Biomedical subjects

D D Taylor

Publications and source records attributed to D D Taylor.

At least 37 records · Page 2Linked to original sources

PubMed1996

Interleukin-2 activation of cytotoxic cells in postmastectomy seroma.

Lymphocytes were isolated from breast seroma fluids and used to study the mechanism of activation of cytotoxic lymphocytes and possible role of immunological potentiation following surgery in breast cancer patients. Single or serial samples were obtained from patients who had undergone mastectomy or lumpectomy with axillary node dissection. Lymphocytes were activated with rIL-2 (interleukin-2) and their cytotoxic activity was studied against Daudi and K562 cells and against a breast tumor line (SKBr-3). All of the patients (21/21) responded to IL-2 stimulation by significant activation of cytotoxic activity. The unstimulated cytotoxic activity of these cells against NK targets was low with less than 10% specific release in cytotoxicity assays. In simultaneous experiments, autologous seroma fluid was included during activation of lymphocytes to study possible regulatory molecules that may be present. In 17/21 patients, the presence of their seroma fluid, during the activation period, enhanced or did not effect the cytotoxic potential of their lymphocytes; inhibition was observed when seroma fluids from 4/21 patients were included. Analysis of the cytotoxic population derived from combined IL-2 and seroma treatments indicates the presence of cells with increased expression of CD56, and CD2, as well as in some cases CD16 expression. Cytotoxic lymphocytes derived from IL-2 and seroma treatments appeared to be more effective killers. Modulation of CD2 expression with seroma alone appeared to result in the generation of this highly cytotoxic population. This study demonstrates the role of CD2 expression in the effectiveness of LAK cell killing and also potential benefit of an immunotherapeutic approach to the postoperative treatment of carcinoma of the breast.

Adult↗

PubMed1996

Modulation of colon tumor oncogene expression by cancer patient-derived lipids.

In an effort to understand the role of specific fats on carcinogenesis, we have studied the effects of lipids derived from cancer patients on components associated with the regulation of proliferation. The treatment of tumor cells with patient-derived fats produced increased cell proliferation, as indicated by shorter doubling times. The effects of patient-derived lipids on the expression of ras, c-jun, c-erbB-2, and p53 gene products were examined. The cellular expression of the ras proto-oncogene product was increased in both colon tumor cell lines, following lipid treatment. However, c-jun proto-oncogene expression was elevated in HT-29 cells and appeared unchanged in SK-Co-1 cells after lipid treatment. Treatment of HT-29 tumor cells with patient-derived fats produced an enhancement of the p53 gene product, whereas fat treatment reduced p53 expression in SK-Co-1 tumor cells. Further separation of the patient-derived fats indicated that the amplification of p53 gene expression in HT-29 cells could be achieved primarily by addition of the diacylglycerides fraction. Addition of the purified fatty acids, comprising the diglyceride fraction, indicated that the fatty acids, 16:1, 18:0, and 18:1, induced the most significant increases in p53 expression by HT-29 cells. These alterations caused by cancer patient-derived fats are consistent with the loss of normal growth regulation and may explain the epidemiologic association between certain fats and carcinogenesis.

Adenocarcinoma, Papillary↗

PubMed1996

Aberrations in normal systemic lipid metabolism in ovarian cancer patients.

Numerous investigations have demonstrated altered systemic lipid metabolism in cancer patients, as well as aberrant lipid utilization by tumor cells. The most common measure of altered systemic lipid metabolism in these individuals has been hyperlipidemia. Although cachexia is not generally considered to be associated with gynecologic cancers, this study demonstrates the presence of lipolysis-promoting activity, detectable in sera and ascites of ovarian cancer patients and indices of altered systemic lipid metabolism. Elevated lipolysis promoting activity was detectable in the sera of 7/9 patients and in the ascites of 5/5 patients. Since previous studies have indicated that cancer patients exhibit a 2.5-fold enhancement in hormone-sensitive lipase (HSL) versus normal controls, as a potential mechanism for elevated lipolysis, the ability of ascites-derived factors to induce HSl was examined. The addition of three of four ascites fluids increased the level of HSL in normal adipocytes. All of the patients' samples exhibited elevated lipid levels versus normal peritoneal fluid. Isolation and analysis of lipids from three ovarian cancer patients revealed four consistent altered lipid parameters compared to normal peritoneal fluid: elevated monoglycerides, diglycerides, and free fatty acids and decreased triacylglycerides. While "classical" cachexia is not a common feature of ovarian cancer, the presence of circulating lipolysis-promoting activity and altered lipid metabolism, generally observed in cachectic individuals, can be demonstrated in these ovarian cancer patients. Based on recent evidence indicating a role of lipids in carcinogenic initiation or promotion, the presence of tumor-derived lipolysis-promoting factor and lipid metabolism alterations may provide a mechanism for the epidemiologically observed association between lipids and certain cancers, including ovarian cancer.

Adult↗

PubMed1996

Role of LFA-3, ICAM-1, and MHC class I on the sensitivity of human tumor cells to LAK cells.

Cellular adhesion molecules have been shown to be involved in tumor cell killing by cytotoxic cells such as natural killer (NK), lymphokine-activated killer (LAK), and T cells, but the precise mechanisms involved have not been clearly determined and a single target molecule has not been identified. We have examined the relative sensitivities of a panel of human tumor cell lines to LAK cell-mediated killing, in order to correlate their sensitivities with LAK cell-tumor cell binding determined by flow cytometry, and also with expression of molecules putatively involved in both the adhesion and recognition process. Two cell adhesion molecules in the immunoglobulin supergene family lymphocyte function-associated antigen (LFA-3) and intercellular adhesion molecule (ICAM-1) expression by tumor cells were examined in detail with respect to the degree of LAK cell-tumor cell conjugation and cytotoxicity. LAK sensitivity of the tumor cell lines was not clearly related to the degree of binding and correlated most strongly with the level of LFA-3 expressed on these cell lines. Major histocompatability complex (MHC) Class I antigen (Ag) expression by tumors was also examined and correlated with an inhibitory effect on LAK cell-mediated killing. Interferon-gamma(IFN) treatment of two of these tumor lines decreased their sensitivity to LAK, and treated cells exhibited a higher level of MHC Class I Ag and ICAM-1 and an increased degree of conjugation with LAK cells. These findings demonstrate roles for LFA-3, ICAM-1, and MHC Class I expression in the LAK cell-tumor cell recognition and triggering of the lytic process.

Antigens, Surface↗

PubMed1996

Effect of patient-derived lipids on in vitro expression of oncogenes by ovarian tumor cells.

To understand the role of specific fats on carcinogenesis, we have studied the effects of lipids derived from the ascites fluids of ovarian cancer patients on oncogenic components, associated with the regulation of proliferation. The treatment of tumor cells with patient-derived fats produced increased cell proliferation, as indicated by an increase in the number of S-phase cells. A similar enhancement in cell proliferation was not observed in normal fibroblasts, following lipid treatment. The effects of patient-derived lipids on the expression of c-jun, c-fos, and c-erbB2 gene products were examined. The cellular expression of the proto-oncogene product, c-fos, was increased in all three ovarian tumor cell lines, following lipid treatment. Expression of c-jun gene product was not detected in SKOV-3 or OVCAR-3 and was not induced by fat treatment. UL-1 cells did not express detectable levels of c-jun prior to fat treatment and treatment with patient-derived fat induced significant levels of c-jun product. All three ovarian tumor cell lines expressed the c-erbB2 gene product and it was generally enhanced by treatment with patient-derived lipids. When specific fatty acids were tested, 14:0, 16:1, and 18:1 were principally responsible for the observed enhancement of c-erbB2 levels, while the fatty acids, 18:0 and 20:4, produced the greatest increase in c-fos expression. Many alterations caused by fats are consistent with the loss of normal growth regulation and may account for the epidemiologic link between certain fats and the risk for ovarian cancer.

Ascitic Fluid↗

PubMed1993

Enhancement of antitumor effects of combined chemoimmunotherapy.

The spontaneously metastatic murine pancreatic tumor, PAN 2, was used to evaluate established regimens of combined chemoimmunotherapy with 5-fluorouracil (5-FU) and levamisole and new protocols based on the immunomodulator, thymopoietin pentapeptide (TP-5). The combination of 5-FU and levamisole reduced the final tumor size by 32% and the mean number of lung metastases by 71%. Based on flow cytometric analysis, the combination treatment increased the percent of helper/inducer (CD4+) lymphocytes and reduced the number of effector (suppressor/cytotoxic) lymphocytes (CD8+). A second combination using 5-FU and TP-5 produced a reduction in tumor growth rate of 52%, with an 88% suppression of lung metastases with TP-5/5-FU (vs. levamisole/5-FU) treatment. The TP-5 treatment also increased splenic T-lymphocyte responsiveness to nonspecific mitogens by 2.3-fold. These results suggest a correlation between enhanced T-lymphocyte functional parameters and reduced tumor growth and metastatic spread produced by these combination therapies. Since TP-5 has been demonstrated to be a superior immunomodulator compared to levamisole, the greater therapeutic effect of TP-5 vs. levamisole further supports the postulated role of immunopotentiation in the success of combined chemoimmunotherapy.

Adenocarcinoma↗

PubMed1992

Identification of a human tumor-derived lipolysis-promoting factor.

Our previous studies have demonstrated the production and release of a tumor-derived factor that promoted lipolysis in normal adipocytes. We further demonstrated that this in vitro lipolysis was correlated with the in vivo loss of total carcass lipids induced by the presence of the same tumor. This study identified and isolated this "lipolysis-promoting" factor (LPF), released into the extracellular environment (conditioned media) by the human A375 melanoma cell line, which appears to be responsible for the previously demonstrated induction of in vitro and in vivo lipolytic activity. Unlike previously described non-tumor-derived molecules, such as tumor necrosis factor-alpha/cachectin, which have been implicated in cancer cachexia, the LPF induces alterations in lipid metabolism similar to those observed in cancer patients. The biochemical nature of human tumor-derived LPF appears to be a heat-stable molecule with an apparent molecular weight of approximately 6000. The lipolysis-promoting activity was trichloroacetic acid precipitable, but not precipitable with protamine sulfate or extractable with chloroform:methanol. Its activity appears to be resistant to enzymatic treatments with protease K, trypsin, Pronase, RNase, and DNase, as well as to periodate oxidation. Immunochemically, LPF appears to be distinct from tumor necrosis factor-alpha/cachectin. Furthermore, in contrast to the mechanism of action of tumor necrosis factor-alpha/cachectin, the mechanism of "lipolysis promotion" by LPF appears to be by the induction of cellular lipase activity.

Adipose Tissue↗

PubMed1992

Identification of a novel cell population in nonhealing wounds in tumors.

We have explored wound healing in tumors as a possible model for tumor-host interaction. This work demonstrated tumor wound healing failure to be the result of intense inhibition of fibroblasts although the tumor cells did not appear to be the direct source of the inhibitors. The inflammatory infiltrate found in tumor wounds was then examined for possible sources of the observed fibroblast suppression. Although the tumor wound infiltrate contains cell populations similar to a normal wound infiltrate, it also contains a large, vacuolated, nonadherent, phagocytic mononuclear cell which has morphologic and cytochemical characteristics of a lipid-laden macrophage. However, the cell also proliferates under normal culture conditions and has an immunophenotype more characteristic of lymphocytes than those of macrophages with striking expression of the CD8 surface antigen. Conditioned media from this cell population markedly inhibit fibroblast proliferation suggesting it is the source of fibroblast inhibitors within the tumor wound. Mechanical dissociation of non-wounded tumors yielded evidence that the tumor wound cell is normally present in small numbers within the tumor.

Animals↗

PubMed1992

Intratumoral rIL2-based immunotherapy in B16 melanoma.

Limiting factors in systemic recombinant interleukin-2 (rIL2) therapy may be overcome by intratumoral (IT) administration. A series of experiments was conducted to assess the efficacy of IT rIL2 alone and in combination with LAK cells and IFN-gamma. C57BL/6 mice bearing B16-F10 subcutaneous tumors were randomly assigned to treatment groups including: noninjected controls, IT placebo (NaCl, D5W), IT bovine serum albumin (BSA), IT rIL2 (centrally and peripherally), IT rIL2/LAK, IT rIL2/IFN-gamma, and intraperitoneal (IP) rIL2. A tumor size-dependent dose of cytokine was injected daily and LAK cells were given weekly. Systemic immune response was assessed by splenocyte mitogenesis and T-cell subset distribution using thymidine radioassay and flow cytometry, respectively. In terms of survival and tumor growth rate, IT rIL2 was superior to noninjected control, IT placebo, IT BSA, and IP rIL2 (P less than 0.05). The addition of IT LAK cells conferred no therapeutic advantage. The combination of rIL2 and gamma IFN-gamma had a slight survival benefit over rIL2 alone (30.8 days vs 20.4 days). Histologic analysis demonstrated an increase presence of intratumoral macrophages in the IT rIL2-treated tumors (P less than 0.05). Lymphocyte mitogenesis and L3T4+ subset were not altered by any treatment. In vitro thymidine uptake by tumor cells was not affected by rIL2 nor IFN-gamma alone but the combination of rIL2 and IFN-gamma resulted in significant tumor cell growth inhibition. Spontaneous lung metastases were more prevalent following central IT rIL2 (75% vs 29%, P = 0.07) not accountable by needle trauma but avoidable by the use of peritumoral injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Intraoperative liver radiation after partial hepatectomy in a rat model.

Hepatic resection of metastatic tumor is a treatment option in selected patients. Resection margin is a prognostic factor of hepatic recurrence and survival. Although intraoperative radiation therapy (IORT) has been clinically useful in some gastrointestinal cancers, there is little information regarding its use following hepatic metastasectomy. In this study, a rat model was employed to evaluate histological changes and DNA synthesis as an indication of hepatic regenerative capacity following hepatectomy and liver IORT. All rats (N = 40) had a partial hepatectomy and were divided into four random groups: a nonradiated group and three groups of 1000, 2000, and 3000 cGy given by IORT. The only deaths occurred in the 3000 cGy group. Routine H and E staining of liver sections after 3, 6, and 10 days suggested progressive hepatocyte damage notably in the 3000 cGy group. Comparison of the final average liver weights at 10 days confirmed a diminished liver mass in the 2000 and 3000 cGy animals. DNA synthesis in hepatocytes measured by [3H]-thymidine label incorporation 3, 6, and 10 days after hepatectomy and IORT indicated a comparative and overall decrease in Day 6 peak activity between the three IORT groups. This study demonstrated delayed but substantial hepatic regeneration in the post-resected liver within the clinically useful IORT dose range (1000-2000 cGy) needed to control minimal residual tumor. This model has importance concerning the feasibility of IORT to the hepatic resection bed for patients where resection margins are inadequate.

Animals↗

PubMed1992

Intestinal myxosarcoma in a thoroughbred mare.

A large fibrotic mass originating from the cecal base was discovered upon surgical exploration of the abdomen in a Thoroughbred mare with a history of chronic colic and weight loss. The mass protruded intraluminally resulting in partial obstruction. Surgical excision was not feasible due to the location of the mass and the inability to exteriorize it adequately from the abdominal cavity. The mass was fibrous with a shiny, gelatinous material present throughout the neoplasm. Histologically, large confluent spaces filled with mucopolysaccharides were identified by staining with Alcian blue. The diagnosis of myxosarcoma was based upon finding of atypical fibroblastic cells, mucinous stroma, local invasiveness, and metastasis to the regional lymph nodes. Myxomatous tumors have not previously been documented to occur in the equine intestinal tract.

Animals↗

PubMed1991

Lymphokine-activated killer cell suppressor factor in malignant effusions.

We examined the possibility that tumor-released products inhibit lymphokine-activated killer cell activation. Lymphokine-activated killer cells from human peripheral blood lymphocytes were activated with recombinant interleukin 2 for 4 days in the presence of malignant effusions or conditioned media from cultured cell lines (10% vol/vol). Eight of 10 malignant effusions/media suppressed the induction of lymphokine-activated killer cell cytotoxicity, as measured in a 4-hour sodium chromate release assay. Seven of 10 effusions/media inhibited lymphokine-activated killer cell proliferation. Suppression was both dose and time dependent. A representative suppressive effusion was fractionated by agarose gel chromatography, treated with detergents disruptive of ionic bonds and lipids, and refractionated using polyacrylamide gel chromatography. Seven suppressive fractions ranging in molecular weight from 1 x 10(5) to 3 x 10(5) d were isolated. It is speculated that this suppressor factor may represent a large multimeric structure with ionic-bonded individual suppressive components.

Cell Division↗

PubMed1991

Aerosolized gamma-interferon and lipopolysaccharide enhances cytotoxicity of murine pulmonary alveolar macrophages.

In vivo stimulation of pulmonary alveolar macrophages (PAMs) may enhance tumor cell cytotoxicity. A model using aerosolized gamma-interferon (gamma-IFN) and lipopolysaccharide (LPS) was developed to induce enhanced PAM activation in vivo in C57BL/6 mice. Mice received four doses of aerosol (2 doses/day) consisting of gamma-IFN (10(4) microU/mouse) and LPS (100 micrograms/mouse). Other groups received either gamma-IFN alone, LPS alone, or saline (control). Cells were harvested by bronchoalveolar lavage. Macrophage cell count demonstrated an increase in macrophage recruitment in the gamma-IFN and LPS group. PAMs were evaluated for in vitro cytotoxicity against B16-F10 melanoma cells. Treatment groups demonstrated enhanced cytotoxicity over controls, and the combination (gamma-IFN plus LPS) was significantly better in cell killing than either treatment modality alone (p less than or equal to 0.02). Activated PAMs selectively killed tumor cells, but did not kill the 3T3 fibroblast cell line. Peritoneal macrophages from mice treated by inhalational gamma-IFN + LPS were enhanced (indicating a systemic effect), but not to the same extent as PAMs. These studies suggest that inhalation of gamma-IFN + LPS can selectively enhance in vivo cytotoxicity of murine PAMs. This may potentially be applicable to human tumor management.

Aerosols↗

PubMed1991

Clinical and cost effectiveness of prophylactic parenteral penicillin in the care of simple wounds undergoing suture repair.

Physicians working in casualty and outpatient departments where adverse conditions prevail often prescribe antibiotic prophylaxis routinely at the time of suture repair of simple wounds. To evaluate this practice, we performed a randomized, controlled study of parenteral chemoprophylaxis of simple wounds undergoing suture repair. Uncomplicated wounds were randomized to either treatment with a combination of benzathine penicillin (2.4 million units) and procaine penicillin (2.0 million units) intramuscularly, or a control group. At the time of suture removal, seven days later, all wounds were reviewed for signs of infection. Of 320 patients enrolled in the study, 173 (54.1%) returned for review. Among treated wounds, 75 of 81 (92.6%) were healing, compared to 79 of 92 (85.9%) controls (p = 0.24). A significantly higher rate of healing was observed when wounds repaired nine or more hours after injury and involving the arms, legs, or trunk were treated (22 of 23, 95.7%) compared to those in whom prophylaxis was omitted (20 of 30, 66.7%) (p = 0.03). Wounds involving the head, and wounds repaired within nine hours after injury had a high rate of healing (greater than 90%), whether prophylaxed or not. Based on a 30% higher healing rate for the patients who benefited from treatment (arm, leg, trunk wounds repaired after nine or more hours), the drug cost of implementing prophylaxis for this group alone was more than five times that of an expectant, non-prophylactic strategy. These results serve to remind practitioners of the possibility that a clinically effective mode of therapy may not necessarily be cost-effective in the delivery of health care.

Cost-Benefit Analysis↗

PubMed1990

Effect of retinoic acid on tumor-mediated immunologic alterations in mice bearing a variant of the B16 melanoma.

This investigation examined the effect of retinoic acid on tumor progression and immunological status of mice bearing the B16-F10 melanoma (previously selected for high lung-colonizing capacity). Tumor cells were implanted s.c. in syngeneic C57BL/6 mice, half of which were treated with beta-all trans retinoic acid (RA). Although RA failed to exhibit direct toxicity on this variant at the concentration used, the immunologic aberrations induced by the tumors were diminished by i.p. RA administration (at 45 micrograms twice/week for 3 weeks). In mice bearing B16-F10 tumors, tumor burdens were decreased from 2.9% of body weight to 1.6%. The mitogenic responses of splenic lymphocytes to concanavalin A (ConA) were increased in tumor-bearing mice following this RA treatment. The presence of these tumor cells decreased the absolute number of CD4- and CD8-positive splenic lymphocytes. Following RA treatment, the CD8-positive population was increased in tumor-bearing mice, while the CD4+ population was not significantly altered. Since previous studies indicated that plasma membrane fragments (or vesicles) could alter lymphocyte distributions and proliferative capacities, the in vitro shedding of membrane fragments from B16-F10 tumor cells was assayed and observed to be decreased after continuous treatment of cultures with 10(-6) M RA for 21 days. Membrane shedding from B16-F10 cells was inhibited by 48.5% following RA treatment. Based on these in vivo and in vitro results, we suggest that RA treatment may diminish tumor growth by decreasing tumor-induced immunosuppressive events.

Animals↗

PubMed1990

Suppression of wound healing in tumor bearing animals as a model for tumor-host interaction: mechanism of suppression.

Tumor wound healing was explored as a possible model for tumor-host interactions. Wound healing within tumors progressed normally through the hemorrhagic and inflammatory stages but failed at the mesenchymal ingrowth phase. Due to this failure of mesenchymal ingrowth, no significant collagen deposition could be detected within tumor wounds. Fluid collected from tumor wounds markedly altered fibroblast cytoskeletal structures and profoundly inhibited fibroblast proliferation and collagen synthesis. This suppression did not appear to be the direct consequence of tumor products, since tumor conditioned media enhanced fibroblast proliferation and had no effects on collagen synthesis and fibroblast cytoskeleton. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of lysed fibroblasts demonstrated that two polypeptides (Mr 280,000 and 240,000) were induced in or adherent to fibroblasts exposed to fluid from the tumor wound but not in fibroblasts exposed to fluid obtained from wounds in normal tissue or tumor conditioned media. These findings suggest that tumor wound healing is a model for mesenchymal inhibition within tumors but that the inhibitors are not tumor derived products.

Actin Cytoskeleton↗

PubMed1990

In vitro killing of human malignant mesothelioma by photodynamic therapy.

Photodynamic therapy was investigated as a potential new modality for the treatment of human malignant mesothelioma (HMM) utilizing the H-MESO-1 HMM cell line and the photosensitizing agent, Photofrin-II (PF-II). Up-take of PF-II by H-MESO-1 was documented by incubating H-MESO-1 cells with PF-II and measuring the fluorescence at 625 nm following excitation at 400 nm. Cytotoxicity of photodynamic therapy was determined by incubating H-MESO-1 cells (2 X 10(5)) in microtiter plates for 24 hr with concentrations of PF-II varying from 0 to 10 micrograms/ml. The wells were exposed to gold vapor laser light (628 nm) in doses ranging from 0 to 24,000 J/m2. Twenty-four hours following treatment, [3H]thymidine (1 microCi) was added to each well. Cells were harvested 24 hr later and counted for tritium incorporation. Five replicates were performed for each combination of light and drug. Peak absorption of PF-II by H-MESO-1 was reached within 8 hr. Maximal doses of light alone caused minimal cell killing. PF-II without light was cytotoxic only at the highest concentrations. However, the combination of PF-II at concentrations at or above 2.5 micrograms/ml and light produced a significant increase in cytotoxicity. These data demonstrate that photodynamic therapy can effectively kill human malignant mesothelioma cells in vitro.

Cell Survival↗

PubMed1990

Alterations of cellular characteristics of a human ovarian teratocarcinoma cell line after in vitro treatment with retinoids.

Differentiation of the human teratocarcinoma derived cell line. PA-1, with retinoids was examined at concentrations (10(-6)-10(-8) M) that did not exhibit an antiproliferative effect during log-phase growth. Treatment with naturally occurring retinoic acid or certain synthetic retinoids (13-cis retinoic acid, Ro10-9359, and Ro13-7410), while not significantly altering the log-phase growth rate, decreased the saturation cell density and mitotic indices after confluence. Retinoid treatment also induced changes in cell morphology, which appear to be related to reorganization of microtubules and microfilaments. Following retinoid treatment, the expression of cell glycoproteins (of 162 kDa, 152 kDa, 143 kDa. and 51 kDa) was altered. Treated cells also exhibited decreased expression of alkaline phosphatase, as well as an increased capacity for intercellular communication as evidenced by gap-junctional transfer of the phosphorylated toxic intermediate of 6-thioguanine to HPRT- cells. Treatment with retinoic acid dramatically reduced the quantity of shed plasma membrane material and altered its composition.

Alkaline Phosphatase↗