is slowing as when the tumor is rapidly growing. As the absolute value of SGR approaches zero, DT approaches infinity and is of no practical use other than...

Three Dimensional Conformal Radiation Therapy 3DCRT

In the early to mid-1908s, three-dimensional conformal treatment techniques became increasingly available. Although these techniques vary in some aspects, they share certain common principles that offer significant advantages over conventional external beam radiation therapy techniques. CT-based images referenced to a reproducible patient position are used to localize the prostate and normal organs and to generate high resolution 3D reconstructions of the patient. Treatment field directions are...

Clinical results of HDR brachytherapy

The reported outcomes of combination of HDR brachytherapy and EBRT are favorable (Table 3). Multiple reports of low- and intermediate-risk patients treated with combination of HDR brachytherapy and EBRT have demonstrated excellent long-term biochemical control rates of 90-100 and 87-98 , respectively (Table 3). Long-term biochemical control rate for high-risk patients treated with combination of HDR brachytherapy and EBRT is also favorable. Yoshioka et al. 99 have performed HDR brachytherapy as...

Intensity Modulated Radiation Therapy IMRT

IMRT is a relatively recent refinement of three-dimensional conformal techniques that uses treatment fields with highly irregular radiation intensity patterns to deliver exquisitely conformal radiation distributions. These intensity patterns are created using special inverse and optimization computer planning systems. Rather than define each shape and weight as is done in conventional treatment planning, planners of IMRT treatment specify the desired dose to the target and normal tissues using...

Abdominoperineal resection

Abdominoperineal resection is a surgery for carcinoma of the rectum and or anus, performed through incisions in the abdomen and perineum. APR involves the removal of the anus, rectum, and the distal portion of the sigmoid colon along with regional lymph nodes. Without an anal opening, the patient has a permanent end-colostomy from the proximal sigmoid colon created through the anterior abdominal wall, typically placed in the left lower quadrant 11-12 . 2.1. Diagnosis of rectal carcinoma In...

Ligand and transcription factor driven survival pathways

Whilst it is often hoped that mutations in a single molecular pathway will be uncovered as the crucial oncogenic event in tumour development and its abrogation lead to meaningful anticancer activity, to date this has been rarely found to be the case for sporadic tumours. Another approach is to consider the factors that cause and or are associated with the development as well as the survival of cancer. The role of androgens and androgen receptor is clear for prostate cancer. Other biological...

Integrins

Integrins belong to a superfamily of transmembrane glycoprotein receptors involved in mediating cell to cell and cell to ECM interactions. They exist as heterodimers composed of a and p subunits bound by non-covalent bonds. To date, 18 a subunits and 8 p subunits have been identified, which can associate to form 24 unique complexes (Table 1) with the different ap combinations possessing distinct ligand binding specificities 7, 8 . There are three distinct regions in each integrin subunit with...

Projected tumor size and projected PSA uncover hidden drug activity

Now that surrogacy of static values of PSA and PSA-DT is being questioned for targeted therapies, new techniques of response evaluation are under study. One attempt to quanti-tate treatment efficacy redirects attention from PSA-DT to PSA-specific growth rate (PSA-SGR) 69, 70, 71 . Generally ignored, projected tumor and marker value play a particularly important role in uncovering and quantifying hidden, cytostatic or cytolentic drug effects. Projected tumor volume or marker value is calculated...

Conventional External Beam Radiation Therapy EBRT

In the 1970s, the treatment field size and portal configuration for radiation therapy were based on estimations of the anatomic boundaries of the prostate defined by plain-film radiography and by the digital rectal examination. At that time, a variety of treatment techniques were used. In general, four fields were used to treat the pelvis and prostate to an initial dose of 45 Gy, with a boost to 70 Gy to the prostate only 1, 2 . Early conventional external beam radiation therapy used total...

Predicting approximate tumor size or marker value for any arbitrary date in the future

Assuming untreated clinical cancers and their markers expand at a relatively constant exponential rate, it is possible to predict values for tumor diameter, volume and marker for any arbitrary future date. Figure 16 displays a PSA projection made for a patient with newly diagnosed prostate cancer who asked if a preplanned three-month holiday before initiation of therapy could jeopardize his chance for a curative procedure. The prediction, assuming constant exponential expansion of serum PSA, is...

Methods for assaying PCSCs

Although, a SC in any type of adult tissue has the common self-renewal and differentiation abilities, it will be wrong to generalize the results obtained from one tissue while defining a SC in another tissue. SCs in different tissues can differ significantly from one another. The actual assay to identify a CSC that has self-renewal and tumor progression capability is an in vivo model known as the serial transplantation in animal models. Other assays are usually generated in an in vitro...

Core binding factor

More than twenty years ago, Nancy Speck and David Baltimore identified a DNA binding activity that bound to the core site (TGTGGTAA) in the enhancer of Moloney Murine Leukemia Virus that, when mutated, altered disease specificity to produce thymic leukemia instead of erythroleukemia 16, 17 . This DNA binding activity, which was named Core Binding Factor, was identified in a variety of cell lines 16 . Dr. Speck's laboratory purified several peptides that had core- binding activity from calf...

The problem

Whilst improvements in patient survival have been realized for a number of haematological and solid malignancies in the last 30 years, new efficacious systemic anti-cancer treatments are still needed. The current, widely used drug development paradigm is often associated with a poor conversion rate from experimental to licensed drug. This process involves a significant investment of resources from sponsors, investigators and patients and to date has only lead to a limited chance of success. At...

T

Structure of the matrix metalloproteinase. MMPs contain the following domains signal peptide (pre-pep-tide), propeptide, catalytic domain, hinge region, and hemopexin-like domain. The cleavage of N-terminal propeptide domain of the latent MMP yields the active form of the enzyme. The gelatinases contain a fibronectin-like region within their catalytic domain. The membrane-type MMPs are characterised by a C-terminal transmembrane domain. The hemopexin-like repeat is absent in...

Salvage radiotherapy SRT

A multi-institutional study suggests that early intervention with radiotherapy is better than delayed intervention for patients with biochemical failure 121, 122 . This analysis included patients with pT3-4N0 disease who received either SRT or early ART. Early ART for pT3-4N0 disease significantly reduces the risk of long-term biochemical progression after radical prostatectomy compared with SRT. Stephenson et al. 123 reported on the outcomes and prognostic factors of 501 men who had salvage...

Clinical results

Clinical results of LDR brachytherapy as monotherapy It is generally accepted that patients with low-risk disease are excellent candidate for LDR monotherapy. There is no randomized data comparing therapeutic outcomes between LDR monotherapy, surgery, and EBRT. However, multiple reports of low-risk patients treated with LDR monotherapy have demonstrated excellent long-term biochemical control rates of 80 -95 (Table 1). Patients with intermediate-risk disease represent a heterogeneous...

Antiangiogenic strategies

Tumor angiogenesis is likely to be an important biologic component of prostate cancer growth and progression. An elevated levels of the potent angiogenic molecule vascular endothelial growth factor (VEGF) have been shown to correlate with advanced clinical stage and survival. Microvessel density in clinically localized prostate cancer is an independent prognostic for progression and survival 87, 88 . Antiangiogenic agents using monoclonal antibodies to VEGF, such as bevacizumab...

Current therapy implications and future directions

The reciprocal interactions and interplay between the AR and PI3K AKT axis suggests that the underlying mechanism potentiating CaP progression is complex and impacts the very balance of these prosurvival pathways. Current literature shows that there is indeed crosstalk between the AR and PI3K AKT pathway occuring at various levels. The integration of these oncogenic pathways potentiates CaP tumorigenesis and this is further complicated by the levels of androgens and stage of CaP progression. In...

Brachytherapy implant characteristics

Patients received one implant and one fraction of HDR. Fraction dose is 20.5 Gy because it is considered to correspond biologically (biologic effective dose) to > 90 Gy administered at 2 Gy fraction according to the linear quadratic model, assuming an a p of 1.2 Gy (7, 8, 9, 10). Brachytherapy procedure is done under spinal anesthesia with the patient in the lithotomy position (Fig. 1). A Foley catheter is placed, and the bladder is partially filled with 100 cm3 of sterile water. The needles...

Cancer Pal

TSG R1 of vol 1 70 J TSGR2 0 80 d TVDT 40 69 d 1 36 m TVDT2 86 28 d * 2 88 m TD* vol 3 054 TPreRxvol 12 770CC TPosIR* vol 15.598 cc Projeded vol il untreated 96.931 cc TDx lo TPrefix 84 d 2 8 m TProTP slR* I13d m T'.-'j- jv OK7 i Treatment Responde 1 .ft TumorAge -3.S1 years Figure 17. The tool we developed to facilitate calculation of tumor kinetics is named CancerPal . The software App is available from Apple Corporation's App store. The App analyzes kinetic changes of tumor markers and or...

Acute and late adverse events of HDR brachytherapy

Acute urinary symptoms such as urinary urgency and frequency are common and usually resolve within a few months. Urinary retention occurs in less than 5 of patients treated with combination of HDR brachytherapy and EBRT 89, 94, 104, 105 . Urinary strictures are reported in up to 15 of patients, and most commonly seen in the bulbomembranous urethra 106, 107 . Urinary incontinence is extremely rare, and seen in less than 2 of patients 107, 108 . Transient rectal symptoms such as rectal urgency or...

Mammalian Target of Rapamycin mTOR

MTOR is a member of two distinct complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) 83, 117 . It is thought that the mTORC1 complex plays a more dominant role in tumor progression while the mTORC2 complex is more significant to mediating signals to the cytoskeleton 116 and now identified as the factor responsible for the phosphorylation of AKT at S473. This phosphorylation event maximizes the activity of AKT and opens its targets to include PRAS40 and FOXO 83 . Moreover, it is...

Results

In our Centre a total of 70 patients have been treated with this technique and is the first in the medical literature using in patients with favorable risk prostate cancer. Our technique has the great advantage of being practically a one-time procedure which prevents any movement of the needles. In our series acute and late genitourinary toxicity grade 2 or more was not observed in any patient. The median of flow rate test pretreatment in our study was 12.5 ml s (3-30 ml s) but acute urinary...

Progressive loss of AR expression

Numerous studies have focused on AR expression in the epithelial cells during prostate carcinogenesis and the progression of prostate cancer from primary to metastatic cancer and from hormone sensitive to castration resistant prostate cancer (CRPC). It has been established that epithelial AR is continuously expressed throughout prostate cancer disease progression. Increased AR expression has been associated with aggressive disease and decreased progression free survival (PFS) in patients 19 ....

Introduction to permanent implants

Interstitial prostate brachytherapy was first performed by Barringer in 1915 29-31 . Its first widespread adoption occurred in the 1970s, when the retropubic method was popularized 32 . A laparotomy was done for lymph node dissection and exposure of the prostate. Io-dine-125 sources were implanted under direct visualization. The procedure was technically difficult to perform, in part because of limited working space in the pelvis. As a result, retropubic implantation lost popularity in the...

SGR is a useful tool to identify subtle drugassociated tumor or marker kinetic changes of tumors

Mehrara, as part of his PhD thesis at the Department of Radiation Physics, University of Gothenburg, Goteborg, Sweden presented an analysis of tumor growth kinetics based on the tumor specific growth rate constant (SGR). The analysis assumes that for most practical purposes clinically observable tumor growth follows exponential growth. Additionally, this is true for the surrogate PSA tumor marker. SGR is rapidly calculable by hand-held mobile devices and facilitates the rapid identification of...

Antiandrogen therapies

Drugs that reduce circulating levels of androgens or that competitively inhibit the action of androgens remain central to the treatment of prostate cancer. The surgical or medical castration with orchiectomy or gonadotropin-releasing hormone (GnRH) agonists, respectively, suppresses testicular testosterone generation. However, the duration of response to castration is short 12-33 months) and, in almost all patients, is followed by the emergence of a castration-resistant phenotype 34 . The...

Targeting key biological pathways

A leading premise for the treatment for advanced prostate cancer is to target the androgen receptor (AR) axis or to identify cases where a single pathway mutation is thought to drive carci-nogenesis. It is proposed that triaging the current pipeline of agents can be directed by building on prior successes. In light of recent advances in our knowledge of AR pathway signaling, further exploration of this pathway is warranted. Moreover, since molecular interrogation of distinct clones driving...

Introduction to HDR brachytherapy

HDR brachytherapy has been used as the brachytherapy component in combination with EBRT for the treatment of prostate cancer 84-90 . In general, for this approach patients undergo transperineal placement of afterloading catheters in the prostate under ultrasonographic guidance. After CT-based treatment planning, several high-dose fractions are administered during an interval of 24 to 36 hours using 192Ir. This treatment is followed by supplemental EBRT directed to the prostate and periprostatic...

Transcriptional regulation of MMPs

Increased MMP expression in tumors is primarily associated with transcriptional changes rather than genetic alterations, although translocation of MMP23 genes in neuroblastoma and amplification of MMP24 gene have been reported (Llano, 1999). Transcriptional regulation of MMP mRNA expression is subject to influences by several chemical reagents, neurohormones, and cytokines (Liotta et al., 1983 Unemori and Werb, 1988 Galis et al., 1994 Werb et al., 1989 Matrisian and Hogan, 1990). For example,...

Appendix

It is important to realize that CancerPal remains an experimental tool used strictly for analysis of clinical and laboratory data by cancer researchers, pharmacists or clinical research radiation and medical oncologists. The methods used in designing this tool have been discussed primarily in the references listed below with special attention given to the work of Mehrara et al. PNA, A Limited Liability Corporation, cannot be held responsible for any treatment modifications or recommendations...

The role of PI3K isoforms

The catalytic isoform p110 and its regulatory complex p85a have been shown to mediate AR transactivation in the presence of androgens 137 . Overexpression of wild type p110 led to androgen-independent AR transactivation while the overexpression of p110a gene showed no effects. Interestingly, short interference RNA (siRNA) disruption of p110 gene in prostate cancer cells abrogated tumor progression in vivo. Moreover, clinical analysis of tumor samples linked high p110 and p85a expression at the...

Conclusion future directions

It is clear from the foregoing discussion that increased biological knowledge and drug development technologies has resulted in a vast number of agents for clinical trial testing. However, it is paramount that judicious trial designs are employed and match the drug to the tumor by ensuring that the target is present. It is also quite certain that no single drug will work given the inherent multiple redundant survival pathways. This is probably more apparent for castration resistant disease....

Prognostic factors

According to Table 3 the conditional age distributions of the combined T categories 2 until 4 have the same shape and the modus at the age group of 65 until 69. These distributions are shifted slightly towards higher ages with the increasing T category. This simply reflects that it takes time to develop an advanced tumour. However, in those patients diagnosed with T1 category (clinically) the age distribution appears to be totally different. Here 80 of the men are older than 64 (about 60 within...

Regulatory mechanisms of CSCs

Regulatory proteins and pathways establish a balance between a CSC's self-renewal ability and its death by apoptosis. The WNT, SHH, NOTCH, and PI3K AKT mTOR signaling pathways are especially important in this regulation and are often found be impaired in tumors. The WNT signaling pathway is mainly involved in cell proliferation and differentiation. A mutation in one of its components resulting either in an up-regulation or disruption of the signaling cascade can accelerate tumorigenesis...

Posttranslational modification of catenin

The armadillo repeat domains of -catenin are essential for binding to its many partners including E-cadherin, a-catenin and TCF-4. This association of -catenin with various proteins is regulated by post-translational modification at specific sites of the arm repeats (Piedra et al., 2001). Sequences in central arm repeats 4-12 are required for -catenin to associate with E-cadherin (Hulsken et al., 1994). Moreover, phosphorylation of tyrosine residue 654 (located in arm repeat 12) decreases...

Mathematical relationships of exponentially growing tumors and projected tumor marker or tumor sizevolume

The mathematical expression for exponential expansion of growth is Vt V0eat where the tumor volume at time Vt is predictable and is the product of the starting tumor volume V0 and e 2.71828, the base of the natural logarithm raised to the product of the specific growth rate constant a or (SGR) and the duration of growth At or (trt0) . This is given as Vt V0eSGR At and mathematical rearrangement yields SGR Inhibitory drug effects slow SGR and are precisely quantifiable by calculating changes of...

Assessment of molecularly targeted cytostatic or antiangiogenic agents

Bellmunt 53 and others expressed concern that PSA response criteria are not established to properly evaluate molecularly targeted cytostatic or anti-angiogenic agents 54 therefore, certain drug-specific limitations may exist when using PSA or PSA-DT as an indicator of progression or response. One clear example was noted in a study of sorafenib (Nexavar) in castrate resistant prostate cancer, in which two patients with PSA progression were found to have dramatic resolution of bony disease 55 ....

Potential role of PCSCs in metastasis

PC is the second leading cause of cancer death in male but, because of the progress made in the diagnosis and treatment of primary PC, mortality in 70 - 80 of the patients is increasingly linked to its metastatic disease. The bone marrow is the most frequent site for metastasis in PC and stem cells, besides their role in tumorigenicity, are highly migratory cells that are involved in bone metastasis formation 92 . CSCs contain a subpopulation of cells that are exclusively capable of...

Concluding remarks

The cellular localization of E-cadherin and the catenin proteins has a significant role in regulating cancer progression. p-, y- and p120ctn proteins are important components of the E-cad-herin-catenin signal transduction pathway. Elucidating the mechanisms of nuclear localization or nuclear retention of p-, y- and p120ctn proteins, may help us to understand the role of these catenins in regulating E-cadherin downstream signaling events associated with prostate cancer invasion.

Author details

Mario Bernardo Filho1* and Mauro Luis Barbosa J nior2* *Address all correspondence to bernardofilhom gmail.com *Address all correspondence to maurolbarbosajr gmail.com 1 Coordenadoria de Pesquisa, Instituto Nacional de Cancer and Departamento de Biof sica e Biometria, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil 2 Departamento de Medicina de Integral Familiar e Comunit ria, Hospital Universit rio Pedro Ernesto, Universidade...

Endocrine effects on PCSCs

In PC, the stromal niche or microenvironment plays a critical role in regulating differentiation of CSCs, probably by altered endocrine and or paracrine signaling. Direct androgen binding to epithelial ARs is not required for epithelial differentiation, but is essential for the induction and maintenance of a secretory activity 11 . AR is a member of the steroid hormone receptor family and its over-expression is involved prostate tumorigenesis. Consequently, androgen deprivation therapy (ADT)...

Mechanisms and targets in CRPC

The key for the development of new drugs and to optimize androgenic suppression in advanced stages of CRPC is the identification and characterization of molecular targets and mechanisms that lead to tumor growth. Disease progression involves the development of cellular adaptive pathways of survival in an androgen-depleted environment 34 . Experimental evidence assigns an important role to the continuous activation of the androgenic receptors (ARs) in tumor growth, as well as alternative...

Dose selection

Numerous studies have confirmed D90 (the minimum dose received by 90 of the prostate volume) and V100 (percentage of the prostate volume receiving 100 of the prescribed dose) are correlated with outcome 54-56 . Prescription doses for I-125 or palladium-103 (103Pd) are typically 140 to 160 Gy or 110 to 130 Gy, respectively. In practice, many brachytherapists plan a dose higher than the above mentioned doses to compensate for edema, seed misplacement, and so on. Merrick et al. 57 examined...

Other steroidal inhibitors

Other reported steroidal inhibitors of CYP17 are depicted on figure 8. The 17-aza derivative 94 inhibited human CYP17 with an IC50 value of 4.9 jM 123 . Compound 95 inhibited both 5a-reductase and CYP17 with k values of 27 and 14 nM, respectively 124 . The oxime 96 was also a dual inhibitor with the ability to reduce serum and prostatic T and DHT concentrations in vivo 125 .

Pregnanes

Among the pregnane CYP17 inhibitors, compounds 63-65 (Fig. 6, Table 3, entries 1-3) bearing 20-substituents with moderate to strong dipole properties were more active than ketoco-nazole in inhibiting human CYP17, displaying IC50 values of 16 to 230 nM and 16 to 190 nM for the hydroxylase and lyase activities, respectively 90, 110, 111 . In 2000, Hartman et al. tested several pregneneoximes 66-76 among which some were potent inhibitors of both rat and human CYP17 (Fig. 6, Table 3, entries 4-11)...

Bonetargeted treatments

Metastatic prostate cancer has an affinity to spread to the bone. Bone metastases occur in up to 90 of patients with HRPC. These metastases can lead to significant morbidity, including severe pain, fractures, and spinal cord compression tumors in the bone may cause pain, compression, or pathologic fratures, known as skeletal related events (SRE's). Because of the frequent involvement of vertebrae by metastatic prostate cancer, the incidene of cord compression is of particular...