Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium.

The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.

The synthetic peptide related to the central part of human interleukin-2 molecule accelerates growth and vascularization of sarcoma 180 in mice.

The synthetic peptide C-1-6 related to the central part of human interleukin 2 molecule (sequence 59-72; N- and C-modified) had been shown previously to inhibit cytotoxic activity of macrophages converting them to synthesis of growth factors. In this paper the effect of C-1-6 on growth of sarcoma 180 in mice was studied. C-1-6 significantly accelerated tumor growth having been injected into mice in dose 5 or 50 microg per animal since the 4th day after tumor cells transplantation. Supernatants of Mphi in vitro activated by C-1-6 (10 microg/ml) and injected into mice also accelerated significantly sarcoma mass diurnal increasing as compared to mice treated with supernatants of non-activated Mphi or activated with bacterial lipopolysaccharide. A single injection of C-1-6 into mice either at the day or at the next day of tumor cells inoculation increased significantly the number of vessels growing up to transplant, thus the forming of the vascular bed had preceded tumor volume enlargement.

D11, a novel monoclonal antibody specific for human mature macrophages and peripheral blood monocytes.

A new monoclonal antibody designated Mab D11 is described, which shows a restricted reactivity to cells of the monocyte/macrophage system. When tested by light and electron microscopic immunoperoxidase methods, Mab D11 specifically reacts with blood monocytes and stains resident macrophages in a wide variety of human tissues; it does not mark the macrophages of other species, i.e., rat, swine and mouse. Antigen-presenting cells, e.g., Langerhans cells, are Mab D11 negative. Mab D11 reveals the antigen on cryostat and paraffin tissue sections. Ultrastructurally the antigen recognized by Mab D11 in all macrophage types studied is located on the plasma membrane and within cytoplasmic structures including lysosomes. On immunoblotting, Mab D11 detects the 125-kDa antigen in human liver and the 135-kDa protein in tumours of histiocytic origin. The similarity of Mab D11 to known "pan-macrophage" monoclonal antibodies is discussed.

Growth-stimulating phase of macrophage response to activation: the phenomenon and its implications for tumour growth and immunotherapy.

The dynamics of growth-stimulating and cytotoxic activity of mouse peritoneal macrophages (PMo) in response to in vivo and in vitro bacillus Calmette-Guérin (BCG) or bestatin treatment was studied. It was shown that BCG and bestatin induce cytotoxicity in PMo, and that after the cytotoxic response strong growth-stimulating activity develops. PMo, rendered cytotoxic in vivo and afterwards cultivated in vitro, displayed the same switch from a cytotoxic to a growth-stimulating phase. These results suggest that the growth-stimulating phase is the obligatory PMo response to biological response modifiers (BRM) at least to BCG and bestatin. The growth rate of tumours, transplanted into mice during the cytotoxic phase of the response to BCG, was suppressed, whereas tumours transplanted during the growth-stimulating phase were stimulated. It appears that the development of a growth-stimulating phase after the cytotoxic phase of response to activation by BRM could be one of the reasons for the limited effectiveness of immunotherapy based on the application of macrophage activators.

Modulation of growth-stimulating and antitumor activity of macrophages by BCG and cyclophosphamide.

Recently it has been shown that some tumours require macrophage-derived growth factors for in vitro and in vivo proliferation, as well as tumour growth stimulation by macrophages. Furthermore, it has been reported that several biological response modifiers (BRM) stimulated some growth factor production in macrophages. In the present study we tried to define whether some BRM can modulate production of macrophage-derived growth factors for stimulating tumour cells. Results obtained indicate that: 1) growth stimulating activity of macrophages may be co-expressed with antitumor activity; 2) growth stimulating activity could prevail over antitumor effects in the outcome of tumour cell/macrophage interaction in vitro; 3) Some BRM and antitumor drugs can modulate the balance between antitumor and growth stimulating activity of macrophages. It is therefore proposed that growth factors modulation assessment is necessary for new BRM characterization.