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D L Morton

Publications and source records attributed to D L Morton.

At least 181 records · Page 10Linked to original sources
PubMed1989

Ganglioside GM2 expression on human melanoma cells correlates with sensitivity to lymphokine-activated killer cells.

Ganglioside GM2 is expressed on cell surface membranes of a variety of human malignant cells and has been demonstrated to be immunogenic in humans. We have assessed the role of the antigen GM2 on melanoma cells as a recognition structure for lymphokine-activated killer (LAK) cells. LAK cells were generated by stimulation of non-adherent peripheral blood lymphocytes (PBL) from human donors with recombinant interleukin-2 (IL-2). The selection of target cells was based on GM2 content and included 11 human melanoma cell lines and 2 human leukemia lines. Using a single-cell binding assay, LAK cell binding to target lines expressing high levels of GM2 was significantly greater than to those expressing minimum GM2. This cell-binding was specifically inhibited by addition of purified GM2 but not by other gangliosides. LAK-melanoma cell-binding was also specifically inhibited by anti-GM2 monoclonal antibody (MAb). For further analysis LAK cell lysis of melanoma target cells expressing various amounts of GM2 was assessed. A significant correlation occurred with GM2 expression and LAK cell lysis (p less than 0.025; r = 0.623). Three other gangliosides commonly expressed on human melanoma, GM3, GD3 and GD2, had no correlation with LAK cell lysis. These studies suggest that GM2 on melanoma cells is a marker for LAK cell sensitivity, as well as indicate that GM2 is a potential target recognition structure for human LAK cells.

Antibodies, Monoclonal↗
PubMed1989

Gangliosides of human melanoma.

Human melanoma synthesizes a large quantity of gangliosides, glycosphingolipids containing sialic acid. The authors previously have demonstrated that the ganglioside profile differs among individual melanomas and is widely heterogeneous. In the current study, a retrospective study was performed to compare the relationship between the quantity of five major gangliosides of human melanoma (GM3, GM2, GD3, GD2, and alkali-labile ganglioside) and nine clinical factors (sex, age, site, stage, tumor size, pigmentation, histopathologic type of primary tumor, chemosensitivity, and prognosis). Melanoma specimens studied were obtained from patients of our clinic and included 52 biopsy specimens and 28 cultured cell lines. Analysis of melanoma biopsy specimens have shown a differential ganglioside expression among different sites of tumor, pigmentation, and histopathologic types. Results of cultured melanoma cell lines differed from those of biopsy specimens, but ganglioside expression also differed among the site of tumor, tumor size, histopathologic types, and chemosensitivity. GM3 positively correlated with a good prognosis in both biopsy and cultured melanomas.

Combined Modality Therapy↗
PubMed1989

Prognostic significance of pregnancy in stage I melanoma.

The clinical course of 66 patients with stage I melanoma, diagnosed during pregnancy, treated in the Division of Surgical Oncology at UCLA, was retrospectively reviewed. These patients were compared with 619 nonpregnant female patients with melanoma. There was no significant difference between the pregnant population and control population with respect to location of the primary tumor, age at diagnosis, Clark's level, mean depth of invasion (pregnant females, 1.24 mm vs control, 1.28 mm), and histologic type. The 5-year survival for the women diagnosed with melanoma during pregnancy and for the entire population was 86% and 87%, respectively. These results demonstrate that women diagnosed with melanoma during pregnancy fare no worse than their nonpregnant counterparts. Criteria other than the theoretical effect of pregnancy on the tumor should be used to counsel patients diagnosed with melanoma during pregnancy.

Adolescent↗
PubMed1989

Detection of a tumor-associated glycoprotein antigen in serum and urine of melanoma patients by murine monoclonal antibody (AD1-40F4) in enzyme immunoassay.

The urine of 68% of melanoma patients contains a high molecular weight glycoprotein which is expressed by melanoma cells and reacts with autologous antibody. Since high levels of this antigen in urine correlate with disease recurrence in surgically treated melanoma patients, it has been termed urinary tumor-associated antigen (U-TAA). We report the development of a murine monoclonal IgM antibody (AD1-40F4), which is specific for U-TAA. AD1-40F4 showed the same pattern of reactivity as the allo-antibodies previously used for the detection of U-TAA. The antigen recognized by AD1-40F4 has a high molecular weight (590-620 kilodaltons [kd]) and is heat stable. The AD1-40F4-reactive epitope is a protein. When AD1-40F4 was applied in an enzyme immunoassay, it allowed for the detection of U-TAA in the serum of 64% (33/52) of melanoma patients as opposed to only 5% (1/20) of normal controls. Thus, the murine monoclonal antibody AD1-40F4, which has been specifically developed against an allogeneic antibody defined antigen, U-TAA, appears to be important for immuno-prognosis of human melanoma.

Animals↗
PubMed1989

Active specific immunotherapy in malignant melanoma.

We have recently initiated clinical trials of active specific immunotherapy evaluating a new polyvalent melanoma cell vaccine in patients with high-risk and/or recurrent melanoma. The vaccine has been administered alone, or in combination with low-dose cyclophosphamide, as an immunomodulator of suppressor cells. Cyclophosphamide is effective in lowering suppressor cell activity in some patients undergoing active specific immunotherapy. This is not associated with an enhanced humoral immune response to melanoma-associated antigens, nor is the clinical course of those patients receiving cyclophosphamide favorably influenced. We are hopeful that other immunomodulators, alone or in combination with lower doses of cyclophosphamide, may be effective in some patients, particularly in those patients whose suppressor cell activity remains high. The optimization of the vaccine and the use of immunomodulators will enhance humoral and cellular immune responses to antigens in the allogenic vaccine that cross react with those present in the autologous melanoma, which should more favorably influence the prognosis of melanoma patients.

Antigens, Neoplasm↗
PubMed1989

Human monoclonal antibodies: prospects for the therapy of cancer.

Human monoclonal antibodies have been produced in a number of laboratories to a number of cell surface and cytoplasmic antigens. Although currently more difficult to produce than murine monoclonal antibodies, human monoclonal antibodies provide several potential advantages over conventional murine monoclonal antibodies in the therapy of human cancer. We review the human monoclonal antibodies produced to human tumors and describe our clinical experience with the use of human monoclonal antibodies in the treatment of recurrent cutaneous melanoma.

Antibodies, Monoclonal↗
PubMed1989

Induction of antibodies to a tumor-associated antigen by immunization with a whole melanoma cell vaccine.

Urinary-tumor-associated antigen (U-TAA) is a glycoprotein present in the urine of melanoma patients. Previous studies have addressed the role of U-TAA in immunoprognosis. The present investigation was undertaken to determine whether the administration of whole melanoma cell vaccine (MCV) could induce the formation of anti-(U-TAA) antibodies in melanoma patients. The subjects of this study were stage II and III melanoma patients receiving MCV alone or in conjunction with cyclophosphamide. Anti-(U-TAA) IgM and IgG antibody levels were determined by enzyme immunoassay in sequential serum samples from 15 stage II and III melanoma patients receiving MCV. U-TAA purified from the urine of a melanoma patient was used as a target in this assay. The mean anti-(U-TAA) IgM titer prior to vaccination was similar to that of a non-vaccinated melanoma control group (1:1138 +/- 214, n = 15 vs 1:1334 +/- 254, n = 7; P = 0.375) but prevaccination IgG levels were generally higher than in the control group (1:3984 +/- 602 vs 1:2595 +/- 423; 0.1 greater than P greater than 0.05). While only 6 of the 15 patients demonstrated a rise in levels of IgG antibodies (mean 1:2964 +/- 1047 pre-MCV to 1:9958 +/- 2677 post MCV, P less than 0.01), 11 of the 15 patients demonstrated a greater than twofold rise in their anti-(U-TAA) IgM titers following vaccination (1:1051 +/- 259 pre-MCV to 1:2518 +/- 576 post-MCV; P less than 0.005). In addition, patients with visceral metastases consistently elicited anti-(U-TAA) responses equivalent to those with more limited disease. Concomitant administration of cyclophosphamide did not affect the response rates of peak antibody levels. The possibility that these antibody responses were actually against histocompatibility locus antigens (HLA) (contaminating our U-TAA preparation) was ruled out because the target antigen (U-TAA) was devoid of HLA, and because the induction of anti-(U-TAA) antibodies did not correlate with the induction of anti-HLA antibodies. These results demonstrate augmentation of anti-(U-TAA) IgM and IgG antibodies by immunization with the MCV.

Antibodies, Neoplasm↗
PubMed1989

Modulation of human macrophage functions by gangliosides.

In human tumors of neuroectodermal origin cell surface expression of individual gangliosides is either increased or decreased relative to comparable normal cells. We have previously shown that gangliosides shed from melanoma cells can immunomodulate T cell activity. Monocytes/macrophages (m/m) are known to play an important role as accessory and effector cells in immune responses. We therefore investigated the effect of exogenous gangliosides derived from melanoma on m/m functions in vitro. Gangliosides commonly expressed on human melanoma such as GM3, GD3, GM2, and GD2 were investigated, as well as GM1, a major component of human neural tissue. Monocytes were isolated from human peripheral blood mononuclear cell populations, treated with gangliosides in vitro, and evaluated in several functional assays. Treatment of m/m with GM2 and GM3 gave the greatest inhibition of Fc receptor expression. GM1 and GD3 on the other hand most inhibited the production of interleukin-1 (IL-1) by m/m. Production of tumor necrosis factor (TNF) like monocytoxin was not affected by incubation with individual gangliosides. These studies suggest that individual melanoma gangliosides have different regulatory effects on m/m functions.

Gangliosides↗
PubMed1989

A new solution (UCLA formula) for lung preservation.

In previous studies, we revealed the beneficial effects of verapamil and glucose-insulin-potassium solution in lung preservation. In this study, we composed a new solution (UCLA formula) containing both of these factors and compared it with Collins-Sachs solution in a canine autotransplantation model. A total of 15 dogs were used. The animals were assigned randomly to the two study groups. The left lungs of seven dogs were perfused with the UCLA formula and the left lungs of eight dogs with Collins-Sachs. Both solutions were at 4 degrees C. After 6 hours of preservation, the left lungs in both groups were autotransplanted. In the UCLA formula group, seven of seven dogs (100%) survived for the entire period of 2 weeks after the operation. In contrast, two of eight dogs in the Collins-Sachs group (25%) survived for longer than 24 hours. Pulmonary artery resistance (dyne.sec.cm-5) after transplantation was 499.8 +/- 144.8 in the UCLA group and 780.9 +/- 174.5 in the Collins-Sachs group (p less than 0.01). Pulmonary artery resistance was also ascertained with the right pulmonary artery occlusion test and showed 539.5 +/- 95.4 in the UCLA group and 1469.3 +/- 573.6 in the Collins-Sachs group (p less than 0.01). Oxygen tension (mm Hg) after lung transplantation was 74.1 +/- 10.6 in the UCLA group and 35.9 +/- 3.5 in the Collins-Sachs group (p less than 0.01). Postoperative oxygen tension with the right pulmonary artery occlusion test was measured daily for 7 days. Two survivors in the Collins-Sachs group showed significant deterioration of oxygen tension from the third postoperative day. Also, the relationship between the airway pressure and tidal volume showed a significant reduction in the Collins-Sachs group (p less than 0.01). In conclusion, the transplanted lung in which UCLA solution was used demonstrated improved lung function after 6 hours of preservation in comparison with function in lungs preserved with Collins-Sachs solution.

Animals↗
PubMed1989

Lung function after prolonged lung preservation.

Our previous study revealed significant improvement in lung preservation with a new solution, the UCLA formula, which contains verapamil and is based on a glucose-insulin-potassium solution. In this study, we extended the preservation time up to 12 hours and, using various parameters, compared lung function after 12 hours' preservation with that after 6 hours' preservation. The left lung of 15 dogs was perfused with 300 ml of the UCLA formula (4 degrees C) and preserved for 6 hours in eight dogs (group A) and for 12 hours in the other seven dogs (group B). The preserved left lung was then autotransplanted and pulmonary function was evaluated during the following 2 weeks. The oxygen tension was monitored at 2 and 12 hours postoperatively, then daily for 1 week, and on the fourteenth postoperative day. The right pulmonary artery was temporarily occluded to assess the function of the preserved left lung alone. Oxygen tension in group A was maintained within the normal range. By contrast, in group B transient deterioration in oxygen tension was observed from the third to the fourth postoperative day (p less than 0.01), improving toward the normal range by the seventh day. Pulmonary vascular resistance was significantly elevated after transplantation in group B, improving to the normal range by the fourteenth postoperative day. Lung compliance, according to the airway pressure-tidal volume curve, also deteriorated significantly in group B (p less than 0.01), improving to the normal range within 2 weeks. Lung perfusion scintigraphy with technetium-labeled macroaggregated albumin was performed on the fourth day after the operation. The ratio of left to right pulmonary flow on the fourth postoperative day was 57.1 +/- 8.5% in group A and 52.2% +/- 12.3% in group B (no significant difference). In conclusion, temporary deterioration of lung function was observed after 12 hours of lung preservation, manifested by impaired oxygen exchange and loss of compliance.

Animals↗
PubMed1989

An analytical model for intra-arterial versus intravenous infusion of Adriamycin.

Intra-arterial infusion of Adriamycin (doxorubicin) has increasing clinical usage in various chemotherapeutic protocols for treatment of sarcomas and other tumors. This route of drug delivery is generally believed to provide better delivery of drug to the tumor than intravenous infusion. However, the differential delivery of drug to the tumor for the two methods has not been adequately described. An analytical model has been developed to investigate the hemodynamics of intra-arterial Adriamycin in terms of various parameters including location of injection; tumor site, resistance, and blood flow; relative resistances and blood flows in adjacent structures; and the pharmacokinetics of Adriamycin plasma concentration. A three-phase exponential model is fitted to experimental plasma concentration measurements and used in the formulation of equations describing tumor Adriamycin exposure. For typical values of tumor blood flow (4-20 ml/min/100 gr) and size (1,000 gm), it is estimated that with intravenous injection of Adriamycin the tumor is exposed to only 4-19% of the injected drug. Substantially higher doses of Adriamycin are delivered to the tumor by intra-arterial injection. Typically 3-4 times more drug flows through the tumor when injected into a major artery proximal to the tumor-feeding vessel, as into the common femoral artery for a sarcoma of the leg. With injection directly into a major tumor arterial feeding vessel, as much as 6 to 26 times the mass of drug is delivered to the tumor compared to a comparable intravenous injection.hus, smaller doses of drug should be required for tumorcidal activity and systemic toxicity of the drug may be reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Flow Velocity↗
PubMed1989

Tumour necrosis factor production by IL-2-activated macrophages in vitro and in vivo.

Purified human and murine monocytes can be activated in vitro by human recombinant IL-2 to secrete tumour necrosis factor (TNF). TNF mRNA is detected within 4 h of addition of IL-2. Signal transduction does not appear to require expression of the Tac peptide of the IL-2 receptor. IL-2 does, however, induce Tac mRNA and Tac peptide expression on peripheral blood monocytes (PBM). In addition to these in vitro studies, PBM retrieved from IL-2-treated cancer patients and mice have been shown to have a greatly increased capacity for TNF production. These studies identify a pathway for macrophage activation by IL-2 both in vitro and in vivo. They also suggest a mechanism for some of the immunoregulatory and toxic effects of IL-2 based immunotherapy regimens.

Animals↗
PubMed1988

Interleukin-1 and tumor necrosis factor production by tumor-associated mononuclear leukocytes and peripheral mononuclear leukocytes in cancer patients.

The production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) by tumor-associated mononuclear leukocytes (TAML) and peripheral mononuclear leukocytes (PMBL) from 9 otherwise untreated patients with a variety of malignancies (lung, sarcoma, stomach, renal) was assessed. Cells were cultured for 24 hr in vitro in the presence or absence of lipopolysaccharide (LPS), and IL-1 and TNF levels were measured in culture supernatants. TNF production was comparable between TAMLs and PBMLs. However, a striking defect in IL-1 production by TAMLs was noted. There was no basal production of IL-1 and LPS-stimulated TAMLs produced only 1% the amount of IL-1 produced by LPS-stimulated PBMLs.

Biological Assay↗
PubMed1988

Surgical resection for metastatic melanoma to the lung.

From 1971 through December 1986, the courses of 47 patients who underwent thoracotomy for pulmonary metastases from melanoma were retrospectively reviewed to determine the efficacy of this approach in the management of selected patients with melanoma. The overall five-year survival rate was 25% (median survival, 19 months). Thirty-eight patients were free of disease following thoracotomy. These patients fared significantly better than those who had residual disease following thoracotomy, with a five-year survival rate of 31% (median survival, 24 months) compared with 0% (median survival, six months). Survival was not influenced by the addition of adjuvant therapy or duration of time before the development of metastases (less than 12 months vs greater than or equal to 12 months). In selected patients with melanoma metastatic to the lung, thoracotomy with complete excision of the metastatic deposits results in improved survival and should be considered the treatment of choice.

Adult↗
PubMed1988

Thermal resistance of human malignant melanoma modulated by prostaglandin E2.

The inhibition of DNA synthesis in a human malignant melanoma cell line as measured by tritiated thymidine (3H-TdR) incorporation was both time- and temperature dependent. Two components of cell damage were identified: a cytostatic, temporary component from which cells recovered within 2-6 days, and a cytotoxic, permanent component from which no recovery was observed. Thermotolerance was induced in M14 cells by sublethal heat treatment at 41 degrees C for 1 hr. However, induction of thermotolerance was blocked by indomethacin, a prostaglandin synthetase inhibitor. Exogenous PGE2 at concentrations up to 10 micrograms/ml also protected cells from heat damage. These data suggest that prostaglandin synthesis increases during heat stress and may play a role in protecting cells from thermal damage.

Dinoprostone↗
PubMed1988

Testing chemotherapeutic combinations in the Human Tumor Colony--Forming Assay.

A total of 362 tumor specimens were tested in the Human Tumor Colony--Forming Assay for sensitivity to one of eight drug combinations and to each component drug as a single agent. Peak pharmacologically achievable concentrations of drug were used in continuous exposure. In 175 assays greater than 50% inhibition of colony formation, defined as in vitro sensitivity, was observed for at least one drug. The percent inhibition of the most active single agent closely approximated the percent inhibition of the combination. This relationship was maintained for all tumor types and combinations tested. Resistance in vitro to each drug in a combination predicted resistance to the combination. However, our data suggest that the higher activity of combination chemotherapy relative to single agents is due to an increased probability of finding an agent to which the tumor is sensitive, rather than to a synergistic interaction between drugs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Demonstration of a well-characterized tumor-associated antigen on melanoma cell surface.

We have isolated and characterized a melanoma tumor-associated antigen (TAA) from the spent culture medium of a melanoma cell line. Its presence has been detected in 72% of different melanoma specimens but not in normal tissues. Because tumor antigens may stimulate or perhaps block immune reactions to cancer cells, their presence on the cell surface may be a critical factor influencing tumor growth. Therefore, to define further the immunobiological characteristics of melanoma TAA, this antigen was investigated by membrane immunofluorescence. Serum from a melanoma patient known to have a high anti-TAA antibody titer was absorbed quantitatively with lymphoblastoid cells autologous to the target melanoma cells to remove non-anti-TAA antibodies. The absorbed serum was reacted with three cultured melanoma cell lines, UCLA-SO-10 (M10), UCLA-SO-14(M), and UCLA-SO-24 (M24). Of these cell lines, M10 and M14 are known to express the antigen as assessed by radioimmunoassay. Reaction of the antibody(s) to the antigen(s) on the melanoma cell surface was detected by fluorescein-conjugated goat anti-human IgG. The reactivity of the absorbed serum was inhibited by preincubation with purified melanoma TAA. These results clearly demonstrate that melanoma TAA is expressed on the cell surface of cultured melanoma cells.

Antigens, Neoplasm↗