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H I Scher

Publications and source records attributed to H I Scher.

At least 19 recordsLinked to original sources
PubMed2006

ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression.

The interaction between stromal cells and tumor cells is emerging as a critical aspect of tumor progression. Yet there is a paucity of molecular markers for cells participating in such interactions, and only few genes are known to play a critical role in this process. Here, we describe the identification of ADAM12 (a disintegrin and metalloprotease 12) as a novel marker for a subpopulation of stromal cells that are adjacent to epithelial tumor cells in three mouse carcinoma models (models for prostate, breast and colon cancer). Moreover, we show that ADAM12 is essential for tumor development and progression in the W10 mouse model for prostate cancer. These results suggest that ADAM12 might be a useful marker for stromal cells in mouse tumors that are likely to participate in stromal/tumor cell crosstalk, and that ADAM12 is a potential target for design of drugs that prevent carcinoma growth.

ADAM Proteins↗
PubMed2004

Effective antigen cross-presentation by prostate cancer patients' dendritic cells: implications for prostate cancer immunotherapy.

Despite the potency with which dendritic cells (DCs) are able to utilize the exogenous MHC I antigen cross-presentation pathway to cross-present antigen for the activation of killer T cells in model systems, concern about defects in immune function in cancer patients has led to uncertainty regarding whether immune cells derived from patients can effectively be used to generate tumor vaccines. We have undertaken a careful analysis of the potency of using DCs obtained from prostate cancer patients to cross-present antigen derived from human prostate tumor cells for the activation of antigen-specific T cells. Such DCs can be matured ex vivo into functionally active cells and are capable of cross-presenting influenza antigen derived from internalized apoptotic prostate tumor cells. Importantly, we demonstrate effective stimulation of both CD4+ and CD8+ T cells, as evident by production of IFN-gamma, and the ability of CD8+ T cells to differentiate into effector CTLs. These results, defining conditions in which prostate cancer patient DCs can efficiently utilize the cross-presentation pathway and in which apoptotic tumor can serve as a source of antigen for DCs to activate T cells, demonstrate that this system warrants clinical study as a potential immunotherapy.

Antigens, Neoplasm↗
PubMed2003

Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration.

BACKGROUND: Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer. PATIENTS AND METHODS: Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks. RESULTS: Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%). CONCLUSIONS: The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).

Adenocarcinoma↗
PubMed2002

Qualitative and quantitative comparison between images obtained with filtered back projection and iterative reconstruction in prostate cancer lesions of (18)F-FDG PET.

BACKGROUND: Recently, iterative reconstruction with segmented attenuation corrections (IRSAC) has been introduced for reconstruction of (18)F-FDG PET images. IRSAC produces images that are more pleasing to the eye, but qualitative and quantitative comparisons between IRSAC and filtered back projection (FBP) have not been reported for metastatic cancer. Since quantitative data has been widely used as an adjunct to interpretation of PET scans, comparison between IRSAC and FBP is needed. The purpose of this study was to compare image quality and the maximum standardized uptake value (SUVmax) obtained with FBP and with IRSAC in metastatic lesions from prostate cancer. METHODS: Twenty (18)F-FDG PET scans (10 baseline and 10 follow-up) were performed in 10 patients with prostate cancer (ages 66-85 yrs, mean 73.6 yrs). Acquisition began 45 min after injection of 370 MBq of (18)F-FDG. Images were reconstructed using FBP and IRSAC, and submitted to visual and quantitative analysis. SUVmax was obtained for all metastases, on FBP and IRSAC. A Jaszczak phantom study was also performed. RESULTS: IRSAC images showed better image quality than FBP especially in regions of high activity concentrations. IRSAC detected 106 lesions on both baseline and follow-up scans, while FBP detected 100 and 95 lesions on baseline and follow-up scans, respectively. Therefore, 17 more lesions were seen on IRSAC. The mean SUVmax values on baseline scans for FBP and IRSAC were systematically different, at 4.46+/-1.99 and 5.13+/-2.67, respectively. On follow-up scans values were 3.89+/-1.72 for FBP and 4.29+/-1.93 for IRSAC. Comparison of FBP with IRSAC on baseline and follow-up scans were statistically significant (baseline: paired "t"-test p=0.0017; follow-up: paired "t"-test p=0.0008). Phantom studies reveal that these differences can be explained by the type of reconstruction filters used, and IRSAC was more accurate than FBP. CONCLUSIONS: IRSAC detects smaller volumes in phantoms, patient images are easier to interpret and more metastatic lesions were detected. In addition, IRSAC provides reproducible quantitative data, comparable to data provided by FBP. IRSAC SUV and FBP SUV are in close agreement but there was a statistically significant difference between the two, and therefore threshold values of SUV will probably need to be re-determined with IRSAC, and are likely to be 10 to 19% higher than currently reported.

Adenocarcinoma↗
PubMed2001

The Collection of Indirect and Nonmedical Direct Costs (COIN) form: a new tool for collecting the invisible costs of androgen independent prostate carcinoma.

BACKGROUND: There are limited data available regarding the cost of care in patients with androgen independent prostate carcinoma (AIPC), and there are no data on the impact of direct nonmedical and indirect costs (DNM/IC). This lack of data, along with the feasibility of collecting DNM/IC, was examined in patients with AIPC who took part in a randomized trial using a newly developed questionnaire, the Collection of Indirect and Nonmedical Direct Costs (COIN) form. METHODS: Patients with AIPC were randomized to one of three treatment arms: 1) strontium only (strontium 4 Mci in Week 1 and Week 12) (STRONT); 2) vinblastine 4 mg/m(2) per week for 3 weeks then 1 week off and estramustine, 10 mg/kg per day (CHEMO); or 3) a combination of treatments outlined in the arms for CHEMO and STRONT (CHEMO/STRONT). Direct medical costs were collected through the hospital billing system. DNM/IC data were obtained prospectively using the COIN form. Cost data were analyzed for a period of 6 months. RESULTS: Twenty-nine patients were randomized, after which the protocol was closed because of poor accrual. The median survival of the patients was 22.3 months. The mean and median total costs for the 20 of 29 patients with complete cost information were $12,647 and $11,257 over 6 months, respectively. DNM/IC represented 11% of the total cost (range, from < 1% to 42%); in 20% of participating individuals, these costs accounted for 35-42% of total costs. Failure to collect complete cost information was due to early death, administrative difficulties, and loss to follow-up. CONCLUSIONS: In this pilot project, the collection of these cost data using the COIN form was feasible and practical and was limited primarily by logistic, not form specific, issues. DNM/IC were found to be a significant proportion of total costs (up to 42%) in selected patients, and this information proved to be a useful addition to the cost analysis. Approximately 98 patients would be required to detect a 20% difference in total costs between arms in a properly powered, randomized trial. Considering the potentially significant impact on total costs, DNM/IC data should be included in future cost-analysis studies of patients with AIPC and other diseases.

Adenocarcinoma↗
PubMed2001

Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer.

The effects of farnesyl:protein transferase inhibitors (FTIs) were evaluated against hormone-dependent and hormone-independent prostate cancer cell lines harboring mutant and wild type Ras. The combinations of the FTI with hormones and chemotherapy were explored. The effect of FTI on the growth of human prostate cancer lines was examined under anchorage-dependent and -independent conditions. Changes in Ras processing and cellular localization were examined by immunoblotting and immunocytochemistry. Hormone-dependent (LNCaP) and -independent (TSU-Pr1, PC3 and DU145) human prostate cancer cell lines were growth-inhibited by the FTI L-744,832 at concentrations ranging from 100 nM to 20 &mgr;M. The inhibition was accompanied by loss of protein farnesylation and with the accumulation of Ha-Ras as its unprocessed, cytosolic form. No effect on N- and Ki-Ras processing was observed. The transformed phenotype of TSU-Pr1 cells, which possess a Ha-Ras Gly-12-Val activating mutation, reverted following FTI treatment. Enhanced antitumor effects were observed when the FTI was combined with gamma-radiation, etoposide, doxorubicin, cisplatin, estramustine and the antihormone bicalutamide. In particular, the combination of taxol and FTI was synergistic for DU145 cells, a cell line that is only marginally sensitive to the FTI alone. The sensitivity of human prostate cancer cell lines to the FTI is independent of the presence of mutations of tumor suppressors, cell cycle regulators and of the activation of a variety of oncogenes, including Ras. A cell line expressing mutated Ha-Ras is particularly sensitive. Enhanced antitumor effects were observed with an anti-androgen, gamma-irradiation, and several chemotherapeutic agents. These findings support the clinical evaluation of FTIs alone or in combination as treatment for this disease. Prostate Cancer and Prostatic Diseases (2001) 4, 33-43

Journal Article↗
PubMed2001

Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase.

PURPOSE: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells. EXPERIMENTAL DESIGN AND RESULTS: Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID(50) = 100 nM) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared with tumors from vehicle-treated control animals. CONCLUSIONS: The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.

Acetylation↗
PubMed2001

Collocation of androgen receptor gene mutations in prostate cancer.

Consistent with both the development of the normal prostate gland and prostate tumorigenesis being dependent on testicular androgens, targeting the androgen-signaling axis (i.e., androgen ablation therapy) remains the predominant treatment regime for patients with metastatic prostate cancer. Although there is a very good initial response to androgen ablation, these treatments are essentially palliative. Recent evidence suggests that treatment failure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. A consistent finding is that androgen receptor (AR) gene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result in decreased specificity of ligand-binding and inappropriate receptor activation by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence and AF-2, two discrete regions of the ligand-binding domain critical for androgen signaling, we recently proposed that collocation of mutations identified in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-amino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. AR gene mutations have also been identified that collocate to areas in the DNA-binding domain, to the NH(2)-terminal transactivation domain, and to the hinge region in prostate tumors. In nearly every case, missense mutations in the AR gene identified in prostate cancer that collocate to discrete regions of the receptor contribute to altered androgen signaling and provide a potential mechanism to explain the reemergence of tumor growth during the course of hormone ablation therapies.

Androgens↗
PubMed2001

Inverse associations between plasma lycopene and other carotenoids and prostate cancer.

Although dietary intake of tomatoes and tomato products containing lycopene has been reported to reduce the risk of prostate cancer, few studies have been done on the relationship between plasma lycopene and other carotenoids and prostate cancer. This case-control study was conducted to investigate the effects of plasma lycopene, other carotenoids, and retinol, as well as alpha- and gamma-tocopherols on the risk of prostate cancer. The study included 65 patients with prostate cancer and 132 cancer-free controls; all of them were interviewed using a standard epidemiological questionnaire at the Memorial Sloan-Kettering Cancer Center from 1993 to 1997. Plasma levels of carotenoids, retinol, and tocopherols were measured by high performance liquid chromatography. An unconditional logistic regression model was used in bivariate and multivariate analyses using Statistical Analysis System (SAS). After adjusting for age, race, years of education, daily caloric intake, pack-years of smoking, alcohol consumption, and family history of prostate cancer, significantly inverse associations with prostate cancer were observed with plasma concentrations of the following carotenoids: lycopene [odds ratio (OR), 0.17; 95% confidence interval (CI), 0.04-0.78; P for trend, 0.0052] and zeaxanthin (OR, 0.22; 95% CI, 0.06-0.83; P for trend, 0.0028) when comparing highest with lowest quartiles. Borderline associations were found for lutein (OR, 0.30; 95% CI, 0.09-1.03; P for trend, 0.0064) and beta-cryptoxanthin (OR, 0.31; 95% CI, 0.08-1.24; P for trend, 0.0666). No obvious associations were found for alpha- and beta-carotenes, retinol, and alpha- and gamma-tocopherols. Our study confirmed the inverse associations between lycopene, other carotenoids such as zeaxanthin, lutein, and beta-cryptoxanthin, and prostate cancer. This study provides justification for further research on the associations between lycopene and other antioxidants and the risk of prostate cancer.

Adult↗
PubMed2001

HER-2/neu (p185neu) protein expression in the natural or treated history of prostate cancer.

PURPOSE: Amplification of HER-2/neu gene and overexpression of its encoded product, the p185neu (HER-2/neu) tyrosine kinase membrane receptor, have been associated with tumor progression in certain neoplasms. We conducted this study to investigate patterns of HER-2/neu protein expression in prostate cancer, analyzing different points in the natural and treated history of the disease. EXPERIMENTAL DESIGN: Radical prostatectomy cases (83) and 20 metastatic lesions were studied for the association between HER-2/neu protein overexpression detected by immunohistochemistry and clinicopathological parameters, including time to prostate-specific antigen (PSA) relapse. RESULTS: HER-2/neu protein overexpression, defined as complete membrane staining in >10% of tumor cells using the Food and Drug Administration-approved Dako kit, was found in 9 of 45 (20%) of evaluable hormone naïve primary tumors and 23 of 34 (67%) primary tumors after androgen-deprivation therapy (P = 0.0001). Of the 20 metastatic lesions, positivity was noted in 16 (80%) of the cases. On univariate analysis, HER-2/neu overexpression was associated with pretreatment PSA (P = 0.011) and time to PSA relapse (P = 0.02). After controlling for pretreatment PSA, the association between hormone treatment and HER-2/neu was still observed. No association was found between HER-2/neu overexpression and Gleason score, capsular invasion, and tumor proliferative index determined by Ki67. CONCLUSIONS: These data suggest that there is significant HER-2/neu overexpression in primary tumors that persist after androgen deprivation. It also emphasizes the importance of characterizing tumors at determined points in the natural or treated history of prostate cancer when targeting treatment to specific biological processes.

Cohort Studies↗
PubMed2000

Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1.

Treatment of metastatic prostate cancer with androgen-ablation often elicits dramatic tumor regressions, but the response is rarely complete, making clinical recurrence inevitable with time. To gain insight into therapy-related progression, changes in gene expression that occurred following androgen-deprivation of an androgen-dependent prostate tumor xenograft, CWR22, and the emergence of an androgen-independent tumor, CWR22-R, were monitored using microarray analysis. Androgen-deprivation resulted in growth arrest of CWR22 cells, as evidenced by decreased expression of genes encoding cell cycle components and basal cell metabolism, respiration and transcription, and the induced expression of putative negative regulatory genes that may act to sustain cells in a nonproliferative state. Evolution of androgen-independent growth and proliferation, represented by CWR22-R, was associated with a reentry into active cell cycle and the up-regulation of several genes that were expressed at low levels or absent in the androgen-dependent tumor. Androgen repletion to mice bearing androgen-independent CWR22-R tumors induced, augmented, or repressed the expression of a number of genes. Expression of two of these genes, the calcium-binding protein S100P and the FK-506-binding protein FKBP51, was decreased following androgen-deprivation, subsequently reexpressed in CWR22-R at levels comparable with CWR22, and elevated further upon treatment with androgens. The dysregulated behavior of these genes is analogous to other androgen-dependent genes, e.g., prostate-specific antigen and human kallikrein 2, which are commonly reexpressed in androgen-independent disease in the absence of androgens. Other androgen-responsive genes whose expression decreased during androgen-deprivation and whose expression remained decreased in CWR22 were also identified in CWR22-R. These results imply that evolution to androgen-independence is due, in part, to reactivation of the androgen-response pathway in the absence of androgens, but that this reactivation is probably incomplete.

Androgens↗
PubMed2000

Novel strategies and therapeutics for the treatment of prostate carcinoma.

BACKGROUND: An increased understanding of the biology of prostate carcinoma has led to the clinical evaluation of mechanism-based and targeted therapies. Modulating the immune system has been pursued through the use of both active and passive immunity as well as the ex vivo genetic manipulation of effector cells. A variety of gene therapies has been proposed not only to replace defective genes but to localize activation of prodrugs. Angiogenesis and tumor invasion also have been targeted, as have cell cycling and signal transduction. Strategies promoting apoptosis and augmenting differentiation are also under study. METHODS: This study is a review of current clinical strategies using biologic, immunologic, and genetic approaches for the treatment of prostate carcinoma. RESULTS: The clinical development of therapy targeting differentiation, apoptosis, cell signaling, angiogenesis, metastasis, immune surveillance, and others are in various stages of clinical development. A disease states model is used to discuss treatment groups, outcome measures, and other trial design elements in relation to specific therapeutic strategies. CONCLUSIONS: Development of novel agents requires consideration of where in the natural history of the disease they should be applied. In addition, understanding the genetic and molecular alterations that occur as the disease progresses from a localized to a metastatic state, and from androgen dependence to independence, is necessary. Clinical trial design will require consideration of cytostatic and cytotoxic effects, the status of pathways not directly targeted, and potentially unexpected influences on prostate specific antigen expression by these agents.

Angiogenesis Inhibitors↗
PubMed2000

Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo.

Suberoylanilide hydroxamic acid (SAHA) is the prototype of a family of hybrid polar compounds that induce growth arrest in transformed cells and show promise for the treatment of cancer. SAHA induces differentiation and/or apoptosis in certain transformed cells in culture and is a potent inhibitor of histone deacetylases. In this study, we examined the effects of SAHA on the growth of human prostate cancer cells in culture and on the growth of the CWR22 human prostate xenograft in nude mice. SAHA suppressed the growth of the LNCaP, PC-3, and TSU-Pr1 cell lines at micromolar concentrations (2.5-7.5 microM). SAHA induced dose-dependent cell death in the LNCaP cells. In mice with transplanted CWR222 human prostate tumors, SAHA (25, 50, and 100 mg/kg/day) caused significant suppression of tumor growth compared with mice receiving vehicle alone; treatment with 50 mg/kg/day resulted in a 97% reduction in the mean final tumor volume compared with controls. At this dose, there was no detectable toxicity as evaluated by weight gain and necropsy examination. Increased accumulation of acetylated core histones was detected in the CWR22 tumors within 6 h of SAHA administration. SAHA induced prostate-specific antigen mRNA expression in CWR22 prostate cancer cells, resulting in higher levels of serum prostate-specific antigen than predicted from tumor volume alone. The results suggest that hydroxamic acid-based hybrid polar compounds inhibit prostate cancer cell growth and may be useful, relatively nontoxic agents for the treatment of prostate carcinoma.

Animals↗
PubMed2000

Identification and characterization of circulating prostate carcinoma cells.

BACKGROUND: Analysis of prostate carcinoma cells isolated from the peripheral blood suggested a classification based on three categories. METHODS: Centrifugation density gradients and magnetic cell sorting were used to isolate circulating prostate carcinoma cells from peripheral blood. Immunocytochemistry staining and fluorescent in situ hybridization allowed characterization of isolated cancer cells. RESULTS: Terminal cells can be divided into 3 classes: 1) large, buoyant, fragile cells with a large nucleus that were captured in a 1.068 g/mL gradient; 2) enucleate cells (4, 6-diamidino-2-phenylindole [DAPI] negative) that were positive for cytokeratin and PSMA antibodies; and 3) cellular debris exhibiting cytokeratin and PSMA positive staining as well as nuclear debris identified by DAPI staining, which included cytoplasmic debris. Growing cells also exhibited three morphologic characteristics: those possessing stem cell-like morphology and characteristics such as small size, high density, developed cytokeratin systems, PSMA expression, and aneuploidy; those in M phase; and cell clusters. The majority of isolated cells exhibited intermediate characteristics and thus comprised the third group of circulating cancer cells. CONCLUSIONS: Although the significance of the cluster remains undetermined, observation suggests that the cluster has the ability to circulate as a microtumor and subsequently arrest in the small veins and capillaries. It is hypothesized that the clusters could escape certain facets of immune surveillance and possibly gain a selective growth advantage over single cells in a distant site. Further hypothesis proposes that arrested cells recruit growth-promoting nutrients, which would result in the invasion of local blood vessels and vascularization.

Aged↗
PubMed2000

Ligand responsiveness in human prostate cancer: structural analysis of mutant androgen receptors from LNCaP and CWR22 tumors.

Androgen receptors (ARs) belong to the family of hormone receptors that are ligand-dependent transcription factors. Endocrine therapy provides effective treatment for prostate cancer until mutations arise that alter the ligand responsiveness of AR. In this study, structural models were developed for the functional domains of human AR by homology modeling from crystal structures of closely related nuclear receptors. These models were used to locate the sites of two frequently occurring mutations in prostate cancer. The substitutions that develop in LNCaP (threonine-->alanine at residue 877) and CWR22 (histidine-->tyrosine at residue 874) tumor cell lines are both located on helix 11 that forms part of the ligand-binding pocket. However, the results suggest that these mutations influence ligand responsiveness by completely different mechanisms. Residue 877 contacts the ligand directly, and substitution at this site alters the stereochemistry of the binding pocket. Thus, the LNCaP mutation apparently broadens the specificity of ligand recognition. In contrast, residue 874 is located down the helical axis, projects away from the ligand pocket, and does not contact ligand. The side chain of residue 874 lies in a cavity between helices 11 and 12. Substitution of tyrosine for histidine 874 in CWR22 tumors may affect a conformational change of helix 12 and, thus, influence binding of coactivator proteins and their regulatory effect on transcriptional activation.

Amino Acid Sequence↗
PubMed2000

Ifosfamide, paclitaxel, and cisplatin for patients with advanced transitional cell carcinoma of the urothelial tract: final report of a phase II trial evaluating two dosing schedules.

BACKGROUND: A combination regimen of ifosfamide, paclitaxel, and cisplatin (ITP), recycled every 4 weeks, was reported in the treatment of previously untreated patients with advanced transitional cell carcinoma (TCC). This study sought to examine ITP at 3-week intervals to assess its feasibility and toxicity, compare the results for different schedules, and assess the impact of prognostic factors and postchemotherapy surgery on outcome. METHODS: ITP (ifosfamide 1.5 g/m(2) daily for 3 days, paclitaxel 200 mg/m(2) over 3 hours, and cisplatin 70 mg/m(2) on Day 1) was administered to patients with metastatic or unresectable TCC and was recycled every 4 weeks (for 30 patients) or 3 weeks (for 15 patients). Granulocyte-colony stimulating factor was given during each cycle. RESULTS: Thirty of 44 assessable patients (68%; 95% confidence interval, 52-81%) demonstrated a major response (10 complete responses [23%], 20 partial [45%]), with durations of response ranging from 4 to 36 months. At a median follow-up of 28 months, the median survival was 20 months. Eleven patients (25%) were disease free at last follow-up. Overall toxicity for the 15 patients whose treatment was recycled at 3 weeks was similar to that for patients treated every 4 weeks. Hematologic toxicity included anemia, thrombocytopenia, and febrile neutropenia. Febrile neutropenia was observed in 7 patients (16%) and in 3.3% of cycles of therapy. No Grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, renal insufficiency (11%), and neuropathy (9%). CONCLUSIONS: ITP is an active, well-tolerated regimen for previously untreated patients with TCC of the urothelial tract, resulting in a median survival of 20 months. Treatment can be recycled at 3-week intervals without enhanced toxicity.

Adult↗
PubMed2000

Polyclonal antibodies from patients immunized with a globo H-keyhole limpet hemocyanin vaccine: isolation, quantification, and characterization of immune responses by using totally synthetic immobilized tumor antigens.

We have previously reported on a carbohydrate-based vaccine program for immunotherapy in cancer patients. One such vaccine, based on the globo H antigen conjugated to the protein keyhole limpet hemocyanin (KLH), has been in clinical evaluation. Although this and other carbohydrate vaccines have been shown to induce antibody responses, there are currently no quantitative data on the antibody levels achieved in immunized patients by these or other anti-cancer vaccines. We report herein an efficient route to complex synthetic oligosaccharides attached to an affinity matrix for identifying and isolating antibodies elicited against such a carbohydrate-based vaccine in humans. Pre- and postvaccination profiles from serum samples of patients immunized with globo H-KLH were compared. All anti-globo H antibody activity was efficiently separated from other serum constituents. The isolated antibodies were readily quantified, and their specificities were analyzed. Since no comparable data were available on antibodies resulting from the vaccination of other cancer patients, we compared the observed levels with those quoted in studies with bacterial polysaccharide vaccines that had been quantified. Remarkably, cancer patients immunized with globo H-KLH produce anti-globo H antibody levels often exceeding those formed by immunization with bacterial polysaccharides. In addition, substantial quantities of both IgG and IgM antibodies were elicited, clearly indicating a class switch to IgG. Taken together, these analyses serve to clarify several aspects of the immune response to the vaccine and give several new insights to the carbohydrate-based vaccination strategy. Furthermore, antibodies so isolated could well have applications in clinical therapy.

Antibodies↗