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C W Boone

Publications and source records attributed to C W Boone.

At least 19 recordsLinked to original sources
PubMed1992

Natural history of intraepithelial neoplasia in humans with implications for cancer chemoprevention strategy.

Intraepithelial neoplasia is of critical importance to the cancer chemoprevention field because it is a target condition for which drugs must be sought that will prevent its development or stop its progression. The term "dysplasia" refers to the morphological alterations that characterize intraepithelial neoplasia and according to many authors consists of seven basic morphological changes that occur in the majority of human epithelia, as well as in the epithelium of mouse skin papillomas induced by 7,12-dimethylbenz(a)anthracene and 12-O-tetradecanoylphorbol-13-acetate: increased nuclear size; altered nuclear shape; increased nuclear stain uptake; nuclear pleomorphism (increased variation in nuclear size, shape, and stain uptake); increased mitoses; abnormal mitoses; and disordered or absent maturation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. Aneuploidy has been found during intraepithelial neoplasia in many human epithelia, and, in association with other forms of genetic instability, may provide the increase in genetically variant cells required for clonal evolution to occur. It is postulated that two major factors affecting the rate of progression of intraepithelial neoplasia are the cellular mutation rate, which is enhanced by environmental carcinogens, and the cellular proliferation rate, which is enhanced by agents that include sex hormones, inducers of chronic inflammation, and irritant chemicals which stimulate reactive hyperproliferation. A preferred chemoprevention strategy should consist of the development of drugs and drug combinations which will block mutagenic carcinogens or prevent epithelial hyperproliferation or its causes. Two examples of the induction of regression of intraepithelial neoplasia by chemopreventive drugs are the regression of oral leukoplakia produced by beta-carotene and the regression of colorectal polyps in patients with familial polyposis produced by sulindac. It is evident that there is a strong need for more research on the induction of regression of intraepithelial neoplasia with chemopreventive agents. There is also a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Intermediate biomarkers of precancer and their application in chemoprevention.

The Chemoprevention Branch of the National Cancer Institute has established a program for the development of safe and effective cancer chemopreventive agents. This program includes identification of new agents, testing for efficacy in vitro and in animals, studies in animals to model clinical use, and preclinical toxicity and metabolism evaluation. Ultimately, the most promising agents progress to clinical trials. The long period required for cancer onset presents a significant challenge to the design of clinical trials for chemoprevention. Phase III trials in which cancer reduction is the endpoint require large subject groups (tens of thousands) and follow-up duration of more than five years. Because of these requirements, the cost of such trials are high. The Chemoprevention Branch is addressing this challenge by expansion of the preclinical and Phase II clinical efficacy efforts to include intermediate biomarkers of carcinogenesis as study endpoints. The Chemoprevention Branch's studies focus on the development of biomarkers with high reliability and predictive value for cancer. Both single markers and batteries of complementary and parallel markers are evaluated. Among the criteria for biomarkers for chemoprevention studies are the following: (1) differential expression in normal and high risk tissue, (2) appearance early in carcinogenesis (the earlier a reliable biomarker appears, the greater is the chance for successful intervention with a chemopreventive agent), (3) high sensitivity, specificity, and accuracy relative to cancer, (4) ease of measurement (use of non-invasive techniques and small tissue samples is preferable), (5) demonstration of modulation by chemopreventive agents, and (6) correlation of modulation with decreased cancer incidence.

Anticarcinogenic Agents↗
PubMed1992

The natural history of intraepithelial neoplasia: relevance to the search for intermediate endpoint biomarkers.

The development of carcinomas, defined as invasive epithelial neoplasms, is preceded by a preinvasive stage termed intraepithelial neoplasia that typically lasts for years. Intraepithelial neoplasia is the target tissue for the action of chemopreventive agents and the site where biomarkers frequently develop. The term "dysplasia" refers to the morphological alterations that characterize intraepithelial neoplasia and, according to many authors, consists of seven basic changes that are the same for the majority of epithelia. These are increased nuclear size, abnormal nuclear shape, increased nuclear stain uptake, nuclear pleomorphism (increased variation in size, shape, and stain uptake), increased mitoses, abnormal mitoses, and disordered or absent differentiation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. The use of intraepithelial neoplasia as an intermediate endpoint biomarker requires that effective chemopreventive agents cause it to regress. Two examples are the regression of dysplastic oral leukoplakia produced by beta-carotene and the regression of colonic polyps in familial polyposis patients following treatment with the nonsteroidal antiinflammatory drug sulindac. There is a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.

Biomarkers↗
PubMed1992

Introductory remarks: development of chemopreventive agents for prostate cancer.

The 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 drugs 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 reasons for convening this workshop.

Animals↗
PubMed1992

When is intervention warranted?

A chemoprevention trial in prostate cancer would be a formidable but potentially rewarding study. The current status of knowledge of drug interactions with, biomarkers of, and even the natural history of prostate cancer is insufficient to study all levels of men at risk. Currently, the most promising group to study is group I--those men with a high probability of developing prostate cancer but who do not currently have evidence of the disease. This could be a placebo-controlled, prospective and randomized study with the endpoint being clinically-detected prostate cancer. In addition, much may be gained from short-term pilot studies of "chemo-active" agents on morphologic and other biomarkers of prostate cancer initiated immediately before surgical removal. It is hoped that such studies may provide rationale for future efforts directed at preventing progression of premalignant or early prostate cancer lesions.

Anticarcinogenic Agents↗
PubMed1992

Development of chemopreventive agents for bladder cancer.

The term cancer chemoprevention refers to the prevention or prolongation of carcinogenesis by intervention with drugs prior to the malignant (i.e., invasive) stage. The development of chemopreventive drugs is the major objective of the Chemoprevention Branch of the National Cancer Institute. Neoplastic lesions of the urinary bladder present a unique opportunity for evaluating chemopreventive agents because of (1) the accessibility of the lesions to observation and biopsy, and (2) those patients who have been successfully treated for a primary lesion represent a population at unusually high risk for recurrence and/or progression. Although 70-80% of bladder cancers initially present as superficial, papillary transitional cell neoplasms with limited potential for invasion, the incidence of recurrence is high after resection (60-75%). Recurrent tumors are highly unpredictable, and may be of higher grade or stage (progression). Although recurrence is responsible for high treatment-related morbidity, progression represents the greatest potential for mortality. Thus, potential chemopreventive agents considered here would modulate bladder carcinogenesis from initiation of normal-appearing tissue through progression of superficial tumors. Clinical trials of chemopreventive drugs involve healthy target populations, and the endpoints are reduced cancer incidence or mortality, reduced/eliminated precancerous lesions or increased latency, with none to minimal toxicity. Since cancers may not appear for 20-30 years, two of the most difficult aspects of testing these drugs in intervention trials are the long observation periods and large study populations required to measure cancer incidence reduction. However, observing the regression or recurrence of superficial bladder lesions (TIS, T1, Ta) requires relatively short time periods. Thus, these lesions lend themselves to the investigation of intermediate biomarkers, defined as morphologic and/or molecular alterations in tissue between initiation and tumor invasion. It is hypothesized that modulation of one or more biomarkers would interrupt carcinogenesis and result in a decrease in cancer incidence. Thus, evaluation of biomarkers as surrogate endpoints would allow bladder trials to be of even shorter duration, use fewer subjects and be lower in cost. In addition, intermediate biomarkers could predict which superficial lesions (or normal-appearing tissue) have the greatest potential for neoplastic progression. Development of strategies for the design of intervention trials for bladder cancer and review of the current status of intermediate biomarkers in the bladder, and methods for their validation, are major objectives of this workshop.

Animals↗
PubMed1992

Screening for chemopreventive (anticarcinogenic) compounds in rodents.

The Chemoprevention Branch is testing dozens of candidate chemopreventive compounds in the following rodent model carcinogenesis systems: mouse skin papillomas, DMBA/TPA induced, rat mammary adenocarcinoma, DMBA and MNU induced, hamster tracheal squamous cell carcinoma, MNU induced, and lung adenocarcinoma, DEN induced, rat and mouse colon adenocarcinoma, AOM and MAM acetate induced, respectively, and mouse bladder carcinoma, hydroxy BBN induced. Significant chemopreventive (i.e., anticancer) effects have been produced with 4-hydroxy-phenylretinamide, difluoromethylornithine, piroxicam, oltipraz (a dithiolthione), calcium glucarate, N-acetylcysteine, beta-carotene, ibuprofen, dehydroepiandrosterone (DHEA) and a 16-fluoro DHEA analog, 8354, tamoxifen, glycyrrhetinic acid, molybdate, selenite, curcumin, and fumaric acid.

Animals↗
PubMed1992

Chemoprevention clinical trials.

As part of a program to develop drugs which will delay or prevent cancer in humans, the Chemoprevention Branch, National Cancer Institute, National Institutes of Health, is sponsoring 12 Phase I and 22 Phase II and III clinical trials. Three agent classes are significantly advanced in the trials. These are the retinoids, including 13-cis-retinoic acid, retinol, and 4-hydroxyphenylretinamide (nine studies), beta-carotene (seven studies), and calcium compounds (three studies). In addition, six promising new compounds are in Phase I or Phase II trials. These are: piroxicam, ibuprofen, oltipraz (a dithiolthione), difluoromethylornithine, glycyrrhetinic acid, and N-acetylcysteine. Key concepts related to the development of cancer chemopreventive agents are (1) the need for long-term administration, (2) the need for oral route of administration, (3) the matching of toxic side effects to degree of cancer risk.

Anticarcinogenic Agents↗
PubMed1991

Study of postnatal effects of chemopreventive agents on offspring of ethylnitrosourea-induced transplacental carcinogenesis in rats. I. Influence of retinol acetate, alpha-tocopherol acetate, thiamine chloride, sodium selenite, and alpha-difluoromethylornithine.

We studied the influence of the vitamins retinol acetate, alpha-tocopherol acetate and thiamine chloride; the antioxidant sodium selenite and an inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine, on the offspring of transplacental carcinogenesis by ethylnitrosourea in rats. Ethylnitrosourea was given to pregnant rats as a single i.v. injection, at a dose of 75 mg/kg body wt. or 5.5 mg/kg body wt., on the 21st day after conception. Retinol, tocopherol or thiamine was added to the diet, and selenite and alpha-difluoromethylornithine to drinking water of the offspring throughout their postnatal life at moderate doses. In control groups, ethylnitrosourea induced tumors of brain, spinal cord, peripheral nervous system and kidneys in the offspring. alpha-Difluoromethylornithine exerted a slight inhibitory effect; this agent decreased the total tumor multiplicity and the multiplicity of peripheral nervous system tumors and also prolonged survival time. Retinol, tocopherol, thiamine and selenite did not influence the development of the transplacentally-induced tumors.

Animals↗
PubMed1990

Identification of candidate cancer chemopreventive agents and their evaluation in animal models and human clinical trials: a review.

A search of the literature using National Library of Medicine databases and individual cancer journal articles yielded over 500 compounds with published chemopreventive activity in animals. From these, an initial 16 agents or agent combinations have been evaluated in the following animal tumor models: mouse skin papillomas/carcinomas induced by 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate; rat breast adenocarcinoma induced by N-methyl-N-nitrosourea or 7,12-dimethylbenz(a)anthracene; hamster lung carcinoma induced by N-methyl-N-nitrosourea or diethylnitrosamine; mouse bladder papillary carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine; and rat and mouse colon cancer induced by azoxymethane/methylazoxymethanol acetate. Some of the most interesting positive results observed include 4-hydroxyphenyl retinamide plus tamoxifen in breast cancer, piroxicam in colon cancer, dimethylfluoroornithine in breast and bladder cancer, oltipraz in lung cancer, dehydroepiandrosterone in colon cancer, and molybdate in bladder cancer. Eighteen human intervention trials in progress are described that involve the following agents: beta-carotene (eight trials). Retinol/retinoic acid (seven trials), vitamins C and E (three trials), 4-hydroxyphenyl retinamide (one trial), piroxicam (one trial), and calcium (one trial). By organ site these studies involve cancer of the lung (six studies), skin (five studies), colon (four studies), breast (one study), and uterine cervix (two studies).

Animals↗
PubMed1988

Delayed hypersensitivity reactions to virus-augmented syngeneic and allogeneic tumor associated antigens.

Delayed hypersensitivity (DH) reactions to intact MSV-induced tumor cells or their crude membranes (CM) were studied across the H-2 histocompatibility barrier, using the radioisotopic footpad assay. Allogeneic as well as syngeneic tumor cells or their CM produced significant DH reactions in MSV-immune mice. CM from these cells after infection with influenza virus induced a stronger tumor-specific DH reaction in immune mice than did CM from uninfected cells. These results indicate that H-2 histocompatibility is not always required for induction of a cell-mediated immune response to tumor associated antigens and support the feasibility of a tumor specific skin test in humans using CM of autologous or allogeneic cultured human tumor cells.

Animals↗
PubMed1986

Cytomorphologic evaluation of the neoplastic potential of 28 cell culture lines by a panel of diagnostic cytopathologists.

A panel of 7 diagnostic cytopathologists, i.e., physicians trained to diagnose the malignant potential of human cells in Papanicolaou-stained smears, was asked to evaluate two sets of microscope slides of stained coverslip preparations of 28 cell culture lines, 15 of which were neoplastic. Slide Set I consisted of 13 pairs of cell lines, one member of each pair being nontumorigenic and the other tumorigenic; the lines were of mouse (9 pairs), rat (3 pairs), and human (1 pair) origin. Slide Set II contained 4 human lines: one lung cancer, one melanoma, and two fibroblast lines. Of a total of 114 diagnostic decisions by the panel, 88 were correct (66/86, 77%) in choosing which member of a pair was neoplastic and 22 were correct (22/28, 79%) in choosing whether a given individual human line was or was not neoplastic. Two members of the panel were correct more frequently, with 16/17 (94%) correct diagnoses, each. Five nuclear morphologic criteria of malignancy used by cytopathologists were prominent in the tumorigenic lines: altered chromatin pattern characterized by increasing size of chromatin granules and chromatin clumping, sharp angularity of large nucleolar and/or chromocenter borders with spicule formation (pointed projection), irregular parachromatin clearing (increase in the clarity of the clear spaces between chromatin threads, granules and clumps), uneven thickness of chromatin at the nuclear border, and variability in nuclear size and shape from cell to cell. These markers of neoplastic transformation, when added to those previously reported, should increase overall accuracy in the diagnosis of neoplastic transformation of mammalian cells in culture.

Animals↗
PubMed1982

Breast cancer skin test antigens of increased sensitivity prepared from vesicular stomatitis virus-infected tumor cells.

Crude membrane (CM) extracts were prepared from five cultured breast tumor lines (MDA-MB-157, MDA-MB-231, ZR75-1, HS0578T, and MCF-7) which had been infected with vesicular stomatitis virus (VSV) to augment their antigenicity. In skin test trials, CM extracts of uninfected MCF-7 cells elicited positive response in 0 of 13 (0%) tests in breast cancer patients, while VSV-MCF-7 elicited positive responses in 11 of the same 13 patients (84.6%). CM extracts of VSV-ZR75-1 and VSV-MCF-7 elicited greater delayed hypersensitivity responses (mm induration at 48 hr) in breast cancer patients than in patients with lung carcinoma or melanoma. Although the sensitivity of VSV-ZR75-1 was too low (ten of 28, or 35.7% of tests positive) to be useful as a skin test antigen, VSV-MCF-7 elicited positive responses in 30 of 38 (78.9%) tests in breast cancer patients, as compared to two of 15 (13.3%) and two of 13 (15.4%) of tests in patients with lung carcinoma and melanoma, respectively. The "virus-augmented" CM extract of cultured MCF-7 cells exhibited markedly greater sensitivity as compared to control MCF-7 extracts (P less than .005), with a high degree of specificity for breast cancer patients as compared to patients with the other neoplasms (P less than .00001). The results of skin testing with VSV-MCF-7 CM extracts demonstrated antigenic cross-reactivity with a large number of breast cancer patients, a finding of great importance for any potential immunotherapy and/or immunodiagnosis.

Adult↗
PubMed1979

"Sontaneous" neoplastic transformation in vitro: a form of foreign body (smooth surface) tumorigenesis.

Explants of subcutaneous connective tissue from adult BALB/c mice into plastic petri dishes were serially subcultured and tested for tumorigenicity in two ways: by the subcutaneous implantation of cells attached to plastic plates (1 by 5 by 10 millimeters), and by the subcutaneous injection of cells suspended in saline. Cells grown in vitro for 18 or more days before being implanted attached to a plastic plate (2.4 x 10(4) to 3.4 x 10(5) cells per plate) formed tumors after 24 to 79 weeks. The latent period before tumor appearance correlated inversely with the time spent by the cells in tissue culture. Cells inoculated in saline suspension (10 to 100 times the above number per plate) did not form tumors until after 84 days in vitro; plates alone did not induce tumor formation within more than 1 1/2 years of implantation. The tumors arising from the plate-attached cells were transplantable without plates and histologically appeared to be undifferentiated sarcomas. It is well established that smooth-surfaced foreign bodies, regardless of their chemical composition, will produce sarcomas when transplanted subcutaneously in rodents. We interpret our data, particularly the decrease in tumor latent period with time spent in tissue culture, as indicating that a smooth surface was acting as a carcinogen first in vitro (the surface of the tissue culture dish) and then in vivo (the surface of the plastic plate).

Animals↗