Cancer detection and prevention. Supplement : official publication of the International Society for Preventive Oncology, Inc最新文献

Immunomodulatory effect of Isoprinosine are presented in melanoma and HTLV-III/LAV infected patients. Isoprinosine (50 mg/kg) was used as a pulse immunotherapy according to two different schedules: A) 5 days every 15 days and B) 5 days every 15 days for 2 months, then 5 days every 2 months. The patients' immunological profiles were tested before and during the treatment in terms of T-cell subsets, cell number requirement for PHA-induced proliferation, and delayed hypersensitivity reaction to recall antigens. Primary malignant melanoma patients are randomized between surgery alone or associated to isotherapy (schedule A or B). Schedule A, after an initial improvement of surgery-induced immune deficiency, is responsible for an immunodepression, whereas schedule B determines a prolonged restoration in immune responses in melanoma and AIDS related complex or Kaposi sarcoma patients as well. In vitro effects of Isoprinosine on HTLV-III/LAV infection are presented. These data exhibit 1) the need of an immunological follow-up during isotherapy and 2) the immunological benefit of a pulse immunotherapy during acquired immunodeficiencies related to cancer surgery or to HTLV-III/LAV infection in man.

Applying flow cytometric analysis and a panel of monoclonal antibodies that define functional subsets and stages of lymphocyte differentiation, we found both inducer and suppressor regulating subsets of helper T cells to be depressed with concurrent increase in the functionally active effector suppressor T cells in prodromal homosexuals and patients with AIDS. Concomitantly a broad spectrum of aberrations in all stages of B cell developments were observed. Failure of isolated peripheral blood lymphocytes from these subjects to respond to formalin-fixed Staphylococcus aureus cowan 1 (SAC) indicated intrinsic defects in their resting B cells, while impairment in pokeweed mitogen (PWM)-induced blastogenesis coupled with increased levels of Ig secretion signified regulatory defects in their mature B cells, which may be related to helper-suppressor dysfunctions. Based on these findings, a multifactorial immunodysfunction in AIDS was proposed. The antiviral biological modulator drug isoprinosine was shown to enhance PWM-induced, T-cell dependent, B-cell blastogenesis and normalize the spontaneous secretion of Ig while showing no modulative effects on SAC-induced (resting B-cell) transformations. It also modified, in a selective fashion, the phenotypic coexpression of both HLA-DR and Leu8 antigen on helper and suppressor T cells. Among prodromal subjects at risk to develop AIDS, isoprinosine augmented the expression of both helper T-cell subsets while reducing the number of suppressor effector cells and activated suppressor cells. These interferences with the helper-suppressor regulatory loop may explain the therapeutic efficacy of this drug in the early stages of AIDS.

Tuftsin is the tetrapeptide Thr-Lys-Pro-Arg. It is spontaneously released from the Fc fragment of IgG by two specific enzymes. One 25-micrograms dose administered to mice in good immunologic status stimulated phagocytosis, macrophage killing of tumor cells, delayed hypersensitivity, cytolytic T-cell activity, antibody production, antibody-dependent cell-mediated cytotoxicity (ADCC), and natural killer (NK) cell activity. Administered for 6 months at the dose of 10 micrograms once a week to old, immunodepressed mice, tuftsin restored macrophage and T-cell cytotoxic activities. At this dosage, tuftsin prevented spontaneous tumor development. Tuftsin was also well tolerated in phase I studies in humans in increased polymorphonuclear leukocytes and OKT4-positive lymphocytes. Bestatin is extracted from Streptomyces olivoreticuli. One 100-micrograms dose of bestatin injected in young mice with normal immunologic status increased macrophage cytotoxicity, antibody production, ADCC, and NK cell activities. Long-term administration of bestatin (100 micrograms once a week) corrected macrophage and T-cell cytotoxicity and prevented age-related spontaneous tumors. Bestatin inhibited lymphocyte membrane aminopeptidase, which degrades tuftsin into a tripeptide that is an antagonist competing with it for receptors. Tuftsin and bestatin constitute a biopharmacologic system that can be developed as other aminopeptidase inhibitors are available for study.

Biopsy specimens of lymphoid tissues were analysed by two-colour flow cytometry to determine the proportions and phenotypes of natural killer-like cells present in the lesions. No significant difference was found between the proportions of Leu 7+ cells in reactive and malignant nodes. Low numbers of Leu 11+ cells were found in both benign and malignant nodes. The most common phenotype among the tumour-infiltrating Leu 7+ cells in the malignant nodes was Leu 7+OKT3+OKM1-. Only low numbers of Leu 7+ cells in malignant nodes coexpressed OKM1. Isolated Leu 7+ cells from four out of five malignant nodes were unable to lyse autologous B lymphoma cells in vitro. However, in one of five malignant nodes tested, autologous B lymphoma cells were lysed by isolated tumour-infiltrating Leu 7+ cells but not by Leu 7- cells. These observations indicate that tumour-infiltrating Leu 7+ cells are infrequently capable of lysing autologous lymphoma cells.

End-point results of a 4-yr followup survey and a randomized control trial of lentinan (LNT) on patients with advanced or recurrent stomach cancer have been investigated in order to evaluate the clinical efficacy of LNT in combination with chemotherapeutic agent tegafur (FT). Eligible (68) patients in control groups were administered with FT consecutively at doses of 600 mg/day, and eligible (96) patients in the treated group were administered LNT in combination with FT. LNT was injected intravenously 2 mg weekly. Remarkable lifespan prolongation effects of LNT have been observed both at the end of the control trial and at the end of the followup survey (p less than 0.01) using Kaplan-Meier's method and the generalized Wilcoxian test. Remarkable survival at 1, 2 and 3 years has been observed in the treated group using lifetable analysis. Side effects of LNT have been transitional and not serious. Thus, LNT should be effective in combination with FT for patients with stomach cancer.

Three monoclonal antibodies (MAbs), VE7, VIG3, and IXF9, that detect the 52-kd glycoprotein (gp52) of murine mammary tumor virus (MMTV) were tested for reactivity on normal human tonsillar lymphoid cells in an indirect immunofluorescence assay. Two of the MAbs, VE7 and VIG3, reacted with subpopulations of B cells, whereas the third MAb, IXF9, showed only very low-level reactivity with human lymphoid cells. VE7 and VIG3 also reacted with small populations of peripheral blood lymphocytes, and all three MAbs reacted with some transformed human cell lines. The data suggest that subpopulations of normal human lymphocytes express antigens that are cross-reactive with the MMTV gp52, although not all of the viral gp52 epitopes are expressed on the surface of these cells.

In a prospective randomized double-blind study of 60 patients with invasive cervical cancer, 32 were treated with transfer factor (TF) derived from leukocytes of the patients' husbands, and 28 were treated with placebo. Within the first 2 years after radical hysterectomy, five out of 32 TF-treated patients and 11 out of 28 placebo-treated patients developed recurrence of malignancy. Excluding one further patient with intercurrent death this difference is significant (chi 2 = 3.9915; P less than 0.05). Subdividing the collectives, significant differences were found in patients aged below 35 years and in patients with stage I disease. Identical immune profiles were checked in leukocyte donors prior to leukophoresis and were serially checked in patients. Antigen-specific correlations were found between donors' and recipients' reactivities but not between donors' reactivity and recipient's course of the disease.

This study revealed that a hybridoma cell line made from an adenocarcinoma of the colon and autologous enucleated peripheral lymphocytes shared antigenicity of the fusion partners. The hybrid cells could be grown in BALB c nu/nu mice, forming a solid tumor. Gating out hybridoma cells with both CEA and T3 antigens by means of cytofluorometer cell sorting and using them as target cells in a cytotoxicity assay against autologous and allogeneic lymphocytes, the susceptibility for cell-mediated lysis within the cultured hybridoma cells was already lost. These findings suggest that transferred membrane component(s) (T3 antigen) from enucleated lymphocytes are candidates for functional regulator(s) in cell-mediated lysis.

Quantitation by flow cytofluorometry of the distribution of human choriogonadotropin (hCG)-like material on the surface of various human and mouse tumor cells grown in tissue culture and as solid tumors has been done using fluorescein-tagged rabbit antisera (IgG fraction) to intact hCG and, in one experiment, by use of two monoclonal antibodies specific for hCG. Fibroblasts were used as a negative (nontumorigenic) cell control, and a rabbit antiserum to human hemoglobin was used as reagent control. All malignant cells tested stained more intensely with the anti-hCG serum than with the antihuman hemoglobin serum. Positive reaction with the monoclonal antibodies specific for hCG provided strong evidence that the material stained was identical to hCG. Heterogeneity of the expression of the hCG-like material was notable both within each cell line and between different cell lines. This heterogeneity was not associated with cell-cycle phase. 3T3 fibroblast-like cells in vitro were originally negative for hCG but acquired reactivity with anti-hCG serum after ten passages.

We studied the effects of preimmunization with a synthetic carboxy-terminal peptide of the beta-subunit of human choriogonadotropin (hCG) conjugated to diphtheria toxoid on the growth of two tumor models, the transplantable Lewis lung carcinoma in C57BL/6J mice and the spontaneous mammary carcinoma in C3H/OuJ mice. Immunization with the conjugate prior to Lewis lung tumor implantation significantly (P less than 0.05) retarded the growth of tumors as measured by tumor weight 18 days following transplantation. The weights of Lewis lung tumors in animals preimmunized with the hCG immunogen were inversely correlated (r = 0.61) with the levels of circulating antibodies against human chorionic gonadotropin, whereas no statistical correlation was found between tumor weights and the levels of antibodies reactive to diphtheria toxoid. The number of conjugate-treated C3H/OuJ mice that developed mammary tumors was significantly (P less than 0.05) reduced compared to their vehicle-treated cohorts. Pretreatment with the synthetic muramyl dipeptide analog utilized as an adjuvant with both immunogens did not show any effect on the tumor growth in either tumor system.