Biomedical subjects

E Neely Atkinson

Publications and source records attributed to E Neely Atkinson.

At least 19 recordsLinked to original sources

PubMed2006

Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer.

PURPOSE: ARHI expression is lost or markedly down-regulated in the majority of ovarian cancers. The mechanism by which ARHI is down-regulated in ovarian cancers is still not clear. Our previous reports indicated that ARHI promoter activity was reduced in ovarian cancer cells, due in part to the effects of negative regulatory transcription factor(s). EXPERIMENTAL DESIGN AND RESULTS: We now show that E2F1 and E2F4, but not E2F2, E2F3, or E2F5, bind to the ARHI promoter and repress its activity in ovarian cancer cells. Consistent with this observation, immunochemical staining of cell lines and of 364 samples of ovarian cancer tissue show that the expression of E2F1 and E2F4 proteins is much higher in ovarian cancer cells than in normal ovarian epithelial cells, and that increased expression of E2Fs was negatively correlated with ARHI expression (P < 0.05). Mutation of the putative E2F binding site in the ARHI promoter reversed this inhibitory effect and significantly increased ARHI promoter activity. In addition to the effects of transcriptional regulation, ARHI mRNA also exhibited a significantly reduced half-life in ovarian cancer cells when compared with that in normal ovarian epithelial cells (P < 0.01), suggesting posttranscriptional regulation of ARHI expression. ARHI mRNA contains AU-rich elements (ARE) in the 3'-untranslated region. We have found that these AREs interact with HuR, an ARE-binding protein that stabilizes bound mRNAs, possibly contributing to the rapid turnover of ARHI mRNA. Finally, reduced HuR ARE binding activity was observed in ovarian cancer cells when compared with normal ovarian surface epithelium. CONCLUSIONS: Taken together, our data suggest that ARHI expression is regulated at both the transcriptional and the posttranscriptional levels, contributing to the dramatic decrease in ARHI expression in ovarian cancers.

Base Sequence↗

PubMed2006

Objective assessment of aesthetic outcomes of breast cancer treatment: measuring ptosis from clinical photographs.

The aesthetic outcome of breast cancer treatment is an important factor in breast cancer survivors' quality of life. We investigated new quantitative, objective measurements of breast ptosis based on ratios of distances between fiducial points manually identified in oblique and lateral clinical photographs. Ptosis refers to the extent to which the nipple is lower than the inframammary fold. The new objective measures were compared to ratings made using an existing subjective scale. The variability in the objective measurements due to intra- and inter-observer variability in marking fiducial points was shown to be equivalent to less than one point on the subjective ptosis scale.

Adult↗

PubMed2005

Interactive dynamic graphical techniques for the exploration of functional data.

INTRODUCTION: The use of interactive dynamic graphics has become a common practice for the exploration of multidimensional data sets. The availability of powerful and inexpensive hardware and software for graphical computing makes the use of such techniques feasible for the examination of complex forms of data. This paper describes some simple techniques, which were implemented in the LISP-STAT environment, for the visualization of functional data arising from studies of optical technologies used for the detection of cervical intraepithelial neoplasia or squamous intraepithelial lesions. MATERIALS AND METHODS: The methods demonstrated have been implemented in software coded in LISP-STAT, a free statistical computing package available for most computer systems. The data used in this paper are drawn from a previous study in which fluorescence spectroscopy was measured from cervical sites at 337 nm, 380 nm, and 460 nm excitation in cervical screening patients. The goal of the project is to explore biographical variables to better understand the biology of fluorescence. RESULTS: 199 measurements were taken in 55 women with normal Pap smears. The data are recorded as spectra showing the intensity of emission excitation versus emission in nanometers. Covariate variables available for analysis are current smoker vs. nonsmoker premenopausal vs. postmenopausal, tissue type (columnar, squamous, and transition zone), and age in years. Although the optical measurements show consistent changes between normal and abnormal tissue in individual patients, there is wide variation in the intensity of the measurements between patients, even for normal tissue. Patient age affects the fluorescent spectrum showing increasing intensity with increasing age. Menopausal status affects the fluorescent spectra coincidentally with age. Smoking and race do not appear to affect the spectra in this sample of patients. CONCLUSIONS: The use of interactive graphical techniques permits the data analyst to examine multidimensional data in intuitive ways. These explorations allow non-statisticians to explore the data in a perceptive manner that may lead to new approaches in algorithm development for optical technologies.

Analysis of Variance↗

PubMed2005

Results of a pilot study of multispectral digital colposcopy for the in vivo detection of cervical intraepithelial neoplasia.

OBJECTIVE: Fluorescence spectroscopy is a promising technology for the detection of cervical squamous intraepithelial precancers and cancers. To date, many investigators have focused on point spectroscopy as an adjunct to diagnostic colposcopy. A device that visualizes the whole field of the cervix is needed for screening. To that end, we have developed a multispectral digital colposcope that works through the colposcope to image with white light, UV excitation at 345 nm, and blue light at 440 nm excitation. Here, we report the pilot study that precedes a Phase I trial. METHODS: The MDC system is composed of a light source, a colposcope, and a video rate color CCD camera with a frame grabber and takes approximately less than 1 min to make images of the cervix. Patients were measured at baseline and after acetic acid placement with white light, 345 nm excitation, and 440 nm excitation from the xenon arc lamp. The white light is in the visible spectrum, 345 nm excitation is in the UV spectrum and is not visible, and 440 nm excitation is blue light in the visible spectrum. White light generates a pink image of the cervix. 345 nm excitation, the UV light, excites fluorophores to emit a blue image. 440 nm excitation, the blue light, excites fluorophores to emit a green image. The patients underwent a loop excision procedure and the histopathology was inked and cut into 12 sections by the study pathologists. The histopathologic slides were scanned and the images were then reconstructed into maps. A diagnostic algorithm was calculated. The data were preprocessed, transformed, and analyzed by the K-means clustering method. Disease maps were generated using the algorithm and classifier and compared to white light colposcopy and the blue and green images obtained at 345 and 440 nm. RESULTS: Forty-six patients were measured at four clinical sites. Images were made of the cervix with white light, 345 nm excitation, and 440 nm excitation and are presented in the figures. As the study went on, images improved with improvements in the instrument. The white light and fluorescence images are presented with crudely constructed histopathologic maps and algorithmic maps. At 345 nm excitation, the UV light, histologically confirmed CIN appears darker blue; while at 440 nm excitation, the blue light, histologically confirmed CIN appears lighter green. CONCLUSIONS: This pilot study shows that MDC images can be matched to both histopathologic and algorithmic maps. The device and the algorithm are evolving but show promise. A Phase I trial is planned.

Adult↗

PubMed2005

Classification using the cumulative log-odds in the quantitative pathologic diagnosis of adenocarcinoma of the cervix.

INTRODUCTION: This study develops a method that discriminates between normal and cancerous tissue sections (i.e., populations of cells) using a statistical model applied to high-dimensional quantitative measurements made on a sample of cells. MATERIALS AND METHODS: We use a cumulative log-odds model to create a score for a tissue section using the information from the cells within that tissue section. Then, a threshold is determined using receiver operating characteristic (ROC) curve analysis. The method was tested using data from cervical adenocarcinomas, adenocarcinoma in situ, and normal columnar tissue. RESULTS: Using 120 potential features, we analyzed the data for staining-independent features. Twenty-two features were statistically significant. We then calculated the log-odds and created a score, followed by ROC curve analysis. The operating point which maximizes the sum of the specificity and sensitivity achieved a sensitivity of 100% with a specificity of 85%. CONCLUSION: The cumulative log-odds performs well in classifying tissue sections using high-dimensional data measured at the cellular level, like that of quantitative pathology. This methodology potentially has applications in pathology, radiology, and optical technologies.

Adenocarcinoma↗

PubMed2005

Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial.

BACKGROUND: Several genetic alterations have been described in cervical cancers including: human papillomavirus (HPV) E6 and E7 oncoproteins, subtle sequence changes, alterations in chromosome number, chromosome translocations, and gene amplifications. This report focuses on establishing chromosome 9 polysomy as a cervical biomarker of chromosome instability and using it in a chemoprevention trial. Chromosomal instability is a feature of most human cancers and is probably an early event in the process. METHODS: We used 37 cervical cone specimens to validate chromosome 9 polysomy as a biomarker and then tested its modulation in a randomized clinical trial of 4-hydroxyphenylretinamide (4-HPR) in 39 patients with three blinded histopathologic reviews. No confounders were identified. In the present study, immunohistocytochemical analysis of Chromosome 9 polysomy was carried out and quantitatively measured. RESULTS: The Cell Index, the ratio of the number of total chromosome 9 copies to the total number of ells, increases significantly in archival samples as the cervix changes from normal to CIN to invasive cancer. In the chemoprevention trial, chromosome 9 polysomy was used as a biomarker and supported the histological analysis showing that 4-HPR impaired the natural regression response. CONCLUSIONS: Chromosome 9 polysomy appears to be a marker of genetic instability that can be used in chemoprevention trials as a surrogate endpoint biomarker. In this randomized trial of 4-HPR, the chromosome 9 polysomy measurements supported the clinical histopathologic reading in a quantitative manner suggesting that 4-HPR at 200 mg/day may have been inhibiting the regression seen in the placebo arm by inducing genetic instability.

Aneuploidy↗

PubMed2005

Age and FSH effects in fluorescence spectra from the cervix: an exploratory analysis.

INTRODUCTION: Real-time optical technologies that could diagnose cervical cancer could improve the detection of cervical cancer. Our group is studying the technology assessment of optical devices in the screening and diagnosis of cervical neoplasias. METHODS: We have conducted a diagnostic trial in 850 patients with referral Papanicolaou smears showing ASCUS or greater. Each colposcopically abnormal site and two normal sites were measured with fluorescence and reflectance spectroscopy and then biopsied. Each site generates a fluorescence excitation emission matrix that has a 3-dimensional map with peaks and valleys. RESULTS: The early exploration of these data is presented and shows an effect of age, Follicle Stimulating Hormone or FSH, and, curiously, of their interaction. We have examined other biographical variables like smoking, HPV positivity, grade of CIN, device used, probe used, race, ethnicity, gravidity, parity, previous treatments, and others. None are significant predictors of this finding of increased intensity, except age and FSH. CONCLUSIONS: The effect of age supports the work done on fresh tissue slices in trying to better understand the biology of fluorescence. The effect of FSH is not a surrogate for age, but an independently significant effect, for which we currently do not have an explanation. We are exploring if FSH is a surrogate for estrogenization by measuring estradiol levels and calculating the BMI.

Age Factors↗

PubMed2005

Results of a phase II double-blinded randomized clinical trial of difluoromethylornithine for cervical intraepithelial neoplasia grades 2 to 3.

PURPOSE: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m2, versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels. EXPERIMENTAL DESIGN: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix. RESULTS: There were no statistically significant differences among the arms in histopathologic response. This could no be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology. CONCLUSIONS: DFMO is no active at 0.125 and 0.5 gm/m2 for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noted in trials of actinic keratoses.

Adolescent↗

PubMed2005

Optical technologies for cervical neoplasia: update of an NCI program project grant.

Cervical cancer is the second most common cancer in women worldwide and the leading cause of cancer mortality in women in developing countries. In the United States, over $6 billion is spent annually in the evaluation and treatment of low-grade lesions, many of which do not develop into full-blown cancer. In developing countries, however, the chief concern is that cervical cancer goes undetected because of the cost of testing and the lack of resources and trained personnel to screen and diagnose the disease. The goal of the National Cancer Institute Program Project Grant CA82710 is to assess the emerging technologies of fluorescence and reflectance spectroscopy and quantitative cytology and histopathology for the diagnosis of cervical neoplasia. All of these technologies should decrease mortality, morbidity, and the cost of treating cervical cancer.

Computational Biology↗

PubMed2004

The effects of repeated spectroscopic pressure measurements on fluorescence intensity in the cervix.

OBJECTIVE: Fluorescence spectroscopy is a promising technology for the detection of cervical squamous intraepithelial lesions (SILs). In this study we took repeated measures in the cervix to determine whether the order of measurement produces changes in fluorescence intensity and whether there are differences in variation due to pressure. METHODS: A pressure sensitive fiber-optic probe to measure fluorescence spectra was calibrated at light, medium, and firm levels (0.2, 0.4, 0.6 N). Measurements were made 3 times at each of 2 sites in the patient's cervix. Spectroscopic data were preprocessed and analyzed to compare order of pressure and intensity variability as a function of pressure on measurements. RESULTS: Four providers took 3 measurements from 2 sites each in 18 patients, yielding 108 measurements. After corrections for multiple comparisons, neither the order of probe pressure nor the variability of probe pressure significantly affected variations in fluorescence intensity. CONCLUSION: This study shows that the probe pressure variability is probably not an issue for these devices.

Adult↗

PubMed2004

Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo.

Lung cancer is one of the leading causes of death in the world. The underlying cause for lung cancer has been attributed to various factors that include alteration and mutation in the tumor suppressor genes. Restoration of normal function of the tumor suppressor gene is a potential therapeutic strategy. Recent studies have identified a group of candidate tumor suppressor genes on human chromosome 3p21.3 that are frequently deleted in human lung and breast cancers. Among the various genes identified in the 3p21.3 region, we tested the antitumor activity of the FUS1 gene in two human non-small-cell lung cancer (NSCLC) xenografts in vivo. Intratumoral administration of FUS1 gene complexed to DOTAP:cholesterol (DOTAP:Chol) liposome into subcutaneous H1299 and A549 lung tumor xenograft resulted in significant (P = .02) inhibition of tumor growth. Furthermore, intravenous injections of DOTAP:Chol-FUS1 complex into mice bearing experimental A549 lung metastasis demonstrated significant (P = .001) decrease in the number of metastatic tumor nodules. Finally, lung tumor-bearing animals when treated with DOTAP:Chol-FUS1 complex demonstrate prolonged survival (median survival time: 80 days, P = .01) compared to control animals. This result demonstrates the potent tumor suppressive activity of the FUS1 gene and is a promising therapeutic agent for treatment of primary and disseminated human lung cancer.

Carcinoma, Non-Small-Cell Lung↗

PubMed2003

Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases.

OBJECTIVE: The aim of this study was to identify clinical and pathologic characteristics of patients with uterine papillary serous carcinoma (UPSC) who were all surgically managed at a single institution. The identified characteristics were then correlated with overall survival (OS). METHODS: One hundred twenty-nine patients with FIGO stage I-IV UPSC who were surgically staged at the University of Texas M. D. Anderson Cancer Center between 1989 and 2002 were identified. For each patient, medical records and pathology reports were reviewed. The Kaplan-Meier method was used to generate OS data. Factors predictive of outcome were compared using the log-rank test and Cox regression analysis. RESULTS: There were 52 patients with stage I disease, 5 with stage II, 41 with stage III, and 31 with stage IV. The median age at the time of diagnosis was 68 years (range, 44-93 years). A personal history of breast cancer was reported by 12.4% of the patients, and a family history of breast cancer was reported by 16%. The 5-year OS among all patients was 45.9%. Among the stage I patients (IA, n = 19; IB, n = 26; and IC, n = 7), the 5-year OS was 62.9% (IA, 81.5%; IB, 58.6%; and IC, 34.3%). The 5-year OS for patients with stage III and IV disease was 37.3 and 19.9%, respectively. Pathologic features predictive of OS included lymph node status (P </= 0.01), lymph vascular invasion (P </= 0.05), and depth of uterine invasion (P </= 0.05). Among patients with no uterine invasion (n = 32), surgical staging revealed that 37% had stage III or IV disease. Among stage III patients, those who received chemotherapy had a longer OS than those who did not receive chemotherapy (P = 0.03). CONCLUSION: In this population of nonselected patients with UPSC, approximately 20% had a personal or family history of breast cancer. Stage, lymph node status, lymph vascular invasion, and depth of myometrial invasion were all risk factors for a worse prognosis. Traditional risk factors, however, did not predict the presence or the absence of metastasis. Among patients with noninvasive uterine disease, there was a high proportion with abdominal metastasis. Therefore, complete surgical staging of these patients is vital in determining their prognosis.

Adult↗

PubMed2003

beta-catenin nuclear localization is associated with grade in ovarian serous carcinoma.

OBJECTIVE: beta-Catenin has been previously associated with oncogenic activity in human cancers. We evaluated whether beta-catenin also plays a role in papillary serous ovarian neoplasms. METHODS: Immunohistochemistry for beta-catenin was performed on the primary ovarian serous neoplasms of 105 women. Of these, 10 were low malignant potential (LMP) serous tumors, and 95 were serous cancers. Nuclear beta-catenin staining was correlated with grade of tumor and median survival. OVCAR-3, OVCA-420, OVCA-432, and MDAH-277-10c were evaluated for beta-catenin localization and transfected with a T-cell factor (TCF) responsive reporter to evaluate beta-catenin transcriptional activity. RESULTS: Of 105 serous tumors, 13 (12.3%) demonstrated beta-catenin nuclear staining. Eleven of 48 high-grade serous carcinomas (23.0%) demonstrated nuclear staining compared with 1 low-grade serous carcinoma (2.1%) (P = 0.006). One LMP tumor had nuclear staining. beta-Catenin nuclear localization was undetectable in the cell lines tested. Furthermore, transient transfection of the cell lines with a TCF-responsive reporter did not demonstrate significant constitutive transcriptional activation. CONCLUSIONS: We found a statistically significant correlation between beta-catenin nuclear localization and ovarian high-grade serous carcinomas. Thus, deregulation of beta-catenin may play a role in the pathogenesis of ovarian high-grade serous carcinomas in contrast to ovarian low-grade serous carcinomas and LMP serous tumors.

Adult↗

PubMed2003

Effects of biographical variables on cervical fluorescence emission spectra.

Diagnostic algorithms can classify tissue samples as diseased or nondiseased based on fluorescence emission collected from the intact cervix. Such algorithms can distinguish high-grade squamous intraepithelial lesions from low-grade squamous intraepithelial lesions. An understanding of the effects of the values of biographical covariates, such as age, race, smoking, or menopausal status on the emission spectra for each patient could improve diagnostic efficiency. The analysis described was performed using data collected from two previously published clinical trials; one study measured spectra from 395 sites in 95 patients referred to a colposcopy clinic with abnormal Pap smears, and the second study measured spectra from 204 sites in 54 patients self-referred for screening and expected to have a normal Pap smear. For this analysis, data about age, race, menstrual cycle, and smoking were collected. The principal components from normalized data were compared. There are clear intensity differences observed with age and menopausal status; postmenopausal patients exhibit higher emission intensities. Differences associated with biographical variables need to be tested in larger studies, which stratify adequately for these variables. The addition of these biographical variables in the preprocessing of data could dramatically improve algorithm performance and applicability.

Adult↗

PubMed2002

Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo.

A group of candidate tumor suppressor genes (designated CACNA2D2, PL6, 101F6, NPRL2, BLU, RASSF1, FUS1, HYAL2, and HYAL1) has been identified in a 120-kb critical tumor homozygous deletion region (found in lung and breast cancers) of human chromosome 3p21.3. We studied the effects of six of these 3p21.3 genes (101F6, NPRL2, BLU, FUS1, HYAL2, and HYAL1) on tumor cell proliferation and apoptosis in human lung cancer cells by recombinant adenovirus-mediated gene transfer in vitro and in vivo. We found that forced expression of wild-type FUS1, 101F6, and NPRL2 genes significantly inhibited tumor cell growth by induction of apoptosis and alteration of cell cycle processes in 3p21.3 120-kb region-deficient (homozygous) H1299 and A549 cells but not in the 3p21.3 120-kb region-heterozygous H358 and the normal human bronchial epithelial cells. Intratumoral injection of Ad-101F6, Ad-FUS1, Ad-NPRL2, and Ad-HYAL2 vectors or systemic administration of protamine-complexed vectors significantly suppressed growth of H1299 and A549 tumor xenografts and inhibited A549 experimental lung metastases in nu/nu mice. Together, our results, coupled with other studies demonstrating a tumor suppressor role for the RASSSF1A isoform, suggest that multiple contiguous genes in the 3p21.3 120-kb chromosomal region may exhibit tumor suppressor activity in vitro and in vivo.

Adenoviridae↗

PubMed2002

Why phase II trials in cervical chemoprevention are negative: what have we learned?

Cervical cancer is an important cause of mortality in women worldwide, and the cervix is a well-established clinical, cytologic, and histopathologic model of carcinogenesis. The cervix is easily accessible for examination and biopsy, and colposcopy improves visualization. Identifying chemopreventives in cervical cancer requires rigorous study design: dose de-escalating phase I, IIa trials; placebo-controlled phase IIb trials; and multicenter phase III trials. Reduction in disease incidence and surrogate endpoint biomarkers (SEB) may be trial endpoints. The goal of chemoprevention studies is to prevent or delay the development of cancer. Each agent requires a phase I or IIa trial for each organ site. Phase I, IIa studies of micronutrients, retinoids, alpha-difluoromethylornithine, and indole-3-carbinol have demonstrated response rates of up to 70%, but results of placebo-controlled phase IIb studies have been disappointing and their findings confounded by the high regression rates in placebo-treated patients. Enhancement of research methods, including sufficient enrollment guided by power calculations, uniform biopsy at study entry and exit, and strict progression through trial design phases would ensure valid and reliable results. Because human papillomavirus (HPV) is the major etiologic agent, pretrial laboratory and animal studies should have demonstrated the efficacy of the chemopreventive agent to decrease HPV viral protein expression or HPV tumor induction. SEB modulation must be characterized in any trial's earliest phases before use in phases IIb and III. Lessons learned in chemoprevention will serve as a basis for immunoprevention and vaccine trials.

Carcinoma, Squamous Cell↗

PubMed2002

Optimal excitation wavelengths for discrimination of cervical neoplasia.

Fluorescence spectroscopy has shown promise for the in vivo, real-time detection of cervical neoplasia. However, selection of excitation wavelength has in the past been based on in vitro studies and the availability of light sources. The goal of this study was to determine optimal excitation wavelengths for in vivo detection of cervical neoplasia. Fluorescence excitation-emission matrices (EEMs) were measured in vivo from 351 sites in 146 patients. Data were analyzed in pairs of diagnostic classes to determine which combination of excitation wavelengths yields classification algorithms with the greatest sensitivity and specificity. We find that 330-340-, 350-380-, and 400-450-nm excitation yield the best performance. The sensitivity and specificity for discrimination of squamous normal tissue and high-grade squamous intraepithelial lesion (HGSIL) were 71% and 77% on cross validation using three excitation wavelengths. These results are comparable with those found in earlier in vivo studies; however, in this study we find that the proportion of samples which are HGSIL influences performance. Furthermore stratification of samples within low-grade squamous intraepithelial lesion and HGSIL also appears to influence diagnostic performance. Future diagnostic studies should be carried out at these excitation wavelengths in larger groups so that data can be stratified by diagnostic subcategory, age and menopausal status. Similarly, large studies should be done in screening populations.

Carcinoma, Squamous Cell↗

PubMed2002

Fluorescence spectroscopy as a biomarker in a cell culture and in a nonhuman primate model for ovarian cancer chemopreventive agents.

OBJECTIVE: The objective of this study was to compare the effects of chemopreventive agents on natural fluorescence emission of ovarian cells in a cell culture and in a primate model as a feasibility trial to monitor drug activity. METHODS: Fluorescence emission spectra were collected from normal (NOE) and immortalized ovarian surface epithelial cells at 290, 360, and 450 nm excitation. Redox potentials were calculated and compared to % apoptosis and cell survival. Fluorescence emission spectra were collected from 18 female rhesus macaques receiving fenretinide [N-(-hydroxyphenyl)retinamide (4-HPR)] orally and/or oral contraceptive pills (OCP) or no medication. Fluorescence intensities and redox ratios were compared using a two-tailed Student's t test. RESULTS: Apoptosis and cell survival correlated with fluorescence emission consistent with metabolically active proteins [flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD(P)H)] and the resulting redox ratio in cells grown with 4-HPR. The 4-HPR consistently inhibited cell survival in a dose dependent manner. Degree of correlation varied between different cell lines. In primates receiving 4-HPR, fluorescence emission was increased at 450 nm excitation, 550 nm emission consistent with FAD presence, whereas those receiving OCP showed decreased emission at 350 nm excitation, 450 nm emission consistent with decreased NAD(P)H presence. Redox ratios were increased by both drugs. CONCLUSIONS: Fluorescence intensity and redox ratio appear to be altered by 4-HPR treatment in vivo and in cell culture and by OCP in vivo. Fluorescence intensity may be useful to monitor chemopreventive agents in clinical trials.

Animals↗