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K J Pienta

Publications and source records attributed to K J Pienta.

At least 55 records · Page 3Linked to original sources
PubMed1999

The role of the nuclear matrix in cancer chemotherapy.

The nuclear matrix is the site of many nuclear functions including transcription, replication, formation of chromatin loops, and control of DNA supercoiling. It contains various structural and functional components that represent targets for antineoplastic agents. Antimetabolites and topoisomerase II inhibitors interact specifically with matrix-associated enzymes, DNA primase, and DNA topoisomerase II, respectively. Alkylating agents and ionizing radiation interact with nuclear matrix proteins and matrix-associated DNA. Many nuclear functions, including multidrug resistance, and others which lead to cell death, have been shown to be compromised when these anticancer agents interact with the nuclear matrix.

Antineoplastic Agents↗
PubMed1999

Oral chemotherapy in the treatment of hormone-refractory prostate cancer.

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.

Administration, Oral↗
PubMed1999

Paclitaxel in the treatment of hormone-refractory prostate cancer.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men in the United States. In 1997 it was estimated that more than 41,000 men died of this disease. Treatment of metastatic disease remains palliative, with androgen ablation used as first-line therapy. After failure of androgen ablation, chemotherapy can now be used to induce a remission in many men. Treatment regimens that include paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have been particularly successful in treating hormone-refractory prostate cancer in the phase II setting. We have conducted a trial of estramustine 280 mg orally three times per day for 14 days combined with etoposide 50 mg/m2/d (in general, one 50-mg tablet twice a day) for 14 days, with paclitaxel 135 mg/m2 over 1 hour on day 2. This regimen is repeated every 21 days for a maximum of six cycles. Patients responding to therapy are then given a break and re-treated at physician discretion. On preliminary analysis, 24 of 38 patients demonstrated a decline in pretreatment prostate-specific antigen of more than 50% (63%). The regimen was well-tolerated and only seven patients demonstrated grade 3 or 4 neutropenia. Further analysis is ongoing.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Vitamin E, alpha- and gamma-tocopherol, and prostate cancer.

Vitamin E is one of the most researched compounds in medicine. Vitamin E is actually a general name for potentially eight different compounds, so supplements can contain several forms and vitamin E in the diet also differs from the form found over the counter. There has been a strong interest in this supplement in the prostate cancer arena primarily because of a Finnish study that demonstrated a lower morbidity and mortality from this disease in men taking 50 mg of synthetic (alpha-tocopherol) vitamin E daily. In addition, observations from laboratory and clinical studies dealing with heart disease have found that gamma-tocopherol may also play a significant role in prevention; therefore, we decided to test the ability of this compound (versus synthetic vitamin E) to control the growth of a human prostate cancer cell line. Gamma-tocopherol was found to be superior to alpha-tocopherol in terms of cell inhibition in vitro. Both forms of vitamin E (and others) should be thoroughly evaluated in the future to provide the most effective chemoprevention information to the patient.

Dietary Fats↗
PubMed1999

Novel molecular targets for prostate cancer therapy.

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.

Angiogenesis Inhibitors↗
PubMed1998

Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation: a potential early step in drug resistance.

The chemotherapeutic agent paclitaxel disrupts microtubule dynamics causing mitotic arrest, which leads to cell death. However, in paclitaxel-resistant tumor cells, treatment with paclitaxel induces abnormal progression through prophase resulting in a multimininucleated phenotype. Multimininucleation and subsequent polyploidization have been correlated with paclitaxel resistance. Paclitaxel treatment of HeLa cells resulted in cell death via typical activation of the apoptotic machinery, whereas treatment of the relative paclitaxel-resistant prostate cancer cell line PC-3 induced an attenuated caspase activation and multimininucleation. The multimininucleated phenotype could be mimicked in HeLa cells treated with paclitaxel and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a peptide caspase inhibitor. Interestingly, we observed no discernible difference in the pattern of cdc-2 kinase activation or phosphorylation of bcl-2-like proteins in PC-3 and HeLa cells treated with paclitaxel, which demonstrated that these molecules could not be used as indicators for the degree of caspase activation. In this study, we establish a connection between relative paclitaxel resistance, caspase attenuation/inhibition, and the multimininucleated phenotype.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line.

BACKGROUND: In virtually all patients with advanced prostate cancer, the disease metastasizes to bone and causes osteoblastic growth. However, the mechanisms that contribute to bone metastasis are poorly understood. It has been hypothesized that the bone provides a favorable growth environment for prostate cancer cells, which nonselectively seed the bone marrow from the bloodstream. Alternatively, prostate cancer cells may preferentially bind to bone marrow endothelial cells. We developed an in vitro model of bone endothelium and tested the hypothesis that prostate cancer cells adhere preferentially to bone marrow endothelial cells. METHODS: We isolated and characterized a human bone marrow endothelial (HBME-1) cell line. Cells were transfected with the simian virus 40 large T antigen for immortalization. Cell surface receptors were characterized by immunohistochemistry and flow cytometry. The adhesion of cancer cells to HBME-1 and to endothelial cell lines from other organs was tested in an in vitro binding assay as were inhibitors of adhesion. RESULTS: The immortalized HBME-1 cell line demonstrated many properties characteristic of endothelial cells, including positive staining for von Willibrand factor and rapid formation of tubule structures when exposed to extracellular matrices. In an in vitro assay, prostate cancer cells adhered preferentially to human bone marrow endothelium when compared with endothelium derived from other sources. Preferential adhesion was blocked, in part, by antibodies to galectin-3 and LFA-1. IMPLICATIONS: These data suggest that the propensity of prostate cancer cells to establish themselves in bone is due, at least in part, to their preferential adhesion to human bone marrow endothelial cells.

Bone Marrow Cells↗
PubMed1998

A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer.

OBJECTIVES: To test the use of 1 mg/day of oral diethylstilbesterol (DES) as a treatment for patients with advanced prostate cancer who had failed primary hormonal therapy. Approximately 40,000 men this year will experience first-line hormonal therapy failure for their metastatic prostate cancer. At this time there is no standard therapy for men whose first-line hormonal manipulation has failed. This clinical problem has been exacerbated by the use of prostate-specific antigen (PSA) as a proved biomarker to follow disease progression. Patients who are experiencing hormonal therapy failure now present with a rising PSA, and virtually all are asymptomatic. The dilemma of how to treat these patients represents a new clinical problem for the medical oncologist and urologist that needs to be answered. METHODS: We conducted a Phase II trial of oral DES in 21 patients. Patients were followed for response by PSA criteria and toxicity. A decrease in two serial measurements of PSA of greater than 50% from baseline was judged to be a partial response. RESULTS: Nine of 21 patients achieved a PSA response (43% response rate with 95% confidence intervals of 22% to 64%) leading to early cessation of this Phase II trial. Eight of 13 patients (62%) who had only one prior hormone manipulation that failed demonstrated a PSA response, whereas only 1 of 8 patients (13%) who had received two or more hormone treatments responded (P = 0.07). The median follow-up is 82 weeks (range 8 to 122) among 16 surviving patients. The survival rate at 2 years is 63% (95% confidence interval 41% to 99%). CONCLUSIONS: DES appears to be an active agent for second-line hormone therapy for metastatic prostate cancer. Because it has been taken off the market for economic reasons, DES should be considered for development under the orphan drug strategy.

Administration, Oral↗
PubMed1998

Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer.

PURPOSE: Prostate-specific antigen (PSA) has been used as a marker of advanced prostate cancer but remains controversial. To evaluate PSA as a predictor of survival, we analyzed data from sequential phase II trials of estramustine and etoposide. METHODS: A landmark analysis that used data from 62 men with PSA levels at baseline and 8 weeks was conducted. The best PSA measure (of six evaluated) was incorporated into a multiple regression model with performance status (PS); relative change in PSA level; and pretreatment PSA, alkaline phosphatase, and hemoglobin values. RESULTS: A decrease in PSA of 50% or greater at 8 weeks was associated with a significantly increased survival (P=.0005, two-sided log-rank test). Median survival from the landmark was 91 weeks in patients with a 50% or greater decrease at 8 weeks versus 38 weeks in those without this decrease. Modeling showed that PS, pretreatment hemoglobin level, and relative change in PSA level were significant prognostic factors, with a significant interaction between PS and pretreatment hemoglobin level. In the final model, a relative change in PSA level at 8 weeks of less than 50% had an adjusted relative risk of 2.20 (95% confidence interval, 1.21 to 4.00). A decrease in PSA level of 50% or greater at any time during therapy was associated with a response in measurable disease (P=.0369, two-sided Fisher's exact test). CONCLUSION: The PSA value after 8 weeks of this cytotoxic regimen does predict survival. A decrease in PSA level is associated with both survival and response in soft tissue lesions and should be incorporated into the response criteria and reporting of trials of cytotoxic agents in prostate cancer.

Aged↗
PubMed1998

Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice.

PURPOSE: Human prostate cancer is variably lethal, shows heterogeneous progression, and exhibits a spectrum of histopathology. Traditional rodent models of prostate cancer lack these characteristics. An alternative, autochthonous model of prostate cancer consists of transgenic mice which develop prostate cancer due to prostatic expression of SV40 T antigen. Lethal progression of such cancers in individual mice has not been previously characterized. Studies were undertaken to characterize the longitudinal progression of prostate cancers in these transgenic mice. METHODS: A prospective longitudinal cohort study was undertaken to characterize prostate cancer volume, progression, lethality, and histological heterogeneity in a transgenic mouse model of prostatic adenocarcinoma. Fifty-one transgenic mice were followed prospectively to determine the age at onset of palpable tumor and age at cancer-related death. Tumor volume was followed longitudinally by magnetic resonance imaging (MRI) in a subset of these mice and lethal cancers were evaluated by histopathology. RESULTS: Primary tumors became palpable at 10-38 weeks of age. Palpable tumors always preceded lethal progression. Cancer death followed 2-9 weeks later, and age at cancer death varied from 24 to 39 weeks of age. The histopathological changes were heterogeneous. Primary tumors were detectable by MRI before they became detectable by palpation. MRI showed that, analogous to human prostate cancers, volume of early stage primary tumors did not necessarily predict age at cancer death. CONCLUSION: Prostate cancer in transgenic mice mimics heterogeneic tumor progression in human prostate cancer, providing a uniquely relevant pre-clinical model. Tumor detection by MRI and palpation are valid surrogate measures of tumor progression in this model.

Animals↗
PubMed1998

A model to study c-myc and v-H-ras induced prostate cancer progression in the Copenhagen rat.

Normal rat prostate epithelial cells (EPYP-1) were isolated and immortalized with the Simian Virus-40 (SV40) large T-antigen, and transfected with the v-H-ras (EPYP-1-ras) and the c-myc oncogenes (EPYP-1-myc; EPYP-1-ras-myc) to serially create a step-wise model of tumor development in the rat prostate. Pronounced morphological differences were observed between EPYP-1 and the transfected sublines. The immortal epithelial cells (EPYP-1) maintained a cuboidal shape with orderly, contact mediated inhibition of growth. Oncogene transfected clones displayed a spindle shaped structure with multiple overlapping pseudopodia. Transfected cells also exhibited a greater degree of dysplasia, loss of contact inhibition growth and the upregulation of an epithelial tumor marker, cytokeratin-18. All cells exhibited anchorage independent and androgen independent growth. In vivo, EPYP-1 cells and EPYP-1-myc and formed slowly growing non-metastatic, benign tumors in immune compromised mice, while EPYP-1-ras and EPYP-1-ras-myc transfected cells produced rapidly growing, malignant tumors in similar animals. This model augments the hypothesis that tumor initiation and progression can be caused by as few as two discrete genetic events. In addition, the "normal" rat prostate epithelium and transfected daughter cell lines represent a tumor model system with distinct, well understood genetic alterations: activation of ras and myc. This model will be a valuable addition to the current cell lines used in the investigation of prostate cancer carcinogenesis.

Animals↗
PubMed1997

A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer.

OBJECTIVES: We previously demonstrated that the combination of oral estramustine (15 mg/kg/day) and oral etoposide (50 mg/m2/day) is effective first-line therapy for the treatment of hormone refractory prostate cancer. We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment. METHODS: Estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up. RESULTS: Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival. CONCLUSIONS: We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.

Administration, Oral↗
PubMed1997

Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument.

OBJECTIVES: As the incidence of prostate cancer in the United States exceeds 330,000 in 1997, increasingly more men are faced with treatment choices for which there is no clear approach. At every stage of disease, these treatment choices may involve clinically equivalent modalities that differ in side effects and impact upon quality of life (QOL). Comprehensive, yet efficient, questionnaires are needed to measure QOL in patients with prostate cancer. METHODS: Developed as a disease-specific adjunct to the Functional Assessment of Cancer Therapy (FACT) measurement system, a 12-item prostate cancer subscale (PCS) was developed and tested in three independent samples: a subscale development sample (n = 43), validity sample 1 (n = 34), and validity sample 2 (n = 96). The 12 items ask about symptoms and problems specific to prostate cancer. These questions are added to the general (FACT-G) instrument, thereby comprising a 47-item questionnaire. RESULTS: Internal consistency of the PCS ranged from 0.65 to 0.69, with coefficients for FACT-G subscales and aggregated scores ranging from 0.61 to 0.90. Concurrent validity was confirmed by the ability to discriminate patients by disease stage, performance status, and baseline prostate-specific antigen (PSA) level. Sensitivity to change in performance status and PSA score over a 2-month period suggested that some subscales of the FACT-Prostate (P) (including the PCS) are sensitive to meaningful clinical change. CONCLUSIONS: Our findings support use of the FACT-P as a meaningful component of QOL evaluation in men undergoing therapy for prostate cancer.

Aged↗
PubMed1997

The use of prostate-specific antigen as a surrogate end point in the treatment of patients with hormone refractory prostate cancer.

Prostate-specific antigen increasingly is being used as a surrogate end point in trials of new agents in patients with hormone refractory prostate cancer. This article reviews data that support this marker as a surrogate end point and the contradictory data reported recently for trials of suramin. These contrasting views may originate in the different mechanisms of actions of the agents studied. These data suggest that a decline in prostate-specific antigen of at least 50% from baseline may be an important predictor of survival for patients receiving cytotoxic therapy.

Antineoplastic Agents, Hormonal↗
PubMed1997

Modeling signal transduction in normal and cancer cells using complex adaptive systems.

As a first approximation, organisms can be defined by the complement of cell types that they possess. Each cell type is defined by its specific collection of signal transduction pathways. While many pathways are common to most cell types (e.g. glycolysis), others are specific to a particular cell type and serve to characterized that cell. Many diseases, including cancer, are characterized by aberrations in general and specific signal-transduction pathways. These pathways are generally intricate and not easily modeled. The formalism of complex adaptive system theory, however, provides the tools by which these pathways can be investigated. By modeling signal-transduction pathways from the viewpoint of complex adaptive systems, a deeper understanding of their intricacies may result. This could eventually lead to novel methods of therapeutic intervention in diseases that arise from aberrant signal transduction.

Adaptation, Physiological↗
PubMed1997

Phase II chemoprevention trial of oral fenretinide in patients at risk for adenocarcinoma of the prostate.

Prostate cancer is the most common cancer diagnosed in American men. The need to find effective means of preventing this disease is clear. Vitamin A and its analogues (retinoids) act as transcriptional regulators within the nucleus and have been tested as both preventative and therapeutic agents in human malignancy. Fenretinide (N-4-hydroxyphenyl retinamide) (4HPR) has been found to be relatively nontoxic in preclinical experiments and early clinical trials. Its toxicity and feasibility for use as a chemoprevention agent in men at high risk for prostate cancer was evaluated in this study. Twenty-two patients were entered into a clinical trial that involved taking 4HPR for twelve 28-day cycles. Eight patients with negative prestudy biopsies had positive prostate biopsies prior to or at the time of their 12th cycle evaluation. This led to early closure of the study. 4HPR was well-tolerated, and no major toxicities were associated with its use. The significance of this study is limited due to small sample size. Chemoprevention studies such as this can be difficult to complete because of the commitment required of otherwise healthy individuals; nevertheless additional dosages and schedules for 4HPR administration merit further investigation.

Adenocarcinoma↗
PubMed1997

Supportive care in the patient with hormone refractory prostate cancer.

Despite the advances being made in prostate cancer screening and early detection, a large percentage of patients will eventually be classified as "hormone refractory." Patients entering this phase are no longer curable, and therapies instituted in this setting are primarily palliative in nature. As a result, the onus on those working in the field of urologic oncology becomes managing the plethora of symptoms these patients experience as a result of both their disease and the treatment modalities used at this stage. The intent of this article is to provide an overview of some of these symptoms with guidelines for their management. Principles of pain management and additional manifestations requiring supportive care such as anorexia, constipation, anemia, urinary obstruction, and psychological concerns are discussed.

Anemia↗