摘要:

AbstractThe term “cancer chemoprevention” refers to the prevention of cancer by intervening with drugs prior to the malignant (i.e., invasive) stage of carcinogenesis. The development of chemopreventive drugs is the major objective of the Chemoprevention Branch at the National Cancer Institute.The testing of drug for cancer chemoprevention differs from testing of those for cancer treatment. Chemopreventive drug trials involve healthy target populations, and the endpoints of reduced cancer incidence or mortality, reduced/eliminated precancerous lesions, or increased latency must be achieved with little or no drug toxicity.The design of cancer chemoprevention trials for prostate presents several problems, such as the age of the study population and undependable methods for detecting microscopic foci by sequential sampling. A major motivation for organizing this workshop is the development of strategies for the design of chemopreventive intervention trials for prostate cancer.One of the most difficult problems of chemoprevention drug testing is the necessity of lengthy trials due to the long developmental period of many cancers. This is especially true for prostate cancer. A major solution to the problem is the use of intermediate biomarkers, defined as morphological or molecular intraepithelial changes that can constitute short‐term endpoints in chemoprevention clinical trials. They are categorized as histological, genetic, proliferation‐related, and differentiation‐related. Modulation of intermediate biomarkers, instead of cancer incidence, as trial endpoints would allow chemoprevention trials to be of shorter duration, to use fewer subjects, and to be of lower cost. Review of the current status of prostatic intermediate biomarkers, and methods for identifying and validating them, are also major reason for convening this workshop. © 1992 Wiley

ISSN:0730-2312    

DOI:10.1002/jcb.240501203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0730-2312    

DOI:10.1002/jcb.240501204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractProstatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations within prostatic ducts, ductules an acini. Two grades of PIN are identified (low grade and high grade), and high grade PIN is considered to be a precursor to invasive carcinoma. The continuum which culminates in high grade PIN and early invasive cancer is characterized by basal cell layer disruption, basement membrane disruption, progressive loss of secretory differentiation markers, increasing nuclear and nucleolar abnormalities, increasing proliferative potential, and increasing variation in DNA content (aneuploidy). Clinical studies suggest that PIN predates carcinoma by ten years or more, with low grade PIN first emerging in men in the third decade of life. The clinical importance of recognizing PIN is based on its strong association with carcinoma; its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. © 1992 Wiley‐Liss, I

ISSN:0730-2312    

DOI:10.1002/jcb.240501205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAll analysis of the efficiency of therapy for prostate cancer must control for the natural history of the disease. Over the past years, several long‐term series involving several hundred patients have helped to describe the results of untreated disease. In general, most patients will not die of their disease, although approximately half of the patients will develop disease progression within 10 years. Predictors of progression include tumor stage, grade, and ploidy status. © 1992 Wiley‐Liss,

ISSN:0730-2312    

DOI:10.1002/jcb.240501206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractOur group has been studying the progressive molecular changes in prostatic epithelium which precede the invasive phenotype. Initial studies revealed similar alterations in cytoskeletal proteins between high grade prostatic intraepithelial neoplasia (PIN) lesions and invasive carcinoma. Specifically we observed an increased expression of certain cytokeratins and decreased expression of vimentin. We also noted a change in glycosylation as detected byUlex europaeusstaining. Using the latter technique we were able to microdissect and isolated nuclei from areas of low and high grade PIN lesions as well as from invasive carcinoma for morphometric analysis. Similarities in nuclear size, chromatin heterogeneity, and nuclear DNA content between low and high grade PIN and invasive carcinoma in carcinomatous specimens were noted. In contrast, these parameters were significantly different in low grade PIN lesions obtained from benign prostatic transurethral resection (TURP) specimens. In addition, DNA histograms revealed similar proliferative indices between high grade PIN and invasive carcinoma, which differed significantly from low grade PIN. Parameters thought to be relative to the invasive phenotype were also examined, such as the members of the metalloproteinase family; although normal luminal cells fail to express detectable levels of these enzymes, invasive carcinoma and even low grade PIN lesions express both the 72 kDa and 92 kDa type IV collagenase. Taken together, these data indicate that the dysplastic cells of PIN lesions and carcinomas are similar in nuclear and genomic features as well as protease expression. Our current working hypothesis is that these cells are already armed with the necessary proteases to invade the basal lamina but in an inactive form. Tumor progression requires an additional event of protease activation. © 1992 Wiley‐Liss, I

ISSN:0730-2312    

DOI:10.1002/jcb.240501207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0730-2312    

DOI:10.1002/jcb.240501208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractProstate‐specific antigen is a kallikrein‐like serine protease that is produced exclusively by the epithelial cells of all types of prostatic tissue, benign and malignant. Physiologically, it is present in the seminal fluid at high concentration and functions to cleave the high molecular weight protein responsible for the seminal coagulum into smaller polypeptides. This action results in liquefaction of the coagulum. Prostate‐specific antigen is also present in the serum and can be measured reliably by several different assays.Although the protein is prostate‐specific, it is not prostate‐cancer‐specific. As a result, benign conditions such as benign prostatic hyperplasia, prostatitis and infarction, as well as prostatic intraepithelial neoplasia, can be associated with elevated serum levels of prostate‐specific antigen. Approximately 25% of men with benign prostatic hyperplasia have an elevated serum value of prostate‐specific antigen, whereas 35% to 40% of patients with organ‐confined prostate cancer have a level within the reference range. Prostate‐specific antigen can identify some cancers not detectable by digital rectal examination; alternatively, this examination can identify cancers not detectable from the serum prostate‐specific antigen concentration. Thus, the most complete evaluation of the prostate gland is achieved when both the prostate‐specific antigen value and the digital rectal examination are used.The density and the rate of change of serum prostate‐specific antigen are new concepts to improve the ability of prostate‐specific antigen to detect early prostate cancer. Preliminary results are encouraging, but additional studies are required to determine the true usefulness of these new variables. Thus, in 1992, determination of the prostate‐specific antigen value is a valuable new tool for the practicing physician and will be instrumental in our campaign to diagnose clinically significant prostate cancer at an early, curable

ISSN:0730-2312    

DOI:10.1002/jcb.240501209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe nuclear DNA content of prostate cancer specimens, both needle biopsies and aspiration biopsy specimens as well as transurethral resection (TUR) chips and radical prostatectomy specimens, can now be reliably measured by standardized methods of flow and static image cytometry. For prostate carcinomas of every clinical stage (A1‐D2), DNA diploid tumors have a better prognosis than tumors of a similar stage and grade which are non‐diploid. Of particular importance to this symposium is the fact that DNA diploid stage D1 and D2 tumors treated early by androgen deprivation generally have a remarkably good prognosis. In contrast, those patients with DNA non‐diploid tumors progress early despite androgen deprivation. Such a result suggests that DNA ploidy can be used to identify prostate cancers which are potentially sensitive to hormonal manipulation. Additional investigations from several groups indicate that early stage prostate malignant lesions, for example stages A1, A2, B1, and B2, are generally DNA diploid (about 75%). Swedish data suggest a steady progression of prostate cancer from early diploid to tetraploid, to non‐tetraploid aneuploid, to multiple stemline aneuploid tumors with time and advancing stage. Taken together, these data suggest that the earliest detectable prostate carcinomas should be overwhelmingly DNA diploid. A large majority of these patients with early tumors should be candidates for “chemoprevention” by pharmacologic methods which reduce the effective androgen stimulation of prostate tumor cells. © 1992 Wil

ISSN:0730-2312    

DOI:10.1002/jcb.240501210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractQuantitative analyses (QAs) of prostatic intraepithelial neoplaisa (PIN) helped to objectively define some traditional features of the lesion because, first, changes in value are represented by numbers and not by subjective evaluation of morphologic clues. QAs have also helped to identify subtle abnormalities. For example, the degree of nucleolar margination is a new diagnostic feature which can be easily evaluated as the proportion of nucleoli touching the nuclear membrane. Thirdly, QAs have provided useful insights into understanding some morphologic changes. PIN, in fact, appears to be characterized by complex changes which involve the secretory cells as well as the basal layer and which affect the surrounding stroma. In the epithelial lining, two types of simultaneous changes take place, the first in the nucleus (expression of abnormal proliferative and/or renewal activity) and the second in the cytoplasm (expression of the disorder in cell differentiation), pointing out that only PIN samples of high grade can be considered as having acquired the characteristics of a neoplasitc lesion. © 1992 Wiley‐Liss, I

ISSN:0730-2312    

DOI:10.1002/jcb.240501211

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractUsing the mouse prostate reconstitution (MPR) model system, under conditions where therasandmyconcogenes are introduced via a recombinant retrovirus into both the mesenchymal and epithelial compartments of the urogenital sinus, poorly differentiated prostate cancer is produced with high frequency (>90%) using inbred C57BL/6 mice. Northern blotting and immunohistochemical analysis showed that the transition from benign prostatic hyperplasia (BPH) to prostate cancer is invariably associated with the induction of elevated transforming growth factor‐β1 (TGF‐β1) expression. Similar analysis of TGF‐β1 in human BPH and prostate cancer is consistent with our MPR results and indicates that the accumulation of extracellular TGF‐β1 is significantly more intense in prostate cancer compared to normal or benign prostate tissues. Interestingly, where benign pathologies are observed in the prostatic stroma in the presence of benign prostatic epithelium, extracellular TGF‐β1 is seen predominantly in the stromal compartment. Experimental studies clearly demonstrate that mRNA levels of TGF‐β1 and other growth related genes are regulated by androgens in prostate cancer cells. Overall, our results suggest that elevated TGF‐β1 is involved in the development of prostate cancer. Direct determination of TGF‐β1 levels and distribution as well as analysis of localized and systemic effects produced by TGF‐β1 may serve as useful biomarkers for prostate canc

ISSN:0730-2312    

DOI:10.1002/jcb.240501212

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY