HER-2/neu过表达与雄激素非依赖性前列腺癌Gleason分级和临床分期的相关性研究

目的:检测HER-2/neu基因在雄激素依赖与雄激素非依赖性前列腺癌(PCa)组织中的表达情况,推测这一基因在雄激素非依赖性PCa发生中的意义。方法:收集30例雄激素依赖性PCa标本(雄激素依赖组)和24例激素非依赖性PCa标本(雄激素非依赖组),采用免疫组化方法检测HER-2/neu基因的蛋白表达,对照临床分期、Gleason分级进行分析。结果:HER-2/neu在雄激素依赖性PCa标本中的阳性表达率为10%,在雄激素非依赖性PCa的表达为33%;Gleason分级≤7分病例中HER-2/neu阳性表达率显著低于Gleason分级>7分病例组(14.29%vs26.92%,P<0.01);临床分期>T2病例中HER-2/neu阳性表达率显著高于≤T2病例组(34.62%vs7.14%,P<0.01)。结论:HER-2/neu在雄激素非依赖性PCa标本中阳性表达率高,而且随临床分期和Gleason分级的升高其阳性表达率升高。     

Role of coordinated molecular alterations in the development of androgen-independent prostate cancer: an in vitro model that corroborates clinical observations

OBJECTIVE: To investigate the role of potential downstream targets of HER-2/neu, including the cell-cycle regulator p27, proliferation-associated protein Ki-67, apoptosis inhibitor Bcl-2, and signal-transduction molecule Akt (which is associated with cell survival), as the development of androgen-independent prostate cancer (AIPC) in patients who are initially responsive to androgen-ablation therapy (AAT) is a significant clinical problem. PATIENTS AND METHODS: Earlier studies showed that high levels of HER-2/neu tyrosine kinase receptor expression as assessed by immunohistochemistry were significantly associated with the development of AIPC, and we hypothesised that HER-2/neu overexpression provides an alternative proliferative stimulus upon androgen depletion. We established a unique clinical model system, comprising patients who received no AAT, or who had preoperative AAT, or those with advanced tumours resistant to AAT. To test our hypothesis in vitro, we stably transfected full-length HER-2/neu cDNA in androgen-responsive LNCaP cells and examined the effects of HER-2/neu overexpression on cell proliferation, apoptosis, androgen-receptor activation, and Akt phosphorylation upon androgen deprivation by using immunohistochemistry and Western blot technique. RESULTS: p27 expression was initially induced on exposure to AAT, and significantly decreased in AIPC (P < 0.001). There was also a significant increase in the Ki-67 index in AIPC (P = 0.001). Elevated Bcl-2 expression was closely associated with AAT (P = 0.002), suggesting that Bcl-2 expression is induced on initial exposure to AAT. Further, Bcl-2 expression was highest in hormone-resistant cancers (P < 0.001). Using the HER-2/neu transfected cell-line model, we confirmed the mechanistic basis of the clinical observations which elucidate the pathway leading to HER-2/neu-mediated androgen independence. On androgen deprivation, the HER-2/neu transfected cells had higher proliferation rates, lower G1 arrest, inhibited p27 up-regulation, a lower apoptotic index, and higher Bcl-2, prostate-specific antigen and phosphorylated Akt expression than the mock-transfected LNCaP cells. CONCLUSION: This study suggests that prostate cancer cells undergo a series of coordinated changes after exposure to AAT, which eventually result in the development of androgen independence. Further, in support of previous results, it appears that a major factor in this process is the induction of HER-2/neu overexpression, which occurs after initial exposure to AAT. HER-2/neu may contribute to the development of androgen independence through: (i) maintaining cell proliferation; (ii) inhibiting apoptosis; and/or (iii) inducing AR activation in a ligand-independent fashion. These effects may be mediated, at least in part, through activation of the PI3K/Akt pathway.     

Antibody immunity to prostate cancer associated antigens can be detected in the serum of patients with prostate cancer

PURPOSE: Several immune based therapies targeting prostate cancer associated proteins are currently undergoing clinical investigation. In general, however, little is known about the immunogenicity of prostate cancer or which prostate cancer associated proteins elicit immune responses. We determine whether patients with prostate cancer have antibody immunity to known prostate cancer associated proteins, what the prevalence of this immunity is and whether immunity to individual proteins is associated with the stage of disease. MATERIALS AND METHODS: We evaluated the inherent humoral immune response against prostate specific antigen (PSA), prostatic acid phosphatase, p53 and HER-2/neu, all known prostate cancer associated proteins, in 200 patients with various stages of disease and male controls. RESULTS: Antibody immunity to PSA was significantly different between the patient (11%, 22 of 200) and control populations (1.5%, 3 of 100, p = 0.02), and titers 1:100 or greater were particularly prevalent in the subgroup of patients with androgen independent disease (11%, 6 of 56). Antibody immunity to prostatic acid phosphatase and p53 was detected (5.5%, 11 of 200 and 6%, 12 of 200), and was not different from the control population (4%, 4 of 100, p = 0.57 and 7%, 7 of 100, p = 0.74). Antibody immunity to HER-2/neu was significantly higher in patients with prostate cancer (15.5%, 31 of 200) compared to controls (2%, 2 of 100, p = 0.0004), and titers 1:100 or greater were most prevalent in the subgroup of patients with androgen independent disease (16%, 9 of 56). CONCLUSIONS: These findings suggest that prostate cancer is an immunogenic tumor. Moreover, for PSA and HER-2/neu the prevalence of antibody immunity was higher in patients with androgen independent disease, indicating that even patients with advanced stage prostate cancer can have an immune response to their tumor.     

The utility of tissue transglutaminase as a marker of apoptosis during treatment and progression of prostate cancer

PURPOSE: To determine the extent of cell proliferation and apoptosis during treatment and progression of prostate cancer and to determine whether staining for tissue transglutaminase is a better histological marker than TUNEL for neoadjuvant androgen ablation treatment of localized prostate cancer. MATERIALS AND METHODS: Immunocytochemistry techniques were used on archival prostate tissue from four groups of men: 14 men with BPH, 18 men with untreated, localized prostate cancer, 21 men with localized prostate cancer who received neoadjuvant hormone therapy prior to prostatectomy and 18 men with metastatic androgen-independent prostate cancer. Cell proliferation was evaluated by staining for the Ki67 nuclear antigen, and apoptosis was evaluated by staining for DNA fragmentation (TUNEL technique) and tissue transglutaminase (tTG). Image analysis was used to quantitate the results. RESULTS: TUNEL staining increased by 37% in localized prostate cancer compared with BPH, with a further increase of 43% seen after neoadjuvant therapy, although variation was such that neither was statistically significant. In androgen-independent cancer, TUNEL staining was decreased compared with neoadjuvant hormone treated cancer (p = 0.02). Staining for tTG was not increased in untreated prostate cancer compared with BPH; however, staining more than doubled after neoadjuvant therapy, compared with untreated prostate cancer (p = 0.04). Staining for tTG was markedly decreased in androgen-independent cancer (p = 0.07 compared with BPH and p = 0.0004 compared with neoadjuvant hormone treated cancer). Ki67 immunoreactivity did not significantly change in localized prostate cancer, either before or after neoadjuvant therapy, compared with BPH, but it more than doubled in androgen-independent prostate cancer (p = 0.07 compared with BPH and p = 0.05 compared with untreated prostate cancer). CONCLUSIONS: This study shows that cell proliferation increases and apoptosis decreases as prostate cancer progresses to androgen independence, and, that of the markers used in this study, tissue transglutaminase most accurately reflects the anticipated effect of neoadjuvant hormone therapy on localized prostate cancer. An assessment of these parameters provides a valuable tool for appraising new prostate cancer therapies.     

Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy

INTRODUCTION AND OBJECTIVES: Progression of prostate cancer to androgen independence (AI) results in part from the upregulation of anti-apoptotic genes following androgen withdrawal, and androgen-independent disease remains the primary obstacle to improved survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the anti-apoptotic protein clusterin, which is upregulated in response to cellular compromise as observed in normal and malignant tissues undergoing apoptosis. Systemic administration of antisense clusterin oligonucleotides in prostate cancer xenograft models delays progression to AI and enhances chemosensitivity. The objective of this study was to define changes in clusterin expression following neoadjuvant hormone therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS: Archival radical prostatectomy (RP) specimens were obtained for 128 patients who received either no NHT or treatment for 2-8 weeks, 3 months, or 8 months. Paired needle biopsy specimens were acquired for 30 patients and all tissues were subjected to clusterin immunohistochemistry. Western blot analysis was performed on frozen tissue from 5 untreated and 5 treated patients. RESULTS: Clusterin expression in malignant prostatic tissue was significantly greater in patients who underwent preoperative NHT (P < 0.001). Needle biopsies obtained prior to NHT consistently demonstrated lower staining intensity than corresponding RP specimens (P < 0.001). Western blot analysis confirmed clusterin levels increased 17-fold beginning within 4 weeks after androgen withdrawal. CONCLUSIONS: Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer.     

Comparison of serum HER2/neu with immunohistochemical HER2/neu expression for the prediction of biochemical progression in metastatic prostate cancer

Objectives:   To examine whether pretreatment serum human epidermal growth factor receptor 2 (HER2/neu) and immunohistochemical HER2/neu expression predict biochemical recurrence-free survival in advanced prostate cancer.
Methods:   We studied 75 untreated patients with metastatic prostate cancer and compared them to a control group of 97 patients without histologically diagnosed prostate cancer. Serum samples were collected for HER2/neu protein analysis before the patients started endocrine therapy. HER2/neu expression in the prostate tissue was evaluated using immunohistochemical analysis.
Results:   Serum concentration of HER2/neu in patients with prostate cancer was significantly higher than in those without cancer ( P  = 0.005). Based on the median HER2/neu value, a cut-off level of 12.5 ng/mL was established to separate low from high serum HER2/neu levels. The biochemical recurrence-free survival rate was significantly lower in patients with a high serum HER2 level ( P  < 0.001). HER2/neu overexpression was found in 18 patients (24%) by immunohistochemical analysis. Biochemical recurrence-free survival rates did not show a statistically significant difference between HER2/neu positive and negative groups. Multivariate analysis showed that the pretreatment serum HER2/neu value was an independent predictor of biochemical recurrence ( P  = 0.02).
Conclusions:   Pretreatment serum HER2/neu may represent a more valuable tool than immunohistochemical HER2/neu expression for the prediction of biochemical recurrence in metastatic prostate cancer patients.     

Prognostic value of HER-2/neu and p53 expression in node-positive breast cancer. HER-2/neu effect on adjuvant tamoxifen treatment

HER-2/neu and p53 expression, conventional clinical and pathologic prognostic factors, were evaluated in a retrospective series of 283 node-positive breast cancer patients. Overexpression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks. Twenty one percent were HER-2/neu positive and 40% p53 positive. HER-2/neu expression was related to axillary lymph node metastasis (P=0.014), inflammatory infiltrates (P=0.004), and the absence of oestrogen (ER) (P=0.0026) and progesterone (P=0.01) receptors (PR). p53 expression was related to lymph node involvement (P=0.03), necrosis (P=0.036), absence of ER (P=0.028) and PR (P=0.065). p53 was not associated with outcome. HER-2/neu was an unfavourable prognostic factor for disease-free (DFS) (P=0.05) and overall survival (OS) (P=0.02) in univariate analysis. Multivariate analysis showed that the number of involved axillary nodes (P<0.00001), age (P=0.004), grade (P=0.04), and PR (P=0.04) were independent predictors for OS. ER-positive patients treated with adjuvant tamoxifen had shorter DFS and OS when they were HER-2/neu positive.     

Elevated levels of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential

BACKGROUND: In this study, we investigated the expression of HER-2/neu and AR in clinically organ-confined prostate cancer to determine whether alterations in these signaling pathways contribute to the development of metastatic disease. METHODS: HER-2/neu and AR immunoreactivity were evaluated in archived prostatic tissues obtained from 53 men with clinically organ-confined disease who underwent radical prostatectomy. Associations between AR and HER-2/neu immunostaining and disease outcome were determined. RESULTS: Seventy percent (37/53) of tumors exhibited high levels of HER-2/neu immunostaining and 68% (36/53) of tumors had elevated AR levels. Patients with high levels of both HER-2/neu and AR had the highest rate of PSA failure (56%, 15/27) compared with no PSA failures amongst seven patients with low levels of both HER-2/neu and AR (log rank statistic 7.69, P = 0.021). Concurrent high levels of HER-2/neu and AR expression were significantly associated with high pathological stage (P = 0.027) and development of metastatic disease (P = 0.022). CONCLUSIONS: These findings support the notion that both the HER-2/neu and AR signaling pathways may contribute to development of metastatic disease. The subset of prostate tumors with increased HER-2/neu and AR levels may benefit from treatment strategies that target both signaling pathways.     

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.     

PSP94 expression after androgen deprivation therapy: a comparative study with prostate specific antigen in benign prostate and prostate cancer

PURPOSE: To examine the clinical use of PSP94 (prostate secretory protein of 94 amino acids) as an androgen independent marker, we conducted a comparative study of prostate samples including benign tissue and cancers which did and did not have androgen deprivation. MATERIALS AND METHODS: Among 163 radical prostatectomy cases 75 had androgen deprivation before operation, while surgery was performed in the remainder without prior hormone treatment. Considering the pathological up grading following hormone therapy, contiguous sections from radical prostatectomy samples were stained for PSP94 and prostate specific antigen (PSA) by immunohistochemistry, and equivalent tumor foci were evaluated by assessing the intensity and extent of the staining. RESULTS: In untreated benign prostate tissue PSP94 and PSA staining was positive and identical in all sections in the no pretreatment group. However, PSP94 expression in the androgen deprivation group was significantly higher than PSA in intensity (p = 0.0005) and extent (p = 0.034). In untreated cancer cases PSP94 intensity and extent demonstrated strong inverse association with Gleason grade (p <0.0001). In contrast, PSA expression was high in every grade, resulting in no statistical association with tumor grade. In the androgen deprivation group PSA staining was decreased in every grade compared to the no pretreatment group. On the other hand, PSP94 expression was decreased in grade 3 tumor foci but increased in grades 4 and 5 tumor foci compared with samples of the corresponding grade in the no pretreatment group (p = 0.0034). CONCLUSIONS: PSP94 expression in benign prostate persists under androgen deprivation compared to PSA. PSP94 synthesis in high grade tumor appears to be activated in the absence of androgen stimulation, indicating the possible alternative pathways in the regulation of PSP94.     

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目的　研究HER 2 /neu(c erbB 2 )在结、直肠恶性肿瘤中的表达及其与肿瘤分期的相关性。方法　收集 2 0 0 2年 1月至 2 0 0 3年 5月治疗的 2 8例结、直肠恶性肿瘤的临床资料。按Dukes分期标准进行分期 ,其中A、B期共 17例 (17/2 8,6 0 7% ) ,C、D期 11例 (11/2 8,39 3% )。采用HER 2单克隆抗体试剂套盒行免疫组织化学染色 ,并以染色细胞数目的多少及染色程度为分级标准 ,认为 2 以上 (含 2 )为过表达 (报告为 ～ 的 ,记为阴性 )。结果　该蛋白在A、B期肿瘤中的过表达率为 11 8% (2 /17) ;C、D期肿瘤中过表达率为 5 4 5 % (6 /11)。该蛋白的过表达率在有转移和无转移的病例之间差异有显著意义 (P <0 0 5 )。结论　虽然在结、直肠恶性肿瘤病例中HER 2 /neu的过表达率不高 ,但仍提示HER 2 /neu过表达程度与肿瘤的进展或侵袭性生物学行为相关。     

Associations of serum testosterone with microvessel density,androgen receptor density and androgen receptor gene polymorphism in prostate cancer

PURPOSE: We investigate potential associations of serum testosterone with microvessel density, androgen receptor expression and AR gene polymorphism in men with untreated prostate cancer. MATERIAL AND METHODS: Serum luteinizing hormone, follicle-stimulating hormone, estradiol and testosterone were determined in men with newly diagnosed prostate cancer. The number of tumor vessels per 0.46 mm. and androgen receptor density (as the percent positive nuclei) were quantified immunohistochemically on prostate cancer areas of prostate biopsy specimens. Polymorphisms within the AR gene (number of CAG repeats) were determined by polymerase chain reaction and restriction fragment length polymorphism analysis using DNA from peripheral blood. RESULTS: The 39 men entered into this study were grouped into 16 with low (3 ng./ml. or less, group 1) and 23 with normal (greater than 3 ng./ml., group 2) serum testosterone. Mean prostate specific antigen +/- SD was significantly lower in group 1 than in group 2 (18.8 +/- 11.1 versus 27.2 +/- 12.2 ng./ml., p = 0.03). Mean Gleason score (7.4 +/- 1.3 versus 6.0 +/- 1.2, p = 0.01), androgen receptor density (96.6% +/- 2.8% versus 84.8% +/- 7.2%, p = 0.03) and tumor vessel density (63.0 +/- 30.8/0.46 versus 39.0 +/- 22.9/0.46 mm.2, p = 0.007) were significantly higher in group 1 than in group 2. The number of CAG repeats within the AR gene did not correlation with serum androgen. CONCLUSIONS: Low serum testosterone in men with newly diagnosed prostate cancer is associated with higher tumor microvessel and androgen receptor density as well as with higher Gleason score, suggesting enhanced malignant potential.     

Prognostic values of p53 and HER-2/neu coexpression in invasive bladder cancer in Taiwan

OBJECTIVES: To explore the clinical significance of p53 and HER-2/neu coexpression by immunohistochemistry in patients with invasive bladder cancer in Taiwan. METHODS: Paraffin-embedded tumor blocks were obtained from 67 patients with invasive bladder cancer subjected to radical cystectomy, bilateral lymph node dissection, and urinary diversion with or without systemic chemotherapy. Two observers (N.H.C. and T.S.T.), blinded to clinical outcome, reviewed the immunohistochemical staining for p53 (PAb1801) and HER-2/neu (Ab-17). The results were analyzed for progression-free survival and patient survival. RESULTS: Positive staining for p53 and HER-2/neu was found in 30 (44.8%) and 39 (58.2%) patients. In contrast to HER-2/neu, p53 expression was significantly associated with tumor grade and pathologic stage (p = 0.040 and 0.004, respectively), and tended to be related to the nodal status (p = 0.080). Most importantly, coexpression of p53 and HER-2/neu significantly correlated with nodal metastases (p = 0.020). Univariate and multivariate analysis revealed p53 and nodal status as two independent prognostic factors. Additionally, patients with p53 and HER-2/neu coexpression had the shortest time to relapse and overall survival, irrespective of whether adjuvant chemotherapy was given or not (p = 0.005 and 0.030). CONCLUSIONS: In invasive bladder cancer, p53 was an important prognostic factor since its expression correlated with tumor grade and stage, even nodal status, whereas HER-2/neu did not show prognostic significance. Tumors with p53 and HER-2/neu coexpression were associated with nodal metastases, probably resulting in decreased progression-free survival. Although some basic studies provide some important supports, studies including larger patient cohorts would still be required to prove the hypothesis that p53 and HER-2/neu-coexpressing tumors have a worse prognosis and are more resistant to a cisplatin-based multidrug regimen.     

Prostate specific antigen in hormonally treated stage D2 prostate cancer: is it always an accurate indicator of disease status?

The clinical significance of serum prostate specific antigen (PSA) values in hormonally treated prostate cancer patients and the effect of hormonal therapy on the serum PSA concentration, independent of the response observed from its antitumor activity, are not well defined. To elucidate further the influence of antiandrogen therapy on serum PSA expression, 81 randomly selected patients with stage D2 prostate cancer were evaluated with respect to serum PSA concentration. These patients were divided into 2 groups on the basis of previous hormonal therapy. Group 1 consisted of 43 patients 55 to 89 years old (mean age 71 years) who had received no prior therapy for prostate cancer. Group 2 included 38 men 58 to 84 years old (mean age 72 years) who had received only androgen deprivation therapy with either bilateral orchiectomy or diethylstilbestrol. The mean interval between initiation of antiandrogen therapy and evaluation of these patients was 14 months (range 8 to 31 months). At the time of PSA determination both groups were similar in all respects, including tumor grade, disease symptoms and bone scan findings. The median serum PSA concentration was 96.0 ng./ml. in group 1 and 16.5 ng./ml. in group 2 (p less than 0.001), despite both groups having similar symptoms and widespread metastatic disease on radionuclide bone scan. In group 1 only 1 patient (2%) had a serum PSA level less than 4.0 ng./ml., whereas 13 men (34%) in group 2 had a serum PSA concentration below 4.0 ng./ml. (p less than 0.001). Of the patients in group 1, 2% and of the men in group 2, 45% had a serum PSA concentration less than 10 ng./ml. (p less than 0.001). These findings demonstrate that the serum PSA level in prostate cancer patients treated hormonally may have a significantly different meaning than the same serum PSA value in patients without hormonal therapy. In addition, these observations suggest that PSA expression may be under hormonal regulation and that androgen deprivation therapy may have a direct effect on the serum PSA concentration, independent of the response obtained from any antitumor activity. However, the exact mechanism of this androgenic influence on PSA expression awaits further investigation at the cellular level.     

Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer

OBJECTIVES: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer treated with the 3-month luteinizing hormone-releasing hormone agonist (LH-RH) therapy. METHODS: Total serum testosterone was determined in 234 patients with prostate cancer in a cross-sectional study. A subset of 90 patients submitted to radical prostatectomy was used as the control group (group 1), and 144 patients with advanced prostate cancer under androgen suppression therapy were included in the study group (groups 2 and 3). The study group was divided into 93 patients (group 2) treated with 50 mg daily bicalutamide and LH-RH agonist (maximal androgen blockade, MAB) and 51 patients treated with the LH-RH agonist alone (group 3). Median follow-up after androgen suppression was 42 months. The castrate testosterone level was defined below 50 ng/dl. RESULTS: The mean serum testosterone level was 29.1 ng/dl in patients undergoing MAB (group 2) and 29.5 ng/dl in patients treated with the LH-RH agonist (group 3; p > 0.05). In group 1, the mean serum testosterone was 445.2 ng/dl (p < 0.0001). The rate of patients with a serum testosterone level higher than 50 ng/dl was 10.9% in patients undergoing androgen suppression, 10% in patients with MAB treatment and 12.5% in those with LH-RH agonist therapy (p > 0.05). In group 1, 98.9% of the patients had a serum testosterone level higher than 50 ng/dl. CONCLUSIONS: A small but clinically significant rate of patients under 3-month LH-RH agonist therapy fail to achieve or maintain castrate testosterone serum levels. This finding supports the need of monitoring testicular response during LH-RH agonist therapy.     

Enhanced transgene expression in androgen independent prostate cancer gene therapy by taxane chemotherapeutic agents.

PURPOSE: Chemotherapy is often used as a primary therapy for metastatic cancer because it kills cells en masse. However, high doses of chemotherapeutic drugs can cause toxicity in nontarget organs. Gene therapy may provide a better alternative to chemotherapy because its targeting of specific genes may reduce the undesirable toxicity associated with chemotherapy. We evaluated whether the chemotherapeutic agent docetaxel or paclitaxel may be combined with gene therapy to create a new therapeutic regimen for metastatic androgen independent prostate cancer. MATERIALS AND METHODS: The 2 androgen independent prostate cancer cell lines PC-3 and DU 145 were treated with docetaxel or paclitaxel. Three recombinant adenoviruses containing p21WAF-1/CIP1, p53 protein or beta-galactosidase complementary DNA under the control of cytomegalovirus promoter were used to determine transgene expression. They were evaluated by Western blot analysis, beta-galactosidase activity or in vitro growth assays. The [(3)H] labeled E1 deleted adenovirus dl312 was used to determine adenovirus uptake into cells. RESULTS: Docetaxel and paclitaxel enhanced adenovirus mediated transgene expression. Docetaxel appears to be a more potent growth inhibitor in vitro. Elevated transgene expression in virus infected cells induced by these 2 drugs was produced by increased cytomegalovirus promoter activity rather than increased virus uptake. CONCLUSIONS: The potential synergy of gene therapy with docetaxel and paclitaxel may be an important direction for future therapy for metastatic androgen independent prostate cancer.     

Overexpression of p53 and HER-2/neu proteins as prognostic markers in early stage breast cancer.

OBJECTIVE: Overexpression of the p53 and HER-2/neu oncogenes are the two most common genetic abnormalities associated with breast cancer. Shorter survival time has been reported in patients with tumors with p53 or HER-2/neu. This report analyzes a retrospective cohort of early stage breast cancers for both oncogenes and relates overexpression to clinicopathologic parameters and survival. METHODS: Immunostaining for p53 and HER-2/neu was performed on 230 paraffin-embedded specimens of stage I and II breast cancers diagnosed and treated at Duke University Medical Center between 1984 and 1987. Positive staining for both p53 and HER-2/neu in paraffin-embedded tissues indicates an underlying genetic abnormality: point mutations in the p53 gene and amplification of the HER-2/neu gene. RESULTS: In this cohort of patients, 24% were positive for p53 and 17% for HER-2/neu. Four per cent were positive for both oncogenes. Significant correlations were found between p53 immunostaining and increasing tumor size, stage, and low estrogen and progesterone receptor contents. Univariate analysis showed that p53 and HER-2/neu were indicators of overall and failure-free survival. An additive effect on survival was observed in patients with both oncogene abnormalities. Nodal status, HER-2/neu, and p53 all attained independent prognostic value in a multivariate analysis. CONCLUSIONS: The p53 and HER-2/neu oncogenes have proven but limited prognostic value. An approach that combines several molecular genetic markers with established pathologic criteria may help physicians to make more accurate predictions of prognosis in patients with early stage breast cancer.     

Expression and role of Foxa proteins in prostate cancer

The molecular mechanism(s) for prostate cancer progression to androgen independence are poorly understood. We have recently shown that Foxa1 and Foxa2 proteins are differentially expressed in epithelial cells during murine prostate development, growth, and adult function. Currently, the role of Foxa proteins in prostate cancer development and progression is unknown. Foxa protein expression was investigated in the LPB-Tag LADY mouse prostate cancer models, in human prostate cancer specimens, and various prostate cancer cell lines using Western blot and immunostaining analysis. In vitro transient transfection, studies were performed to investigate Foxa/prostate-specific gene regulation. Foxa1 was strongly expressed in areas of prostatic intraepithelial neoplasia (PIN) in both the androgen dependent 12T-7f and in the metastatic, androgen independent 12T-10 LADY models. Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice. Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas. Foxa proteins were also differentially expressed in three prostate cancer cell lines. Importantly, in vitro functional assays demonstrated that Foxa2 could activate androgen-dependent prostate-specific genes in an androgen receptor and ligand-independent manner. These results suggest that Foxa proteins are important in prostate carcinogenesis. In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence. As such, Foxa proteins may represent novel targets for therapeutic intervention.     

Association of body mass index with response and survival in men with metastatic prostate cancer: Southwest Oncology Group trials 8894 and 9916

PURPOSE: We evaluated the effect of body mass index on prostate specific antigen response, and progression-free and overall survival in men with androgen dependent or androgen independent metastatic prostate cancer. MATERIALS AND METHODS: We examined the prognostic impact of body mass index in patient cohorts from phase III randomized studies coordinated by the Southwest Oncology Group. The first study included 1,006 men treated with androgen deprivation for metastatic prostate cancer. The second study included 671 patients treated with chemotherapy for metastatic, androgen independent prostate cancer. RESULTS: Among men with androgen dependent disease, higher body mass index was associated with longer overall (p <0.001) and progression-free (p = 0.009) survival, as well as with an increased likelihood of achieving a prostate specific antigen nadir less than 4 ng/ml (p = 0.008). In multivariate analysis adjusting for risk factors, increasing body mass index was positively correlated with overall survival (p <0.01) and overweight but not obese patients (body mass index 27 to 29.9) had a significantly improved outcome compared to normal weight patients, with hazard ratios for risk of progression and death of 0.82 (95% CI 0.69, 0.98) and 0.75 (95% CI 0.63, 0.89), respectively. Among men with androgen independent prostate cancer, no clear association could be detected between body mass index and progression-free survival, overall survival or prostate specific antigen response. CONCLUSIONS: This study revealed higher body mass index to be associated with better overall and progression-free survival in patients with androgen dependent metastatic prostate cancer. Among men who had androgen independent disease, no significant association was found between body mass index and survival.     

Prognostic significance of changes in short-term prostate volume and serum prostate-specific antigen after androgen withdrawal in men with metastatic prostate cancer

OBJECTIVE: Endocrine therapy is the standard treatment for metastatic prostate cancer although progression to androgen independence is inevitable. To evaluate prognostic factors in metastatic prostate cancer, patients who had been treated with endocrine therapy were investigated especially for the change in prostate volume. METHODS: Fifty-nine patients with untreated metastatic prostate cancer who received endocrine therapy were included in the present study. Blood chemistry, histological grade, extent of bony metastasis, clinical response to hormone therapy including the short-term change in prostate volume and serum prostate-specific antigen (PSA), and prognosis of the patients were evaluated. RESULTS: With univariate analysis, hemoglobin concentration, serum alkaline phosphatase, lactate dehydrogenase (LDH), histological grade, extent of bony disease, the short-term change of prostate volume and response of PSA at 3 months were shown to be significant prognostic factors. Response of PSA, LDH and the change in prostate volume were significant for predicting prognosis with multivariate analyses. Five-year survival rate in patients whose prostate had regressed 20% or more at 1 month and whose PSA had been normalized at 3 months was 67%, whereas that in patients whose prostate had regressed less than 20% and whose PSA had not been normalized was 0%. CONCLUSIONS: The patients in whom PSA had not been normalized at 3 months and the prostate volume had regressed less than 20% at 1 month were in the high-risk group. New or more aggressive treatment should be considered.