Biomedical subjects

R R Perry

Publications and source records attributed to R R Perry.

At least 37 records · Page 2Linked to original sources

PubMed1995

Clinical review 72: diagnosis and management of functioning islet cell tumors.

Functional islet cell tumors cause recognizable clinical syndromes based on the peptide products they secrete (Table 1). Frequently, the diagnosis of these tumors is delayed. A high index of suspicion coupled with the use of appropriate biochemical and provocative tests should lead to earlier diagnosis. A suggested management plan for patients suspected of having an islet cell tumor is shown in Fig. 1. Earlier diagnosis coupled with advances in preoperative and intraoperative localization techniques have resulted in an increased number of patients being cured.

Adenoma, Islet Cell↗

PubMed1994

Intratumor variability in prognostic indicators may be the cause of conflicting estimates of patient survival and response to therapy.

The DNA index, percentage of S-phase cells, proliferation fraction, and glutathione (GSH) content were determined at more than 1100 separate sites in 140 human tumors and 140 normal tissues. The study showed that the variability was so great from site to site within a tumor that there was only a 61% chance of identifying an aneuploid tumor clone (when present) if only a single site sample was analyzed for DNA content. Similar broad variability was observed in the percentage of S-phase cells, proliferation fraction, and glutathione content. Since these tumor characteristics are often used to predict the outcome of therapy and patient survival, the inaccuracy and underestimation of the test results may cause conflicting or erroneous predictions. The probability of finding an aneuploid clone or elevated percentage of S-phase cells proliferation fraction and GSH content increased dramatically as the number of sample sites studied per tumor was increased. Statistical analyses indicated that in order to achieve a 90% probability that the test results for these parameters were representative of the whole tumor: (a) all single site testing should be abandoned; (b) assays should be performed on samples taken from 3-7 different sites within each tumor; or (c) samples from each tumor should be pooled and the analyses run on a thoroughly mixed or homogenized aliquot of the multisite sample.

Breast Neoplasms↗

PubMed1994

Effect of alpha-interferon on P-glycoprotein expression and function and on verapamil modulation of doxorubicin resistance.

Human alpha-interferon (IFN-alpha) is one of the three major classes of interferons which possess antiviral, antiproliferative, and immunomodulatory activities. We recently reported synergism between IFN-alpha and tamoxifen in the modulation of doxorubicin (DOX) cytotoxicity and accumulation in multidrug resistant Chinese hamster ovary ChR C5 cells (Y. Kang and R. R. Perry, Cancer Res., 53: 3040-3045, 1993), but the mechanism was uncertain. In the present study, IFN-alpha (500 units/ml) pretreatment of ChR C5 cells similarly increased verapamil (VPL) modulation of DOX cytotoxicity in a time-dependent manner. Measurement of intracellular DOX fluorescence showed a parallel increase in DOX accumulation. Western blot analysis revealed that IFN-alpha induced a time-dependent increase in p-glycoprotein (p-gp) expression, accompanied by an increase of mdr-1 mRNA as measured using Northern analysis. MDR-1 gene copy number measured using Southern analysis remained unchanged. Assay of specific photoaffinity labeling of p-gp by [3H]-azidopine showed that, although IFN-alpha is not a substrate of p-gp, it significantly increased the ability of VPL to bind to p-gp. These data suggest that IFN-alpha may effect the expression of p-gp in multidrug-resistant ChR C5 cells by transcriptional or posttranscriptional control of mdr-1 gene expression. IFN-alpha enhances the ability of VPL to modulate DOX cytotoxicity and accumulation, possibly by altering the accessibility of p-gp binding site(s) to VPL. By using relatively low concentrations of IFN-alpha and VPL it may be possible to develop less toxic regimens to reverse multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Cancer of the male breast.

A retrospective review of 28 male breast cancer patients at Eastern Virginia Medical School and affiliated hospitals was performed to learn about patient characteristics, treatment, and outcome. The mean age of the patients was 64 years, and 60 per cent of patients were obese. The most common presenting symptoms were mass in 79 per cent and nipple discharge in 29 per cent. The median duration of symptoms was 3.3 months. All patients except two underwent mastectomy, and most tumors were early stage (0, I, or II). Many patients, particularly those with advanced disease, were also treated with chemotherapy, radiation therapy, and/or endocrine therapy. At a median follow-up of 29 months, the actuarial 5-year survival was 43 per cent, somewhat worse than the survival of female breast cancer patients in the literature. Male breast cancer patients are treated in a similar fashion to female patients. Aggressive systemic treatment should be considered for patients with poor prognosis disease. The high frequency of estrogen receptor positivity suggests tamoxifen may prove to be particularly useful in these patients.

Adult↗

PubMed1993

Biochemical characterization of a mitomycin C resistant colon cancer cell line variant.

Resistance may limit the clinical usefulness of a variety of chemotherapeutic drugs including mitomycin C (MMC). The MMC-sensitive HT-29 colon cancer cell line and its MMC-resistant subline, HT-29R13, were studied in vitro under aerobic conditions to help characterize the mechanisms associated with MMC resistance. HT-29R13 cells exhibit approximately 2-fold resistance to MMC compared with HT-29 cells and lack the typical multidrug-resistance pattern; resistance is stable in the absence of drug exposure. Levels of glutathione (GSH) and total glutathione-S-transferase (GST) activity were not different between the two cell lines; however, levels of GSH reductase and GSH peroxidase were increased significantly in HT-29R13. Although total GST activity was unchanged, GST-pi and GST-alpha isoenzyme expression as measured using western blot were increased significantly in HT-29R13 compared with HT-29. DT-diaphorase levels and topoisomerase II activity were decreased significantly in HT-29R13. Both cell lines had equal P-glycoprotein expression. Multiple drug resistance mechanisms are present in HT-29R13 including decreased drug activation (decreased DT-diaphorase), increased drug detoxification (increased GST-pi and GST-alpha, GSH reductase, GSH peroxidase), and decreased accessibility of DNA targets (decreased topoisomerase II). Further work will be necessary to determine the degree to which each of these mechanisms contribute to MMC resistance in this model.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Glutathione levels and variability in breast tumors and normal tissue.

BACKGROUND: Glutathione (GSH) is important in in vitro models of radiation and drug resistance, but its clinical relevance is uncertain. GSH levels were measured prospectively in 35 patients with breast cancer to establish normal ranges and to determine whether differences exist between tumor, lymph node metastases (when present), and normal breast tissue. METHODS: Fresh tissue was obtained immediately from discarded surgical specimens, and total GSH levels were measured with the Tietze cyclic reduction assay. When possible, multiple sites were assayed in each tumor to assess intratumor variability. RESULTS: GSH levels in primary breast tumors were more than twice the levels found in normal breast tissue, and levels in lymph node metastases were more than four times the levels in normal breast tissue. The levels of GSH in normal lymph nodes were similar to levels in normal breast tissue. GSH levels in different areas of the same breast tumor ranged from below those of normal breast tissue up to 11 times normal tissue levels. No correlation was found between tumor GSH levels and common clinical parameters such as tumor size, nodal status, stage, estrogen receptor levels, or progesterone receptor levels. CONCLUSIONS: GSH appears to be a marker of breast malignancy that is independent of hormonal receptor status and stage and may be a marker of cells with increased potential for dissemination. Because of tumor heterogeneity, multiple sites should be sampled whenever possible. Long-term clinical follow-up will be necessary to ascertain the usefulness of tumor and lymph node GSH levels in predicting prognosis.

Breast↗

PubMed1993

Modulatory effects of tamoxifen and recombinant human alpha-interferon on doxorubicin resistance.

Doxorubicin (DOX) resistance is frequently due to the multidrug resistance gene product P-glycoprotein. This study examined the effects of two biochemical modulators, recombinant human alpha-interferon (IFN-alpha) and tamoxifen (TAM), on the DOX sensitivity, DOX retention, and P-glycoprotein expression of the multidrug-resistant Chinese hamster ovary cell line ChR C5 and the parent AuX B1 cell line. In the absence of either modulator, the 50% inhibitory concentration for DOX after 1-h incubation as determined using a microculture tetrazolium assay was 8.3 microM in ChR C5 cells and 0.4 microM in AuX B1 cells. In ChR C5 cells, IFN-alpha (500 units/ml) for 24 h had no affect on DOX cytotoxicity, but tamoxifen (1.0 microM) for 24 h enhanced DOX cytotoxicity with the 50% inhibitory concentration decreased by 2-fold to 4.2 microM. A combination of IFN-alpha (500 units/ml) for the initial 24 h followed by TAM (1.0 microM) for another 24 h was even more effective in ChR C5 cells with the DOX 50% inhibitory concentration decreased by 4-fold to 2.1 microM. The combination IFN-alpha and TAM dramatically increased DOX accumulation in the resistant ChR C5 cells without significantly affecting P-glycoprotein expression as measured using flow cytometric analysis. IFN-alpha and/or TAM had no effect on DOX cytotoxicity or accumulation in parent DOX-sensitive AuX B1 cells. Both cell lines were estrogen and progesterone receptor negative. These data indicate that synergism between IFN-alpha and TAM may partially reverse DOX resistance and may potentially be useful in enhancing the clinical effectiveness of DOX.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Development and initial characterization of a mitomycin C-resistant colon cancer cell line variant.

Resistance may limit the clinical usefulness of a variety of chemotherapeutic drugs, including mitomycin C (MMC). In order to study resistance to MMC, a variant of the HT-29 human colon cell line was isolated by exposure to repeated doses of MMC. The 95% inhibitory concentration of MMC for this isolate (HT-29R13) was found to be approximately twice that for the parent line. The level of resistance did not increase with additional drug exposure, and resistance was stable for at least 6 months in the absence of drug exposure. HT-29R13 cells exhibit cross-resistance to melphalan and 5-FU but not to doxorubicin, cis-platinum, or etoposide. HT-29R13 cells are characterized by slightly decreased plating efficiency and slightly increased total protein compared with the parent line. This model of stable, low-level MMC resistance with an unusual cross-resistance pattern may prove useful for the study and characterization of MMC resistance mechanisms.

Cell Cycle↗

PubMed1993

Effects of diflubenzuron and clanfenur on mouse bone marrow cells.

Diflubenzuron (DFB) and Clanfenur (CFN) belong to a group of compounds called Benzoylphenyl Ureas (BPUs). Several BPUs regulate cell growth in insects and/or inhibit growth of B-16 murine melanomas. In view of potential clinical use for these compounds, DFB and CFN were selected as examples of BPUs and tested for effects on hematopoiesis in C57Bl/6 mice housed in a conventional environment. DFB and CFN exhibit anti-tumor activity in mice, cause little or no morbidity and mortality and rather than causing bone marrow suppression, which is usual for anti-cancer drugs, these agents stimulate hematopoiesis in vivo and in vitro. Stimulation in vivo was evidenced by increased (up to 112%) peripheral blood granulocytes 6 days after a single injection and enhanced granulopoiesis (approximately 25%) in bone marrow up to 18 days after treatment. That effects of DFB and CFN were on hematopoietic stem cells were indicated by 47% and 48%, respectively, increases in numbers of CFUs and 97% and 95%, respectively, increases in CFUgm. Further, bone marrow cells treated in vitro contained about twice the number of CFUs and CFUgm as control bone marrow cells. Almost all of the increase in number of spleen colonies, whether derived from donors treated in vivo or bone marrow cells treated in vitro, was accounted for by a corresponding increase in number of undifferentiated colonies. These data indicate that DFB and CFN treatment enhance numbers of pluripotential stem cells both in vivo and in vitro. The mechanism of enhancement, direct or indirect, remains to be determined.

Animals↗

PubMed1993

Phyllodes tumors.

Phyllodes tumors are rare lesions of the breast with unpredictable behavior. A review of 18 patients with phyllodes tumors was performed to determine if pathologic and cellular characteristics correlated with clinical behavior and to determine the influence of the extent of the operation performed on clinical outcome. Local excision, primarily breast biopsy, was performed in 14 of the 18 patients. At a median follow-up of 26 months (range: 3 to 164 months), there have been three recurrences, two in patients with low-grade tumors and one in a patient with a high-grade lesion, who eventually died as a result of widespread metastases. Recurrences were noted from 2 to 56 months after the original operation. Poor correlation was noted between standard pathologic criteria or flow cytometry and the risk of recurrence. Phyllodes tumors exhibit a wide spectrum of clinical behavior. Most patients will not experience a recurrence, but even small, low-grade tumors may recur if inadequately excised. Occasional patients have extremely aggressive disease that may result in death.

Adolescent↗

PubMed1992

Effect of treatment duration and glutathione depletion on mitomycin C cytotoxicity in vitro.

Glutathione (GSH) has been shown to modulate the cytotoxicity of a variety of chemotherapeutic agents. The effect of mitomycin C (MMC) treatment duration and the effect of GSH depletion on in vitro cytotoxicity against the human colon cancer cell line HT-29 was studied under aerobic conditions. Continuous-exposure experiments revealed that the cytotoxicity of 0.1 microM MMC, as measured by clonogenic cell survival, exhibited a shoulder until exposure time was at least 12 h, after which time exponential cytotoxicity was observed. Lowering GSH levels to less than 3% of control using buthionine sulfoximine (BSO) did not enhance cytotoxicity of MMC given for 1 h or continuously for less than 12 h. However, GSH depletion did enhance cytotoxicity of MMC given continuously for at least 12 h, with a dose-modifying factor at 1% survival of 1.4 for a 24-h treatment. GSH depletion under these conditions enhanced cytotoxicity of even minimally cytotoxic MMC concentrations (0.02 microM). Absolute levels of GSH-related enzymes, including glutathione-S-transferase, and the MMC-metabolizing enzyme DT-diaphorase did not change appreciably. A tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay was used to verify the results further and to determine the optimal sequence of BSO administration with a 24-h MMC treatment. BSO added simultaneously with MMC did not increase cytotoxicity, compared to MMC alone. BSO added and then removed prior to MMC was effective (dose-modifying factor at 50% survival = 1.3), but the greatest cytotoxicity was noted when BSO was present before and during MMC treatment (dose-modifying factor = 1.5). GSH depletion in another cell line (SW480) showed similar enhancement of 24-h MMC cytotoxicity. These studies show that aerobic cytotoxicity of MMC is improved by administration of the drug in continuous fashion for at least 12 h, as opposed to continuous administration for shorter periods or 1-h bolus administration. Cytotoxicity of continuous (at least 12-h) MMC treatment can be modestly enhanced by GSH depletion, which must precede MMC exposure in order to be effective.

Buthionine Sulfoximine↗

PubMed1991

Intravenous vs intraperitoneal sensitizer: implications for intraperitoneal photodynamic therapy.

Photodynamic therapy (PDT) is a potential treatment for peritoneal carcinomatosis. However, little data is available regarding the relative distribution of sensitizer to tumor and intra-abdominal organs, optimal route of sensitizer administration, and maximal tolerated light dose. Tumor and normal tissue sensitizer levels were measured by tissue extraction 3, 24, 48 and 72 h after 10 mg/kg of Photofrin II was given intraperitoneally (IP) or intravenously (IV) in a mouse peritoneal tumor model, and the maximal tolerated PDT light dose determined. Equivalent tumor sensitizer levels were obtained regardless of the route of sensitizer administration. Route of administration, however, did affect the kinetics of tumor sensitizer elimination, with the half-time for elimination (T1/2) 113.6 h for IP drug and 60.6 h for IV drug. Route of administration also affected sensitizer levels in several intra-abdominal organs, resulting in somewhat higher tumor to liver and kidney levels at 24 and 72 h after IP sensitizer administration. Despite these tissue distribution differences, route of sensitizer administration did not significantly affect PDT toxicity or mortality when mice were treated with 630 nm light. The maximum tolerated light dose was 1.04 J/cm2. These parameters will prove helpful in designing large scale animal trials assessing the efficacy and safety of intra-abdominal PDT.

Animals↗

PubMed1990

Sensitivity of different human lung cancer histologies to photodynamic therapy.

The relative sensitivities of different cancer histologies in a single site to photodynamic therapy (PDT) are unknown and methods to predict PDT sensitivity have not been described. The in vitro response to PDT of six established human lung cancer cell lines and one normal lung fibroblast cell line was studied using the clonogenic assay. Dose-response curves were determined for cells incubated in 25 micrograms/ml of Photofrin II for 2 h, followed by exposure to 630-nm light to total energies of 0-3150 J/m2. None of the cell lines were sensitive to sensitizer alone or light alone. Differences in inherent PDT sensitivities as evaluated by survival curve parameters n, Do, and light dose to yield 1% survival were observed among the cell lines. No clear correlation was found when inherent PDT sensitivity was compared with sensitizer uptake; however, a general association was noted between PDT sensitivity and the plating efficiency of the cell line. These data illustrate that differences in inherent PDT exist for in vitro systems. Such differences may explain some of the failures seen in clinical PDT.

Cell Line↗

PubMed1990

Survival after surgical resection for high-grade chest wall sarcomas.

Indications for chest wall resection of metastatic or locally recurrent sarcoma and for subsequent bony reconstruction are controversial. Twenty-eight patients had chest wall resection for high-grade primary, metastatic, or recurrent sarcoma. In all patients, resection with selective reconstruction of the bony thorax was performed without operative mortality. Since 1980, only patients with four or more ribs resected have had selective bony reconstruction. Follow-up ranged from 8 to 132 months (median follow-up, 42 months). All deaths were related to sarcoma recurrence. The overall actuarial survival rate was 85% at 1 year, 65% at 3 years, and 59% at more than 5 years. The overall actuarial proportion without disease recurrence was 64% at 1 year, 52% at 3 years, and 40% at more than 5 years. There was no significant difference in overall or disease-free survival for patients with primary, metastatic, or recurrent tumors. The most important prognostic factors were positive margins and concomitant pulmonary resection for synchronous lung metastases. These data support aggressive resection to obtain pathologically tumor-free margins for chest wall sarcomas, whether primary, metastatic or recurrent. Reconstruction can be individualized based on the extent of resection.

Adolescent↗

PubMed1990

Surgical management of pheochromocytoma with the use of metyrosine.

Despite recommended preoperative preparation with alpha-adrenergic blockers, severe hemodynamic instability may occur during operations to resect pheochromocytoma. We combined the alpha-blocker phenoxybenzamine with the tyrosine hydroxylase inhibitor metyrosine in an attempt to better manage the hypertension of patients with pheochromocytoma undergoing surgical resection. This report reviews the cases of 25 consecutive patients undergoing surgery for known intra-abdominal pheochromocytoma. Each patient had elevated serum or urine levels of catecholamines or their metabolites. Nineteen patients were prepared before operation with phenoxybenzamine and metyrosine and six patients were given phenoxybenzamine alone. There were no significant differences in maximum, minimum, or mean blood pressure before or after tumor resection between patients who received metyrosine and those who did not. However careful review suggested that those who received metyrosine had more severe disease as judged by biochemical criteria. Study of selected patients matched for age and severity of disease suggested that the intraoperative blood pressure management of patients prepared with phenoxybenzamine and metyrosine was facilitated. In addition metyrosine-prepared patients lost less blood and required less volume replacement during surgery than did non-metyrosine-prepared patients. There were no apparent differences in postoperative fluid requirements. Although the study is not a prospective randomized trial, a retrospective review of patients managed with the combination of phenoxybenzamine and metyrosine suggests that surgery to resect pheochromocytoma can be better performed with both drugs than with phenoxybenzamine alone. The combination regimen appears to result in better blood pressure control, less blood loss, and the need for less intraoperative fluid replacement than does the traditional method of single-agent alpha-adrenergic blockade.

Adrenal Gland Neoplasms↗

PubMed1989

In vitro photodynamic therapy of human lung cancer: investigation of dose-rate effects.

The influence of light dose-rate delivery was studied in human lung adenocarcinoma A549 cells treated with hematoporphyrin derivative (Photofrin II)-based photodynamic therapy. Clonogenic cell survival curves were generated for cells treated for 2 h with 25 micrograms/ml of Photofrin II followed by exposure to light delivered at 0.3, 0.15, 0.075, or 0.0375 milliwatts/cm2. Cellular sensitizer levels, as determined by fluorescence measurements, remained constant over the entire time course of all light exposures. As the dose rate of light delivery was decreased, a significant increase in cell survival was observed at equal light energies (225 mJ/cm2). The enhancement in survival from the highest to the lowest dose rate used was 1.6-fold (at the 50% survival level). These findings may have important clinical implications relating to photodynamic therapy of tumors and may provide a partial explanation for treatment failure.

Adenocarcinoma↗

PubMed1989

Profit made, now what? A case study.

A case history of how one not-for-profit mental health center used operationally-generated profit is presented. Actual and potential uses of profit, the concept of financial flexibility, the role of debt and the need for long range planning are discussed. The article concludes with a brief discussion of public relations issues faced by the profitable not-for-profit organization.

Accounting↗

PubMed1989

Potentiation of phototherapy cytotoxicity with light scattering media.

Lung cancer cells are susceptible to photodynamic therapy (PDT) using 630 nm light and dihematoporphyrin ether (DHE). A light scattering media, intralipid (IL), was compared to balanced salt solution (PBS) for PDT of A549 human lung cancer cells. Differences in cellular DHE content after IL or PBS exposure were determined. Cells were incubated in 25 micrograms/ml DHE for 2 hr and then incubated in various concentrations of IL or PBS at room temperature for 2.5 to 10.0 min. Significant amounts of DHE were lost from IL-incubated cells compared to cells incubated in PBS. After 5 min in 1% IL, cellular DHE content was 0.32 +/- 0.04 microgram DHE/10(6) cells compared to 0.56 +/- 0.11 microgram DHE/10(6) cells in PBS-incubated cells (P less than 0.05). Despite this, superior PDT cytotoxicity was noted when cells were treated in IL with energy densities greater than or equal to 105 mJ/cm2. At an energy density of 210 mJ/cm2, the survival fraction (SF) of cells treated in 1% IL was 0.004 +/- 0.001 compared to 0.071 +/- 0.022 in PBS-treated cells (P less than 0.05). SF was dependent upon the IL concentration with the greatest cell killing noted with 1% IL. An apparent loss of cellular DHE ("DHE washout") was confirmed by demonstration of a higher SF of cells incubated in IL, rinsed, and subsequently PDT-treated in PBS with 157.5 mJ/cm2 (SF = 0.85 +/- 0.11) compared to cells incubated and treated in PBS (SF = 0.50 +/- 0.03, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Survival↗