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Biomedical subjects

K A Foon

Publications and source records attributed to K A Foon.

At least 73 records · Page 4Linked to original sources
PubMed1991

Unusual gastrointestinal complications of interleukin-2 therapy.

Minor and reversible gastrointestinal side effects are common when patients receive interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. We treated 42 cancer patients with IL-2 therapy and 3 patients developed serious gastrointestinal problems during treatment. Complications included sigmoid colon perforation, ischemic necrosis of the small and large intestine, and diffuse bowel ulceration. These were not associated with tumor implants or hypotension. Two patients died as a direct result of these problems despite aggressive surgical and medical management. The incidence of major gastrointestinal complications with IL-2 therapy may be greater than previously reported and a heightened awareness of potential gastrointestinal problems may circumvent considerable morbidity and mortality.

Adenocarcinoma↗
PubMed1991

Overview of monoclonal antibodies in the diagnosis and therapy of cancer.

Monoclonal antibodies initially offered the promise of a cure for cancer as "magic bullets" but this hope was quickly diminished as the complexities of the host-tumor relationship were realized. We have acquired a tremendous amount of practical experience since the first cancer patient was treated with a MAb nearly 10 years ago. This experience, combined with recent advances in recombinant DNA technology, has endowed us with a rich variety of opportunities to exploit in the diagnosis and treatment of malignancies. If recent preclinical research studies are clinically applicable and the antitumor responses seen in initial clinical trials can be optimized and confirmed, the next decade will likely be host to remarkable advances in the diagnosis and treatment of cancer with MAbs.

Animals↗
PubMed1991

Anti-idiotype monoclonal antibodies as vaccines for human cancer.

The anti-idiotype therapy approach has been tested and has shown to be effective in several animal models including the L1210/GZL tumor system in DBA/2 mice. Very recently, anti-idiotype antibodies (Ab2) have also been used in human trials. In this review, the generation and characterization of Ab2s which can be used as potential vaccine candidates for two human tumor systems--leukemia/lymphona and gastrointestinal carcinoma have been discussed. We have generated syngeneic monoclonal idiotypic cascades for two different human tumor-associated antigens (TAA) gp37 and carcinoembryonic antigen (CEA). In both cascades we have produced TAA mimicking monoclonal Ab2s and monoclonal anti-anti-idiotypes (Ab3) which bind to the original TAA. Modulation of immune responses in cancer patients by Ab2 immunization will be an important consideration in future studies.

Antibodies, Anti-Idiotypic↗
PubMed1990

Biodistribution, pharmacokinetic, and imaging studies with 186Re-labeled NR-LU-10 whole antibody in LS174T colonic tumor-bearing mice.

Biodistribution, pharmacokinetic, and radioimaging studies were performed with 186Re-labeled NR-LU-10 whole antibody in athymic nude mice bearing the LS174T tumor growing either s.c. or in an experimental hepatic metastasis model. NR-LU-10 is an IgG2b murine monoclonal antibody (MAb) that reacts with virtually all human tumors of epithelial origin. NR-BC-1, a IgG2b murine MAb that reacts with normal human B-cell and B malignancies, was used as an isotype-matched control. These MAbs were radiolabeled with 186Re (3.7-day physical half-life; 1.07-MeV beta particle and 137-keV gamma, 9% abundance) by a preformed chelate approach by using the triamide thiolate ligand system. 186Re-labeled NR-LU-10 (50 microCi) was injected into nude mice bearing LS174T tumors growing s.c. Biodistribution studies revealed that the LS174T tumor retained the highest concentration of 186Re-labeled NR-LU-10 (5.3% injected dose/g) at day 6. The tumor:blood ratio ranged from 0.1:1 to 10.8:1 by day 6, the last day of analysis. In contrast the tumor:blood ratio of 186Re-labeled NR-BC-1, the isotype-matched MAb control, was 1:1 on day 6. Pharmacokinetic analysis indicated that the t1/2 beta of NR-LU-10 for blood and other tissues ranged from 21 to 25 h, while the t1/2 beta for the LS174T tumor averaged 52 h. The area under the curve for tumor compared to blood was 2.8- to 5.7-fold higher than the area under the curve for all other tissues and organs. The mean residence time for NR-LU-10 in blood and all other organs ranged from 23 to 26 h, while the mean residence time for NR-LU-10 in the LS174T tumor was 72 h. Scintigraphic images revealed selective uptake of the 186Re-labeled NR-LU-10, but not of the 186Re-labeled NR-BC-1, at the LS174T tumor site. Studies in an experimental model of hepatic metastasis revealed a similar selective pattern of 186Re-labeled NR-LU-10 accumulation. Scintigraphic images of the LS174T tumor growing within the athymic nude mouse liver were obtained. The biodistribution, pharmacokinetic, and scintigraphic image results suggest that 186Re-labeled NR-LU-10 shows promise as a therapeutic agent for gastrointestinal cancer.

Adenocarcinoma↗
PubMed1990

Shared idiotype expression by chronic lymphocytic leukemia and B-cell lymphoma.

Antiidiotype (Id) antibodies identify unique determinants within the surface immunoglobulin (Ig) that are present on B-cell tumors. Anti-Ids have been used for diagnosis and therapy of B-cell lymphoma and leukemia. A panel of 29 anti-Id monoclonal antibodies (MoAbs) that recognize shared idiotypes (SIds) on B-cell lymphomas was tested for reactivity with both B-cell leukemias and lymphomas. Ten of 40 (25%) cases of chronic lymphocytic leukemia (CLL) reacted with at least one of the 29 anti-SId MoAbs. Three cases reacted with more than one anti-SId MoAb, but there was no repetitive pattern of a single anti-SId MoAb reacting with a large proportion of CLL cases. In contrast, for B-cell lymphoma, in which 11 of 31 (36%) cases reacted, one anti-SId (B4-1) reacted with five of the positive cases; all were diffuse histology. Restricted anti-SId reactivity may lead to important insights into the etiology of certain B-cell lymphomas. In addition, these anti-SIds may obviate the need to develop "tailor-made" antibodies for individual patients.

Antibodies, Monoclonal↗
PubMed1990

Murine monoclonal anti-idiotype antibody as a potential network antigen for human carcinoembryonic antigen.

Carcinomas of the gastrointestinal tract are not curable by standard therapies. Thus, new therapeutic approaches for this disease are needed. This study proposes the use of anti-Id mAb as Ag substitutes to induce anti-tumor immunity in gastrointestinal cancer patients. Recently, we have generated and characterized one monoclonal anti-Id antibody, designated 3H1 (Ab2), which mimics biologically and antigenically a distinct and specific epitope of the 180,000 m.w. carcinoembryonic antigen (CEA) primarily expressed in high density by human pancreatic and colonic tumor cells. This epitope is unique to CEA and not present on other CEA-related lower m.w. members of the Ag family also found on normal tissues. The antigenic determinant as defined by the mAb 8019 (Ab1) against which the Ab2, 3H1 was raised, is absent on normal adult tissues by immunoperoxidase staining and haematopoietic cells including granulocytes by flow cytometry analysis. Anti-Id (Ab2) 3H1 induced CEA-specific antibodies in mice and rabbits. The immune sera from both mice and rabbits competed with Ab1 for binding to the colon carcinoma cell line LS174T and inhibited the binding of radioiodinated Ab1 to Ab2. This indicates that anti-anti-Id (Ab3) in mice and rabbits share idiotopes with Ab1 (8019). Furthermore, monoclonal Ab3 that bind to CEA have been generated from mice immunized with 3H1. The Ab3 (both polyclonal as well as monoclonal) immunoprecipitated the same 180,000 m.w. CEA as Ab1 (8019) by Western blotting analysis and showed almost identical immuno-staining patterns as Ab1 on colonic adenocarcinoma tissue sections from several patients. Collectively these data suggest that Ab2 3H1 could potentially be used clinically as a network Ag for immunotherapy of patients with CEA positive tumors.

Adenocarcinoma↗
PubMed1990

Chronic lymphocytic leukemia: new insights into biology and therapy.

PURPOSE: To review the recent advances in the biologic and clinical research of chronic lymphocytic leukemia. DATA IDENTIFICATION: English-language literature search using MEDLINE (1980 to 1990) and CANCERLIT (1980 to 1990), review of meeting abstracts and reports, and an extensive manual search of bibliographies of identified articles. STUDY SELECTION: Approximately 800 articles, abstracts, and book chapters were selected for analysis. DATA EXTRACTION: The literature was reviewed and 227 articles were selected as representative of the important advances in chronic lymphocytic leukemia. RESULTS OF DATA SYNTHESIS: Chronic lymphocytic leukemia is a disease of lymphocytes that appear to be mature but are biologically immature. These B lymphocytes arise from a subset of CD5-B cells that appear to have a role in autoimmunity. The pathogenesis of chronic lymphocytic leukemia is likely a multistep process, initially involving a polyclonal expansion of CD5-B cells followed by transformation of a single cell. Chromosome studies indicate that trisomy 12 is the most common abnormality, followed by 14q+, 13q, and 11q. These abnormalities portend a poor prognosis. Recent progress in the treatment of chronic lymphocytic leukemia involves three new drugs: fludarabine, pentostatin, and 2-chlorodeoxyadenosine. Recent preliminary results of allogeneic bone marrow transplantation present insights into the potential curability of chronic lymphocytic leukemia. Therapy with intravenous immunoglobulin can prevent or delay moderate bacterial infections in persons with chronic lymphocytic leukemia. CONCLUSION: Major advances in the biologic research of chronic lymphocytic leukemia have resulted in new understanding of this complex disease. New therapies, such as those with intravenous immunoglobulin and fludarabine, may lead to improved outcome.

Agammaglobulinemia↗
PubMed1990

Interferon gamma augments Lym-1-dependent, granulocyte-mediated tumor cell lysis.

Lym-1 is a therapeutically promising IgG2a monoclonal antibody (MoAb) that reacts with variant class II molecules expressed on B-lineage malignancies. To optimize antitumor immunotherapy with Lym-1, we determined whether granulocytes could participate in tumor lysis mediated by Lym-1 and whether recombinant interferon gamma (IFN-gamma) could influence this reaction. Granulocytes had minimal activity in mediating Lym-1 antibody-dependent cellular cytotoxicity (ADCC) compared with peripheral blood mononuclear cells (PBMC). However, IFN-gamma markedly augmented and occasionally induced granulocyte Lym-1 ADCC in a dose-dependent fashion (optimal 100 U/mL). Granulocytes primed with IFN-gamma for 24 hours displayed greatly increased ADCC in the absence of further IFN-gamma exposure. In most individuals, IFN-gamma also enhanced PBMC Lym-1 ADCC. Interferon alfa (IFN-alpha), although able to enhance PBMC-mediated Lym-1 ADCC and non-ADCC lysis, had no effect on granulocyte activity. Lym-1 ADCC involved an interaction between Fc receptor-bearing granulocytes and Lym-1 antigen positive targets based on the following: (1) The reaction was Lym-1 dose-dependent with cytotoxicity detectable at concentrations as low as 0.5 microgram/mL. (2) An irrelevant, isotype-matched MoAb (UPC-10) was unable to mediate ADCC. (3) In the absence of Lym-1, granulocytes--with or without IFN-gamma--displayed no intrinsic tumor lytic ability. Conversely, without granulocytes, Lym-1 or Lym-1 plus IFN-gamma had no effect. (4) Protein A, which binds avidly to Lym-1, inhibited the reaction 95%. (5) IFN-gamma induced granulocyte expression of CD64, the IgG Fc receptor that binds murine IgG2a MoAbs. (6) Of nine malignant human cell lines, only the three that moderately or strongly expressed the Lym-1 antigen were consistently lysed. Preclinical studies such as these may provide a rational basis for designing clinical trials with Lym-1 in combination with IFN-gamma.

Antibodies, Monoclonal↗
PubMed1990

Antibody-dependent, cell-mediated cytotoxicity by an anti-class II murine monoclonal antibody: effects of recombinant interleukin 2 on human effector cell lysis of human B-cell tumors.

Lym-1 is an IgG2a murine monoclonal antibody that reacts with variant Class II molecules expressed on B-cell malignancies. Lym-1 was shown to mediate antibody-dependent cellular cytotoxicity (ADCC) of human effector cells against a variety of malignant B-cell lines. Tumor cell lysis was Lym-1 specific because (a) the reaction was dose dependent with significant ADCC detectable at Lym-1 concentrations as low as 1 microgram/ml; (b) tumor targets not expressing the Lym-1 antigen were unaffected; (c) an isotype-matched irrelevant monoclonal antibody and an IgG1 anti-Class II monoclonal antibody failed to mediate ADCC; and (d) addition of Protein A (which binds avidly to Lym-1) blocked ADCC by 90 to 100%. Peripheral blood mononuclear cells obtained from normal donors as well as from cancer patients were able to interact with Lym-1 to elicit ADCC. Recombinant interleukin 2 (rIL-2) enhanced non-antibody-mediated tumor lysis and Lym-1 ADCC with an optimal concentration of 100 units/ml. Pulse treatment of normal peripheral blood mononuclear cells with rIL-2 was able to augment Lym-1 ADCC but was less effective than having the rIL-2 present through the assay. Peripheral blood mononuclear cells obtained from patients being treated with high doses of rIL-2 administered by continuous i.v. infusion demonstrated Lym-1 ADCC levels which were higher than normal individuals and which were further augmented by in vitro incubation with rIL-2.

Animals↗
PubMed1990

Immunotherapy of gynecologic malignancies.

Systemic Corynebacterium parvum and BCG have limited activity in gynecologic malignancies. Although intraperitoneal C. parvum is active, its toxicity is prohibitive. Intraperitoneal alpha-interferon is an active second line agent for minimal residual disease following combination chemotherapy. Intraperitoneal interferon trials are ongoing. Alpha-interferon is also active against lower genital tract condyloma acuminata. Sufficient numbers of patients have not been evaluated to determine the activity of interleukin-2(IL-2) in gynecologic malignancies. Radioisotope labeled monoclonal antibodies can image gynecologic malignancies and may have a future therapeutic role. The last decade has witnessed a substantial growth in immunotherapy and has demonstrated a role for biologic agents in cancer therapy. Continued improvement in biologic therapies should lead to major advances in gynecologic cancer diagnosis and therapy.

Female↗
PubMed1990

Comparison of cisplatin and carboplatin cytotoxicity in human ovarian cancer cell lines using the MTT assay.

In this study, we compared the cytotoxicity of cisplatin and carboplatin against a panel of human ovarian cancer cell lines using the MTT assay, a rapid colorimetric test that can be used to evaluate the number of residual viable tumor cells following chemotherapy. The established human ovarian cancer cell line OVCAR-3 and the recently isolated and characterized A721, A90, A286, A1, and A121A cell lines were evaluated for chemosensitivity. Each cell line was treated separately with cisplatin and carboplatin at concentrations ranging from 500 to 0.16 micrograms/ml. Various chemotherapeutic exposure periods (1, 4, 24, and 48 hr) were tested to determine maximal efficacy. All cell lines were more susceptible to cisplatin than carboplatin at all drug concentrations and all exposure periods tested (P = 0.005). The overall median 50% inhibitory concentration (ID50) for cisplatin was 107 micrograms/ml compared with 490 micrograms/ml for carboplatin P = 0.005). For both cisplatin and carboplatin a 24-hr exposure was significantly more cytotoxic than a 1-hr exposure (P = 0.003 and P = 0.006, respectively). These in vitro results suggest that cisplatin is significantly more cytotoxic than carboplatin against human ovarian cancer cell lines and that cisplatin should not be replaced by carboplatin in the treatment of advanced epithelial ovarian cancer until randomized trials using maximum dosing of the cisplatin-containing regimen are performed.

Adult↗
PubMed1988

Localization and imaging with radioiodine-labeled monoclonal antibodies in a xenogeneic tumor model for human B-cell lymphoma.

Two MoAbs directed towards human B-cell malignancies have been studied in a preclinical animal model to evaluate their potential for in vivo imaging and therapy of B-cell lymphomas. Anti-B1 reacts with virtually all immunoglobulin-bearing malignancies and non-T acute lymphoblastic leukemia. Anti-J5 reacts with the common acute lymphoblastic leukemia antigen found on non-T acute lymphoblastic leukemia and follicular lymphomas. Anti-T1 which recognizes the CD5 antigen on most T-cell leukemias and lymphomas was used as a control antibody. These monoclonal antibodies were radiolabeled with 125I or 131I by the ICl method. Namalwa (B-cell) and MOLT-4 (T-cell) tumors were grown s.c. in irradiated nude mice. The highest tissue concentration of 125I-labeled anti-J5 in Namalwa-bearing mice was in blood and tumor. The tumor/blood ratio ranged from 0.7-1.2, with the highest ratio 4 days after injection. Pharmacokinetic analysis indicated that the t1/2 beta of anti-J5 from blood and other tissues ranged from 40-50 h, while the t1/2 beta for tumor averaged 65 h. The area under the curve of tumor was 2- to 5-fold higher than the area under the curve of liver, kidney, skin, and muscle. The peak tissue levels of 125I-labeled anti-B1 in Namalwa-bearing mice were again in blood and tumor and 6 days following injection more than 5-fold greater activity was found in tumor compared to normal tissues other than blood. The tumor/blood ratio was 1.2 and 0.7 at 4 and 6 days after injection. 125I-labeled anti-B1 showed minimal uptake in antigen-negative MOLT-4 tumors and 125I-labeled anti-T1 showed little uptake in Namalwa tumors. Scintigraphic images were obtained following the injection of 131I-labeled anti-J5 and anti-B1 in nude mice bearing Namalwa tumors. These results indicate that radiolabeled anti-J5 and anti-B1 show promise as diagnostic and possibly therapeutic agents for human B-cell lymphoma, although there may be a limitation to clinical utility due to cross-reactivity with some normal cells.

Animals↗