Prostatic Neoplasms: Pienta KJ

Scher HI, Eisenberger M, D'Amico AV, Halabi S, Small EJ, Morris M, Kattan MW, Roach M, Kantoff P, Pienta KJ, Carducci MA, Agus D, Slovin SF, Heller G, Kelly WK, Lange PH, Petrylak D, Berg W, Higano C, Wilding G, Moul JW, Partin AN, Logothetis C, Soule HR. · Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. · J Clin Oncol. · Pubmed #14752077 No free full text.

Abstract: PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). RESULTS: Hypothesis: A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. Patient Population: The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. Intervention: Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. Outcomes: An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting: Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. Trial Design: The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. CONCLUSION: Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward.

Pienta KJ. · Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA. · Urology. · Pubmed #19375622 No free full text.

Abstract: Prostate-specific antigen (PSA) is secreted by all types of prostate epithelial cells and has been used for 2 decades as a biologic marker for prostate cancer (PCa). Since the implementation of PSA screening in the United States, the detection of PCa has increased, accompanied by a decrease in the incidence of high-grade cancer and PCa-specific mortality rates. It has been suggested that these decreases have resulted from the enhanced detection of PCa while still curable. These data have been the impetus for early detection programs, which have recommended the initiation of screening as early as 40 years of age. Despite widespread use, PSA screening remains controversial, principally because of the lack of evidence from randomized controlled trials demonstrating a mortality benefit that could outweigh the concerns of the costs of overdiagnosis and overtreatment. Two ongoing, randomized controlled trials are examining whether screening reduces the risk of PCa-related mortality, and the results of these studies are expected soon. Although it has its limitations, PSA still remains the best-studied marker for the detection of PCa.

Pienta KJ, Bradley D. · Michigan Urology Center, University of Michigan, Ann Arbor, Michigan 48109-0946, USA. · Clin Cancer Res. · Pubmed #16551847 links to  free full text

This publication has no abstract.

Mackler NJ, Pienta KJ. · University of Michigan, Ann Arbour, MI, USA. · Nat Clin Pract Urol. · Pubmed #16474654 No free full text.

Abstract: Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies, with two taxanes now in clinical use. Their mechanism of action against tumor cells is by alteration of microtubule dynamics, which causes cell-cycle arrest during mitosis. Docetaxel binds to the microtubules with a higher affinity than paclitaxel, and over a broader range of cell-cycle activities. It has also been shown to promote apoptosis via BCL2 phosphorylation. In hormone-refractory prostate cancer, docetaxel has been studied as both a single agent and in combination with estramustine, and in different treatment schedules, with demonstrated efficacy. Two phase III trials have confirmed a survival benefit, making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer. In urothelial cancer, docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens. A phase III trial comparing docetaxel and cisplatin to methotrexate, vinblastine, doxorubicin, and cisplatin was inferior when evaluating response rates and overall survival. More recent phase II trials combining docetaxel with two additional agents have shown promise, but confirmatory trials are needed.

Loberg RD, Logothetis CJ, Keller ET, Pienta KJ. · University of Michigan, Ann Arbor, MI, USA. · J Clin Oncol. · Pubmed #16278478 No free full text.

Abstract: Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell-microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer-bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.

Pienta KJ, Smith DC. · Michigan Urology Center, University of Michigan, Ann Arbor, MI, USA. · CA Cancer J Clin. · Pubmed #16166075 links to  free full text

Abstract: Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men prostate cancer ultimately progresses to an androgen-independent state resulting in death due to widespread metastases. Multiple mechanisms of androgen independence have now been documented, including amplification of the androgen receptor as well as signal transduction pathways that bypass the androgen receptor completely. In 2004, two landmark studies demonstrated a survival advantage in androgen-independent prostate cancer patients utilizing docetaxel chemotherapy, setting a new standard of care for this disease. In addition, treatments with the bisphosphonate zoledronic acid and systemic radioisotopes have also been shown to have palliative benefits in this population. Building on these advances, several new traditional chemotherapeutic agents as well as new targeted therapies are under development.

Olson KB, Hellie CM, Pienta KJ. · Michigan Urology Center, University of Michigan Medical Center, Ann Arbor, Michigan, USA. · Urology. · Pubmed #16140106 No free full text.

Abstract: Intravenous bisphosphonates are widely used in the management of metastatic bone disease, as well as osteoporosis. Recent published reports have documented a possible link between treatment with intravenous bisphosphonates and osteonecrosis of the jaw. We report a case of osteonecrosis of the jaw in 1 patient with prostate cancer receiving both chemotherapy and intravenous zoledronic acid (Zometa). Bisphosphonates have been demonstrated to alter the normal bone microenvironment and appear to have direct effects on tumors as well. These changes may contribute to the development of osteonecrosis of the jaw, particularly after tooth extractions or other invasive dental procedures.

Pienta KJ, Loberg R. · University of Michigan Urology Center, Ann Arbor, MI 48109-0946, USA. · Clin Prostate Cancer. · Pubmed #15992458 No free full text.

Abstract: In the vast majority of cases, cancer continues to be an incurable disease when it has spread beyond the primary organ. Most cancer research and therapy design to date has focused on chemotherapy directed at killing the replicating tumor cells. Little attention has been placed on targeting the microenvironments of the primary tumor site, the circulating tumor cells, or the metastatic or secondary (target) tumor site and how cancer cells move among them. To develop these targets, a better understanding of metastasis and the mechanisms underlying the spread of tumors is required. This review describes the steps of metastasis using a paradigm of emigration to migration to immigration, with prostate cancer as a model system.

Loberg RD, Gayed BA, Olson KB, Pienta KJ. · Department of Urology, University of Michigan Urology Center, The University of Michigan, Ann Arbor, Michigan 48109-0946, USA. · J Cell Biochem. · Pubmed #15988761 No free full text.

Abstract: The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics.

Loberg RD, Fridman Y, Pienta BA, Keller ET, McCauley LK, Taichman RS, Pienta KJ. · Department of Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0946, USA. · Neoplasia. · Pubmed #15256052 links to  free full text

Abstract: The American Cancer Society has estimated that in 2003, there will be approximately 239,600 new cases of urologic cancer diagnosed and 54,600 urologic cancer-related deaths in the United States. To date, the majority of research and therapy design have focused on the microenvironment of the primary tumor site, as well as the microenvironment of the metastatic or secondary (target) tumor site. Little attention has been placed on the interactions of the circulating tumor cells and the microenvironment of the circulation (i.e., the third microenvironment). The purpose of this review is to present the methods for the detection and isolation of circulating tumor cells and to discuss the importance of circulating tumor cells in the biology and treatment of urologic cancers.

Chay CH, Cooper CC, Hellerstedt BA, Pienta KJ. · Hematology/Oncology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. · Clin Prostate Cancer. · Pubmed #15046708 No free full text.

Abstract: Despite the benefits of local therapy with radical prostatectomy and radiation, many patients with prostate cancer require hormonal ablation. While chemotherapy has proven efficacy when the disease progresses to androgen-independent prostate cancer, patients ultimately succumb to the disease, thus the identification of other active therapies is needed. Future treatment modalities include molecular targeted therapies. Prostate cancer has been an ideal model to study the multiple steps required in the metastatic cascade. These steps have been utilized in the development of metastasis inhibitors. This review will present promising agents that have been tested preclinically or are undergoing clinical investigation for their abilities in preventing prostate cancer metastasis. Because prostate cancer metastasizes preferentially to the bone, special attention will be given to agents that interfere with this pattern of metastasis. Specifically, the efficacy of angiogenesis inhibitors, metalloproteinase inhibitors, inhibitors of prostate cancer cell- endothelial cell interactions, and bisphosphonates will be reported. In addition, the introduction of these novel agents has raised many questions as to the relevance and optimal utilization of current clinical trial designs. Issues regarding combination therapy with chemotherapy, optimal timing of treatment with metastatic inhibitors, and the need for surrogate endpoints for molecular targeted therapies will be discussed.

Cooper CR, Sikes RA, Nicholson BE, Sun YX, Pienta KJ, Taichman RS. · Department of Biological Sciences, University of Delaware, Newark DE 19716, USA. · Cancer Treat Res. · Pubmed #15043197 No free full text.

This publication has no abstract.

Tantivejkul K, Kalikin LM, Pienta KJ. · Department of Urology, Division of Hematology and Oncology, The Michigan Urology Center at The University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA. · J Cell Biochem. · Pubmed #14991762 No free full text.

Abstract: Prostate cancer metastasis to the bone occurs at high frequency in patients with advanced disease, causing significant morbidity and mortality. Over a century ago, the "seed and soil" theory was proposed to explain organ-specific patterns of metastases. Today, this theory continues to be relevant as we continue to discover factors involved in the attraction and subsequent growth of prostate cancer cells to the bone. These include the accumulation of genetic changes within cancer cells, the preferential binding of cancer cells to bone marrow endothelial cells, and the release of cancer cell chemoattractants from bone elements. A key mediator throughout this metastatic process is the integrin family of proteins. Alterations in integrin expression and function promote dissociation of cancer cells from the primary tumor mass and migration into the blood stream. Once in circulation, integrins facilitate cancer cell survival through interactions between other cancer cells, platelets, and endothelial cells of the target bone. Furthermore, dynamic changes in integrins and in integrin-associated signal transduction aid in the extravasation of cancer cells into the bone and in expansion to a clinically relevant metastasis. Thus, we will review the critical roles of integrins in the process of prostate cancer bone metastasis, from the escape of cancer cells from the primary tumor, to their survival in the harsh "third microenvironment" of the circulation, and ultimately to their attachment and growth at distant bone sites.

Loberg RD, Fielhauer JR, Pienta BA, Dresden S, Christmas P, Kalikin LM, Olson KB, Pienta KJ. · Department of Medicine, Michigan Urology Center, University of Michigan, Ann Arbor, Michigan 48109-0946, USA. · Urology. · Pubmed #14747050 No free full text.

Abstract: The relation between tumor kinetics and disease progression in patients with hormone-refractory prostate cancer (HRPC) has not been well described. Biochemical recurrence of prostate cancer is characterized by detectable prostate-specific antigen (PSA) levels after treatment and occurs in approximately 30% of patients after therapy for apparent localized disease. An increase in PSA almost always occurs before clinical evidence of disease. The ability to identify early biochemical failure in patients to assess disease aggressiveness and guide changes in treatment needs to be examined. We examined serial PSA data from 249 patients with metastatic disease to assess PSA doubling time (PSADT) in hormone-naive prostate cancer (HNPC) and HRPC states. In a subset of patients, the relation of PSADT to Gleason score and survival was studied. PSADT decreased from 37.5 +/- 4.5 weeks to 15.6 +/- 1.6 weeks (mean +/- SEM) in patients with HNPC versus HRPC. In this small study, PSADT did not correlate with Gleason score, survival from start of hormonal treatment, length of time receiving hormone therapy, or survival in the HRPC state. The decrease in PSADT with disease state may help provide insight into understanding the biology of late-stage disease.

Hellerstedt BA, Pienta KJ. · Division of Hematology/Oncology, University of Michigan Medical Center, 1150 West Medical Center Drive, Box 0640, 5301 MSRB III, Box 0640, Ann Arbor, MI 48109, USA. · Urol Oncol. · Pubmed #12954498 No free full text.

Abstract: Androgen deprivation therapy (ADT) is a mainstay in the treatment of prostate cancer. The ideal timing, duration and composition of ADT remains undefined. At the present time, first-line therapy consists of orchiectomy, LHRH agonists, or combined androgen blockade (CAB). However, new combinations and treatment settings show promise for improving outcomes and decreasing toxicity.

Cooper CR, Chay CH, Gendernalik JD, Lee HL, Bhatia J, Taichman RS, McCauley LK, Keller ET, Pienta KJ. · Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0946, USA. · Cancer. · Pubmed #12548571 links to  free full text

Abstract: BACKGROUND: Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site. METHODS: The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth. RESULTS: The authors demonstrate that PC cells express protease-activated receptor 1 (PAR1; thrombin receptor), and its expression is up-regulated in PC compared with normal prostate tissue. In addition, this overexpression was very pronounced in bone-derived PC cell lines (VCaP and PC-3) compared with soft tissue PC cell lines (DUCaP, DU145, and LNCaP). The authors report that bone stromal factors, including stromal cell-derived factor 1 (SDF-1) and collagen Type I peptides, are chemoattractants for PC cells, and they demonstrate that some of these factors (e.g., extracellular matrix components, transforming growth factor beta, bone morphogenic proteins [BMPs], and SDF-1) significantly alter PC-HBME interaction in vitro. Finally, stromal factors, such as BMPs, can regulate the proliferation of PC cells in vitro. CONCLUSIONS: Soluble and insoluble elements of the stroma are involved in multiple steps of PC metastasis to bone. The authors hypothesize that PAR1 may play a central role in prostate tumorigenesis.

Keller ET, Zhang J, Cooper CR, Smith PC, McCauley LK, Pienta KJ, Taichman RS. · Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, USA. · Cancer Metastasis Rev. · Pubmed #12085970 No free full text.

Abstract: The majority of men with progressive prostate cancer develop metastases with the skeleton being the most prevalent metastatic site. Unlike many other tumors that metastasize to bone and form osteolytic lesions, prostate carcinomas form osteoblastic lesions. However, histological evaluation of these lesions reveals the presence of underlying osteoclastic activity. These lesions are painful, resulting in diminished quality of life of the patient. There is emerging evidence that prostate carcinomas establish and thrive in the skeleton due to cross-talk between the bone microenvironment and tumor cells. Bone provides chemotactic factors, adhesion factors, and growth factors that allow the prostate carcinoma cells to target and proliferate in the skeleton. The prostate carcinoma cells reciprocate through production of osteoblastic and osteolytic factors that modulate bone remodeling. The prostate carcinoma-induced osteolysis promotes release of the many growth factors within the bone extracellular matrix thus further enhancing the progression of the metastases. This review focuses on the interaction between the bone and the prostate carcinoma cells that allow for development and progression of prostate carcinoma skeletal metastases.

Olson KB, Pienta KJ. · Urologic Oncology, University of Michigan Medical Center, 1500 East Medical Center Drive, 7303 CCGC, Ann Arbor, MI 48109, USA. · Curr Urol Rep. · Pubmed #12084341 No free full text.

Abstract: Recently, several important studies have validated prostate-specific antigen (PSA) as a reliable measure of response to chemotherapeutic treatment in advanced hormone-refractory prostate cancer. Furthermore, although chemotherapy in this setting has always been considered palliative, several analyses of recent clinical trials have demonstrated a significant association between declines in PSA values of 50% or more and prolonged survival. Mitoxantrone, in combination with prednisone, has been shown to provide significant palliation and improved quality of life. The use of combinations of chemotheraputic agents also seems to provide significantly superior objective and subjective responses compared with single-agent regimens. In particular, estramustine has been shown to synergize many of the agents used in prostate cancer treatment and has been demonstrated to provide significant palliation and decline in PSA levels in combination with vinblastine, vinorelbine, etoposide, paclitaxel, and docetaxel. The results of several important trials of the taxanes both as single agents and in combination with estramustine have been completed in the past year and have demonstrated that these agents are very effective in the treatment of hormone-refractory prostate cancer.

Hellerstedt BA, Pienta KJ. · Division of Hematology and Oncology, University of Michigan Medical Center, Ann Arbor, USA. · CA Cancer J Clin. · Pubmed #12018929 links to  free full text

Abstract: Androgen deprivation therapy remains a mainstay of treatment for men with prostate cancer. New uses for hormonal therapy, including use in the adjuvant and neoadjuvant setting, are being evaluated. Prevention of the side effects of therapy has led to the development of alternative schedules and therapeutics.

Cooper CR, Chay CH, Pienta KJ. · Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. · Neoplasia. · Pubmed #11988838 links to  free full text

Abstract: Integrin alpha(v)beta(3) is involved in varied cell biological activities, including angiogenesis, cell adhesion, and migration on several extracellular matrix components. Although alpha(v)beta(3) is not typically expressed in epithelial cells, it is expressed in macrophages, activated leukocytes, cytokine-stimulated endothelial cells, osteoclasts, and certain invasive tumors. Interestingly, the adhesion and migration of breast cancer cells on bone matrix are mediated, in part, by alpha(v)beta(3). Similar to breast cancer cells, prostate cancer cells preferentially metastasize to the bone. The biological events that mediate this metastatic pattern of prostate cancer are not well defined. This review discusses the role alpha(v)beta(3) plays in prostate cancer progression, with specific emphasis on bone metastasis and on alpha(v)beta(3) signaling in prostate cancer cells. The data suggest that alpha(v)beta(3), in part, facilitates prostate cancer metastasis to bone by mediating prostate cancer cell adhesion to and migration on osteopontin and vitronectin, which are common proteins in the bone microenvironment. These biological events require the activation of focal adhesion kinase and the subsequent activation of PI-3 kinase/Akt signaling pathway.

Moyad MA, Pienta KJ. · Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0330, USA. · Urology. · Pubmed #11937431 No free full text.

Abstract: A possible relation may exist between higher insulinlike growth factor (IGF)-1 levels and the risk of premenopausal breast, prostate, or other cancers from recent prospective and case-control studies. Separately, a large prospective study has shown a potential association between chronic depression and cancer risk, whereas other preliminary studies have suggested a link between increasing IGF levels with major depression. Other studies have found that certain standard cancer treatments reduce the effect and levels of IGF, and 1 small study has found that standard antidepressants may reduce IGF levels in some patients diagnosed with major depression. It is possible that IGF-1 (or other IGFs) may be a mediator between depression and cancer, because separately both have been implicated in the risk of various cancers. This hypothesis first and foremost relies on the unsettled notion that an actual relation already exists or may be found in the future. It requires more extensive investigation because several studies have not found an association between IGF or depression and cancer risk, and other limitations such as small sample sizes and other influential factors on IGF levels need to be elucidated. Whether or not a mind-body effect exists with cancer, as seems to be the case with other diseases, remains to be seen. Is depression a potential confounder of human studies that attempts to establish a relation between IGF and disease? All of the studies to date have attempted to at least determine the effect of a variety of factors on IGF levels-including age, sex, diet, family history, weight, smoking status-and then have adjusted their results accordingly. Depression has not been included in this list of potential factors that may need to be considered when analyzing IGF-1 data and cancer risks. The time seems ripe to at least define further the relation, if any, between IGF-1 and depression.

Pienta KJ. · Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109-0946, USA. · Semin Oncol. · Pubmed #11685722 No free full text.

Abstract: Docetaxel, a semisynthetic taxane, has exhibited significant single-agent activity against prostatic tumors. In phase I/II studies, single-agent docetaxel and the combination of docetaxel plus estramustine were effective in inducing prostate-specific antigen reductions of > or =50% in men with androgen-independent prostate cancer (AIPC). The underlying reason for docetaxel's clinical activity against prostate cancer has been a focus of ongoing research. Docetaxel is believed to have a twofold mechanism of antineoplastic activity: (1) inhibition of microtubular depolymerization, and (2) attenuation of the effects of bcl-2 and bcl-xL gene expression. Taxane-induced microtubule stabilization arrests cells in the G(2)M phase of the cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of events that ultimately leads to apoptotic cell death. In preclinical studies, docetaxel had a higher affinity for tubulin and was shown to be a more potent inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine. The pathways for docetaxel-induced apoptosis appear to differ in androgen-dependent and androgen-independent prostate cancer cells. Further elucidation of these differences will be instrumental in designing targeted regimens for the treatment of localized and advanced prostate cancer.

Kamradt JM, Pienta KJ. · University of Michigan Medical Center, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA. · Expert Opin Pharmacother. · Pubmed #11249548 No free full text.

Abstract: Hormone refractory prostate cancer is a disease that kills approximately 39,000 people per year. No single chemotherapeutic agent or regimen has been demonstrated to provide a survival advantage in this disease. Etoposide as a single agent, both in i.v. and oral formulations has not proven to be effective. In the 1990s, however, etoposide has been combined with several agents to create novel treatment regiments for patients with hormone refractory disease. Several of these regimens, all involving oral etoposide, have demonstrated promising results in Phase II trials and early results suggest that they may increase survival for hormone refractory patients, although this remains to be tested in a Phase III trial setting.

Pienta KJ, Kamradt JM, Smith DC. · The University of Michigan Comprehensive Cancer Center, Department of Internal Medicine, The University of Michigan School of Medicine, Ann Arbor 48109-0005, USA. · Drugs. · Pubmed #10711851 No free full text.

Abstract: Oral chemotherapy has become a major component of the treatment of advanced prostate cancer. The recognition that prostate cancer grows very slowly and must be treated continuously with active agents has led to the development of several therapeutic regimens. These regimens employ oral agents such as estramustine, cyclophosphamide, and etoposide, as they can be taken on a daily basis at home by the patients. These regimens have demonstrated activity in patients with hormone-refractory prostate cancer; declines in both prostate specific antigen and soft tissue lesions have been demonstrated.

Kamradt JM, Pienta KJ. · Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor 41809-0946, USA. · Semin Oncol. · Pubmed #10597734 No free full text.

Abstract: The treatment options available for advanced prostate cancer are increasing. These improved therapies are the result of research involving cellular targets other than DNA proliferation. For example, therapy directed against the intracellular matrix has yielded clinical responses in patients. Other novel targets are being investigated. This review examines both laboratory and clinical advances using cell structure, growth factors, differentiating agents, angiogenesis, metastasis, and the cell cycle in the treatment of prostate cancer.