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K J Pienta

Publications and source records attributed to K J Pienta.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cell adhesion and chemotaxis in prostate cancer metastasis to bone: a minireview.

Bone metastasis is a common phenomenon in patients with advanced prostate cancer. The molecular and cellular mechanisms involved in this process are not well understood. Past reviews on this subject primarily focused on prostate tumor growth in the bone marrow and the effects this growth has on bone homeostasis (ie osteoblastic and osteolytic). Cell chemotaxis and adhesion are also important for site-specific metastasis. In this review we have focused on chemotactic and cell adhesion molecules potentially involved in prostate cancer metastasis to bone. In addition, recently developed animal models for prostate cancer metastasis to bone are discussed. Prostate Cancer and Prostatic Diseases (2000) 3, 6-12

Journal Article↗
PubMed2000

Etoposide in prostate cancer.

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.

Anthracyclines↗
PubMed2000

Modified differential display technique that eliminates radioactivity and decreases screening time.

Several techniques are available that detect variations in gene expression between cellular populations. These include subtractive hybridization (SH), differential colony hybridization (DCH) and mRNA differential display, all based on the analysis of mRNA. The first two techniques, however, are limited because they require large amounts of mRNA for SH or several rounds of screening for DCH. Differential display overcomes both of these limitations. However, the conventional differential display technique is plagued by false positives and is labor intensive. The identification of genes that are truly differentially expressed, therefore, becomes a formidable task. We describe a modified differential display technique that overcomes the limitations of the conventional technique. This new technique eliminates a source of false positives, decreases the time required to screen a set of primers and reduces the use of radioactivity.

Animals↗
PubMed2000

Inhibition of prostate specific antigen expression by genistein in prostate cancer cells.

Recent studies have provided convincing evidence for the role of soy-isoflavones, particularly genistein, in the inhibition of prostate cancer cell growth. Prostate specific antigen (PSA) is a biological marker used to detect and monitor the treatment of prostate cancer patients. Previous studies have documented that isoflavones can inhibit the secretion of PSA in the androgen-dependent prostate cancer cell line, LNCaP, however, the effects of genistein on androgen-independent PSA expression has not been explored. In this study, we have utilized a prostate cancer cell line, VeCaP, which expresses PSA in an androgen-independent manner, to determine the effects of genistein on cell proliferation and PSA expression. Here we show that genistein inhibits cell growth similarly in both the LNCaP and VeCaP cell lines, but has differential effects on PSA expression. We demonstrate using concentrations of genistein that have been detected in the serum of humans consuming a soy-rich diet, that genistein decreases PSA mRNA, protein expression and secretion. Conversely, only high concentrations of genistein inhibited PSA expression in VeCaP cells. Additionally, we have demonstrated that genistein inhibits cell proliferation independent of PSA signaling pathways, providing further evidence to support the role of genistein as a chemopreventive/therapeutic agent for prostate cancer irrespective of androgen responsiveness.

Antineoplastic Agents↗
PubMed2000

Rapid ("warm") autopsy study for procurement of metastatic prostate cancer.

In this report, we describe the distribution of metastases from 14 patients who had hormone-refractory adenocarcinoma of the prostate and agreed while alive to undergo directed autopsies after their deaths. These autopsies were undertaken specifically to document the distribution of metastases, characterize tumors phenotypically and immunohistochemically, harvest fresh and snap frozen tumor and normal control tissues suitable for molecular examination, and establish cell lines via passages through generations of severe combined immunodeficient and athymic mice. Achievement of these goals was obtained through the development of a multidisciplinary team approach. Team members included a medical oncologist, pathologists, urologists, and researchers. The autopsy and tissue procurement teams were available on a round-the-clock basis. The tissues harvested from these autopsies yielded high-quality tumor samples, as evidenced by excellent preservation seen by light microscopy, strong prostate-specific antigen immunostaining, and the successful development of xenografts. The development and expansion of this program represent a valuable resource for molecular and clinical researchers.

Aged↗
PubMed2000

Tumor necrosis factor-alpha-induced apoptosis in prostate cancer cells through inhibition of nuclear factor-kappaB by an IkappaBalpha "super-repressor".

Prostate cancer patients experiencing a relapse in disease often express high serum tumor necrosis factor-alpha (TNF-alpha) levels. Many androgen-insensitive prostate cancer cells are TNF-alpha insensitive because of the expression of antiapoptotic genes as part of the nuclear factor-kappaB (NF-kappaB) family of transcription factors. NF-kappaB stimulates gene transcription when expressed in the nucleus; however, in resting cells, this nuclear import is prevented by association with the cytoplasmic inhibitor IkappaBalpha. This cytoplasmic retention of NF-kappaB is uncoupled by many extracellular signals including low levels of TNF-alpha. During normal cell activation, nuclear translocation of NF-kappaB is preceded by phosphorylation and degradation of IkappaBalpha. When phosphorylation is blocked, IkappaBalpha remains intact, thereby blocking NF-kappaB translocation to the nucleus and subsequent activation of antiapoptotic genes that cause TNF-alpha insensitivity. We tested whether a "super-repressor" of NF-kappaB activity could be transfected into prostate cancer cells and make them TNF-alpha sensitive. PC-3 and LNCaP cells were stimulated with TNF-alpha (10 ng/ml) for 24 h in the presence or absence of the IkappaBalpha "super-repressor" (p6R-IkappaB(S32A + S36A)). NF-kappaB activity was measured by electrophoretic mobility shift assay and the steady state levels of the cytoplasmic IkappaBalpha protein were measured by Western blot. Secretory IL-6 and IL-6 mRNA were measured by ELISA. p6R-IkappaB(S32A + S36A) blocked the stimulation of NF-kappaB activity by TNF-alpha in prostate cancer cells. It also subsequently decreased IL-6 production by TNF-alpha. We conclude that these data demonstrate that inhibition of NF-kappaB selectively sensitizes previously insensitive prostate cancer cells to TNF-alpha.

Amino Acid Sequence↗
PubMed2000

Preferential adhesion of prostate cancer cells to bone is mediated by binding to bone marrow endothelial cells as compared to extracellular matrix components in vitro.

We have demonstrated previously that the preferential adhesion of prostate cancer cells to human bone marrow endothelial (HBME) cells may contribute to their preferential metastasis to bone. Although a subject of debate, it has been postulated that the endothelial cells of the bone marrow are fenestrated. It is unknown therefore whether prostate cancer cells adhere preferentially to the extracellular matrix (ECM) or the endothelial cells. It has also been demonstrated in other organ systems that the types of cell adhesion molecules on the surface of endothelial cells lining the organ microvasculature are determined, in part, by the ECM of the organ. We investigated how prostate cancer cell adhesion to HBME cells is affected by growing HBME cells on selected organ-derived ECM proteins in vitro. Growth of HBME cells and immortalized human aortic endothelial cells on bone, kidney, and placenta ECM proteins significantly increased their ability to bind PC-3 cells. This increased adhesion was not dose dependent and was not demonstrated with human dermal microvascular endothelial cells. Scanning electron microscopic analysis demonstrated that prostate cancer cells adhered directly to the endothelial cells and not to the underlying substrata. These results suggest that unidentified cell adhesion molecules are expressed or up-regulated on the apical surfaces of human aortic endothelial cells and HBME cells grown on bone, kidney, and placenta ECMs. These results also strongly demonstrate that the adhesion of prostate cancer cells to bone may be initiated by direct binding to endothelial cells rather than direct binding to exposed ECM components.

Bone Marrow Cells↗
PubMed1999

Parathyroid hormone-related protein as a growth regulator of prostate carcinoma.

Parathyroid hormone-related protein (PTHrP) is produced by prostate carcinoma cells and tumors, but little is known of its role in prostate carcinogenesis. The goal of this study was to evaluate PTHrP expression in the regulation of prostate carcinoma growth using human and animal models. PTHrP expression was assessed in prostate cancer cell lines in vitro. Seven of nine cell lines produced PTHrP, and increased expression was seen during cell proliferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexpression did not alter proliferation of the cells in vitro. However, when PTHrP-overexpressing cells were injected into rat hind limbs, primary tumor growth and tumor size were significantly enhanced as compared with control cells. To evaluate PTHrP in human prostate carcinoma patients, immunohistochemistry was performed on metastatic bone lesions. Immunolocalization of PTHrP protein was found in the cytoplasm and nucleus of cancer cells in the bone microenvironment. Because nuclear localization of PTHrP has been associated with an inhibition of apoptosis, the ability of full-length PTHrP to protect prostate cancer cells from apoptotic stimuli was examined. Cells transfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTHrP (plasmid control) or cells transfected with PTHrP lacking its nuclear localization signal. To determine the mechanism of action of PTHrP in prostate cancer cells, the parathyroid hormone/PTHrP receptor status of the cells was determined. These cell lines did not demonstrate parathyroid hormone/PTHrP receptor-mediated binding of iodinated PTHrP or steady-state receptor message by Northern blot analysis, but they did have a detectable receptor message by reverse transcription-PCR analysis. In summary, PTHrP is expressed in many prostate cancer cell lines in vitro and in metastatic bone lesions in vivo. PTHrP expression positively influences primary tumor size in vivo and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment and/or progression.

Animals↗
PubMed1999

Skeletal metastasis of prostate adenocarcinoma in rats: morphometric analysis and role of parathyroid hormone-related protein.

BACKGROUND: Prostate cancer frequently metastasizes to bone, where it induces osteoblastic lesions. Parathyroid hormone-related protein (PTHrP), a product of normal and neoplastic prostate cells, may promote growth and bone metastasis of certain types of cancer. In this study, we investigated the: 1) pathogenesis and morphology of bone metastases in the MATLyLu rat prostate adenocarcinoma model, and 2) effect of PTHrP overexpression on tumor growth and incidence of bone metastasis. METHODS: MATLyLu cells were stably transfected with a PTHrP expression vector or control plasmid. PTHrP expression was determined in vitro by immunoradiometric assay and Northern blot analysis. MATLyLu cells were injected into the left ventricle of Copenhagen rats to induce bone metastases. Histology and radiography were used to quantify the size and number of bone metastases. Serum alkaline phosphatase isoenzyme concentrations and histomorphometric analysis were used to evaluate bone formation and resorption. RESULTS: All rats developed osteolytic metastases in long bones and vertebrae. There was no evidence of increased intramedullary bone formation. PTHrP overexpression by MATLyLu cells was not associated with any difference in the incidence of bone metastasis, size of metastatic foci or tumor-cell proliferation. CONCLUSIONS: The MATLyLu intracardiac injection model of prostate carcinoma is an aggressive tumor model with a high incidence of osteolytic skeletal metastases, and is not altered by increased PTHrP production by neoplastic prostate epithelial cells.

Adenocarcinoma↗
PubMed1999

Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgen-modulated human prostate cancer.

OBJECTIVES: Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. METHODS: A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. RESULTS: Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. CONCLUSIONS: Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.

Androgen Antagonists↗
PubMed1999

Use of PC-SPES, a commercially available supplement for prostate cancer, in a patient with hormone-naive disease.

OBJECTIVES: PC-SPES, an over-the-counter supplement, is actually a combination of eight different herbs. It is being used by patients to treat cancer of the prostate at different stages of the disease and has been commercially available since November 1996. It has been observed to dramatically decrease prostate-specific antigen (PSA) values in several patients; however, its out-of-pocket cost ($162 to $486/mo) and potential side effects must be weighed against its potential objective benefits. We reviewed its use in 1 patient. METHODS: A patient with clinically localized prostate cancer (T1c) with a PSA of 8.8 ng/mL, who decided to delay any conventional treatment, began treatment with 9 PC-SPES capsules/day. RESULTS: After 3 weeks, his PSA dropped to 1.4 ng/mL and after a total of 8 weeks, his PSA was less than 0.1 ng/mL (undetectable). He has continued on a maintenance dose of 6 capsules per day, decreasing to 4 capsules per day, with a continuing undetectable PSA. During this time the patient also experienced a number of strong estrogenic effects: loss of libido, erectile dysfunction, extreme breast enlargement and tenderness, reduction in overall body hair, pitting edema, and a significant drop in his lipoprotein (a) level (from 46 to 11 mg/dL). CONCLUSIONS: PC-SPES may provide additive advantages (or disadvantages) over prescribed hormonal treatments but must be compared with other hormonal and nonhormonal treatments in clinical trials with hormone-sensitive and -insensitive patients with prostate cancer to determine its future use or nonuse.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line.

OBJECTIVES: To attempt to identify the relationship of the key regulator molecules in paclitaxel-induced apoptosis using two metastatic cell lines: the human prostate carcinoma LNCaP line and the cervical carcinoma HeLa cell line. METHODS: Both LNCaP and HeLa cells were continuously exposed to clinically achievable concentrations of paclitaxel and observed for activation of programmed cell death as measured by cytotoxic dose-response curves, poly(adenosine diphosphate-ribose) polymerase cleavage, bcl-2 phosphorylation, and the activation of caspase-7 (interleukin-1 beta converting enzyme (ICE)-LAP3). RESULTS: Initially, we asked whether paclitaxel-induced bcl-2 phosphorylation is triggered by the spindle assembly checkpoint via an active cdc2 kinase-dependent pathway and whether phosphorylation of endogenous bcl-2 is the signal that activates cell death machinery. Paclitaxel-induced G2/M cell cycle arrest correlated with cdc2 kinase activity and bcl-2 phosphorylation. Olomoucin, a specific inhibitor of cyclin-dependent kinases, inhibited bcl-2 phosphorylation. On the basis of these studies, we then investigated whether bcl-2 was phosphorylated in a cell cycle-dependent fashion. Analysis of synchronized HeLa cells demonstrated that endogenous bcl-2 is phosphorylated in a G2/M cell cycle-dependent manner without apoptosis. CONCLUSIONS: Our results indicate that the events associated with paclitaxel-induced cytotoxicity are connected to each other and represent the signaling network of paclitaxel-induced mitotic arrest and cell death. In addition, we confirmed that the death-decision of paclitaxel-induced apoptosis is not mediated by bcl-2 phosphorylation and believe that this decision may be mediated by the activated spindle assembly checkpoint.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Early castration reduces prostatic carcinogenesis in transgenic mice.

OBJECTIVES: To test the hypothesis that transgenic mouse models of prostate cancer could be useful for testing chemoprevention strategies by evaluating the effects of early castration on prostate carcinogenesis in TRAMP mice. Human prostate cancer, unlike other cancers, requires androgens for oncogenesis yet acquires partial androgen independence in the castrated milieu. This paradigm is the basis for an ongoing clinical trial using selective androgen deprivation for prostate cancer chemoprevention. However, preclinical correlates for hormonal prevention or other chemoprevention strategies of prostate cancer have not previously been demonstrated in autochthonous models of prostate carcinogenesis. METHODS: Magnetic resonance imaging was used to longitudinally measure prostate growth in castrated and noncastrated TRAMP mice, and mice were prospectively examined for the onset of advanced, palpable prostate cancer. Modulation of androgen-responsive oncogene expression, as well as oncogene expression in refractory cancers, was evaluated by Western blot. RESULTS: Early castration significantly reduced prostate tumor growth as measured by magnetic resonance imaging and improved cancer-free survival. Prevention of prostate cancer development in these mice was associated with durable suppression of androgen-responsive oncogene expression (T-antigen expression not detectable by Western blot); prostate cancers refractory to the hormonal prevention strategy demonstrated androgen-independent oncogene expression. CONCLUSIONS: These findings suggest that carcinogenesis related to androgen-responsive oncogene expression can be prevented in some cases by hormonal manipulation and that transgenic TRAMP mice are useful for the preclinical evaluation of hormonal and possibly other strategies of prostate cancer chemoprevention.

Age Factors↗
PubMed1999

Rational use of chemotherapy. It is not just rat poison.

The role of chemotherapy in the management of advanced prostate cancer is expanding. Multiple regimens that use a variety of drugs have been developed. A chemotherapy regimen may appear to be a collection of randomly chosen agents. This article presents the theoretic foundation for the development of combination chemotherapy.

Animals↗
PubMed1999

Oral chemotherapy for hormone refractory prostate cancer. The University of Michigan experience.

The use of oral chemotherapy for the treatment of malignant disease is expanding. The authors' experience with oral chemotherapy for hormone-refractory prostate cancer continues to grow. These therapies are well-tolerated and effective. Already, these regimens are being improved by hybridizing them with intravenous agents such as paclitaxel. Also, oral novel agents are being tested that may offer new options for the treatment of hormone-refractory prostate cancer.

Administration, Oral↗
PubMed1999

Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer.

PURPOSE: To evaluate the combination of intravenous (IV) paclitaxel, oral estramustine, and oral etoposide in patients with advanced hormone-refractory prostate cancer. PATIENTS AND METHODS: Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled onto this phase II trial. Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days, with paclitaxel 135 mg/m(2) IV over 1 hour on day 2 of each 21-day treatment cycle. Patients received a maximum of six cycles of therapy. RESULTS: Thirty-seven patients were assessable for response. Twenty-two had measurable disease at baseline; response was not assessable in six of these patients. Overall response was 45% (10 of 22 patients; 95% confidence interval [CI], 24% to 68%), and response was 63% (10 of 16) in assessable patients. Twenty-six patients had a > or = 50% decrease from their baseline prostate-specific antigen levels during therapy, for a response rate of 65% (95% CI, 48% to 79%) by this criterion. Median duration of response was 3.2 months, with an estimated median survival of 12.8 months. Major toxicities of therapy were leukopenia (eight patients had > or = grade 4 leukopenia) and anemia. Hematologic toxicity seemed to be associated with liver metastases. Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) showed no significant change in quality of life (QOL) as a result of therapy. CONCLUSION: The combination of IV paclitaxel, oral estramustine, and oral etoposide is active in patients with advanced prostate cancer. The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients.

Adenocarcinoma↗