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

The macaque immunodeficiency syndrome has many parallels to AIDS in humans. Affected monkeys develop profound, prolonged T lymphocyte dysfunction and die of lymphomas or opportunistic infections. We recently isolated a virus that we call SIV from four sick macaque monkeys. The morphology, growth characteristics, and antigenic properties of this virus indicate that it is related to the causative agent of human AIDS. The pathogenicity of this newly isolated virus was tested in macaque monkeys. Five of six died between 127 and 352 days following inoculation. The animals developed a wasting syndrome and died with adenovirus pancreatitis and/or pneumonia and primary retroviral encephalitis. Immunological abnormalities in these animals included a decrease in circulating T4+ lymphocytes and depressed peripheral blood lymphocyte proliferative response to pokeweed mitogen. The SIV monkey model holds great promise for testing antiviral agents and for the development of vaccines against AIDS.

In addition to the well known T-cell dysfunctions in AIDS, hypergammaglobulinaemia and autoimmune phenomena indicate an involvement of the B cell as well. Reports of HTLV-III/LAV-infected B cells suggest T-cell-independent B-cell abnormalities. To look for early B-cell dysfunctions, we examined a high-risk group of AIDS consisting of six homosexuals with PGL and HTLV-III/LAV antibodies, comparing these data to those of patients with AIDS/ARC and a normal control. In vitro studies included the B-cell proliferation response (3H-thymidine uptake) to Staphylococcus aureus Cowan I and the differentiation response (Ig secretion into culture supernatants) to T-cell-dependent/-independent polyclonal B-cell activators (PBAs). Profound alterations were found in both the proliferation and the differentiation responses. The weak response even to T-cell-independent PBAs indicates a B-cell dysfunction that is not due only to a T-cell defect in patients with PGL, similar to that observed in AIDS.

We studied the effects of exogenous T cell growth factor (TCGF) (= interleukin-2) and indomethacine on the lymphocyte transformation response in vitro to allogeneic cells, mitogens, and antigens in AIDS patients, those with AIDS-related complex (ARC), and in healthy controls. While low amounts of TCGF reduced the response of peripheral blood mononuclear cells (PBMC) to allogeneic cells in both healthy controls and AIDS patients, large amounts of TCGF augmented the response in both groups, although the response of the patients' cells were still subnormal. By depleting the PBMC for either CD4-positive or CD8-positive cells, the effect of TCGF on suboptimally mitogen-stimulated PBMC from controls was shown to be due to an increased response in both the CD4-positive and the CD8-positive cells. In contrast, with patient cells, TCGF only increased the response of the CD4-positive cells, while that of the CD8-positive cells was largely unchanged. Thus, the lack of normalization of the mitogen response of patient cells upon addition of TCGF may be largely due to unresponsiveness of CD8-positive cells to TCGF. This observation further supports the idea that CD8-positive cells are abnormal. To investigate the role of the inhibitor of TCGF production, PGE2, in AIDS, indomethacine was added to cultures of mitogen-stimulated PBMC from controls and patients. No differences were found between the three groups: the responses to PHA were slightly increased and those to Con A were unchanged.

Immunodepression associated with a variety of situations such as cancer or any of its major modalities of treatment (surgery, irradiation, or chemotherapy) has been effectively alleviated with Imunovir (inosine pranobex-BAN), and this has been associated with demonstrable clinical benefit to these patients. One hundred and six immunodepressed patients with solid tumors undergoing radiotherapy were treated with either Imunovir or placebo; 64% of Imunovir-treated patients were immunorestored after 3 months compared to 23% in the placebo group. Imunovir was also effectively used in 75 patients with malignant hematological disorders both as an immunorestorative agent given prophylactically to prevent infection and as a therapeutic agent to treat infections in these immunodepressed patients. In different studies involving surgical patients treated with either Imunovir or placebo, 70-81% of hypoergic or anergic patients in the Imunovir group became normoergic by day 14 of treatment compared to 5-17% of the placebo group, and this enhanced immunorestoration was associated with lower incidence of local sepsis (P less than 0.05), systemic sepsis (P less than 0.025), and postoperative mortality (P less than 0.05).

Common acute lymphoblastic leukemia (ALL) antigen (CALLA)-like proteins were detected by in vivo labeling experiments carried out with human lymphoblastoid cell line KM3 and also in cell-free translation, directed by CALLA-specific mRNA prepared from immunoadsorbed KM3 polysomes. The CALLA-like structure found in both systems shows an Mr of 95kDa. Additional CALLA-like proteins could be identified in the in vivo experiments with calculated Mrs of 40kDa in the cells and 85 and 38kDa in the culture medium. In the cell-free translation system, an additional product of Mr 80kDa could be detected.

The results today of passive immunotherapy with monoclonal antibodies (MAb) are still very limited, even via its indirect methods (in vitro tumor cell clearance of bone marrow before autologous retransplantation, transport of cytostatic chemicals, and radiation). Tumor cell heterogeneity requires the use of several MAb. Adoptive immunotherapy in the form of the graft vs leukemia (GVL) reaction associated with the graft vs host (GVH) reaction, after an allogeneic bone marrow transplantation, first demonstrated in animals in 1962, has been confirmed in man. The material and operational development of tumor immunology, immunopharmacology, and clinical trial methodology should improve active immunotherapy results and help to convert into a cure what is often a significant but only marginal increase: 1) of disease-free survival or 2) of survival or 3) of survival after relapse. The general ineffective management and use of adjuvant chemotherapy for all tumors except breast carcinoma before menopause will, on the other hand, contribute to necessary new concepts of how to manage the postremission, residual, minimal disease.

Lymph nodes from eight LAS and six AIDS patients were studied by routine histology, immunohistochemistry, and ultraimmunohistochemistry. LAS lymph nodes show a peculiar follicular hyperplasia with a characteristic increase of proliferating dendritic and interdigitating reticulum cells. In AIDS, these cells are reduced and the expression of proliferation-associated antigens is diminished. The immunohistochemical analysis of dendritic and interdigitating reticulum cells and of proliferation-associated antigens in lymph nodes thus allows a clear distinction between LAS and AIDS and may have important prognostic implications.

Experimental studies of the survival curves of different species and of in vitro cell culture survival point to normal aging as a largely preprogrammed process. Reciprocal skin grafting among syngeneic young and old animals further demonstrates autonomous aging of this organ independent of the remainder of the body. This compartmentalization of change with age is also suggested when immune functions of various lymphoid organs are compared at different ages. Experimental studies also show that for some organs their susceptibility to certain carcinogens is diphasic, high early in life and high in senescence. A major question now is if preprogrammed age changes at the molecular level have steps in common with carcinogenetic processes.

It was previously reported that red ginseng extract inhibited carcinogenesis by urethan, DMBA, and aflatoxin B1 [Yun et al: Cancer Detect Prevent 1983; 6:515-25]. In an attempt to investigate the mechanism of the anticarcinogenic effect of ginseng, the natural killer (NK) activity and the incidence of lung adenoma were followed over a period of 48 weeks postinjection with urethan or benzo(a)pyrene. The NK activity was markedly depressed from 4 weeks to 24 weeks after injection of carcinogens. This decreased NK activity was returned to the level of controls by administration of ginseng. At the same time, a lower incidence of lung adenoma was noted following administration of ginseng to urethan-injected mice. However, the lung adenoma induced by benzo(a)pyrene began to occur at 48 weeks in which NK activity had naturally declined to a level too low to be affected by ginseng, and administration of ginseng did not decrease the incidence. In conclusion, these results suggest that the anticarcinogenic effect of ginseng may be related to the augmentation of NK activity.

Alkyllysophospholipids are analogs of the cell membrane component lysophosphocholine. The thioether lysophospholipid BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is already in use in phase I and II trials in human cancer therapy. A direct antitumor effect of this new compound has been shown in vitro using 35 different cell types of murine and human origin. All normal cells investigated were not affected in the concentration range (1-10 micrograms/ml) that was cytotoxic for most tumor cells studied. In vivo, antimalignant and antimetastatic actions have been documented in the Meth A sarcoma, L1210 leukemia, B 16 melanoma and the 3Lewis-lung carcinoma tumor models, respectively. Murine, bone marrow-derived macrophages (M phi), preincubated with BM 41.440, showed an increased cytotoxicity in vitro. Addition of syngeneic spleen cells and low doses of BM 41.440 to this system enhanced tumor cell destruction 20- to 100-fold compared to controls dependent on the target cells used (YAC, ABLS-8.1, L1210, and P815). In vivo, Meth A sarcoma growth was dose and time dependently reduced in CB6F1 mice under therapeutic IV application of BM 41.440-activated M phi. The mean survival time of DBA mice, treated once IP with BM 41.440 4 days before L1210 challenge, increased from 24 to 38 days.