Goro Chihara

T-cell mediated vascular dilatation and hemorrhage induced by antitumour polysaccharides

Antitumour polysaccharide lentinan, capable of potentiating T-cell dependent reactions and some other antitumour polysaccharides such as pachymaran, carboxymethyl-pachymaran and zymosan were found to induce vascular dilatation and hemorrhage(VDH) in CD-1 normal mice starting the following day after a single injection. Polysaccharides which do not have the tumour-regressing activity, several immunopotentiators such as BCG, lipopolysaccharide, dextran sulfate and concanavalin A, and chemical mediators of inflammation such as histamine, serotonin and prostaglandin E1 did not induce VDH in mice. This response seems to be mediated by T-cells and macrophages, because VDH was not observed in CD-1 nu/nu mice treated with lentinan, and carrageenan, an antimacrophage drug, inhibited the appearance of VDH by lentinan. Furthermore, carrageenan inhibited the production of the VDH-inducing serum which was caused by lentinan, capable of passively transferring VDH to another mouse.

Macrophage-mediated acute-phase transport protein production induced by lentinan

A new bioactive factor capable of stimulating the production of acute-phase transport proteins, haptoglobin, hemopexin and ceruloplasmin, was found in mouse serum soon after the administration of lentinan, an immunomodulatory polysaccharide. This factor (APPIF) was produced by macrophages, and may regulate the production of acute-phase transport proteins in hepatocytes. The mice given the serum obtained from donor mice 2-6 h after an injection of 10 mg/kg of lentinan showed a marked increase of the acute-phase transport proteins in their serum 4 days after the serum injection. Pretreatment with the antimacrophage agents, carrageenan and mouse Ia antiserum, before the lentinan treatment to donor mice inhibited the production of acute-phase transport proteins in the recipient mice. Thymus or T-cells had no role in the production of APPIF. As the activity of APPIF disappeared after pronase treatment of the serum, APPIF seems to be a peptide compound. Appearance of APPIF is considered to be one of the earliest manifestations of the mode of action of lentinan in addition to its augmented production of vascular dilatation and hemorrhage inducing factor and interleukin-1. The correlation between these inflammatory and immune responses in earlier stages of the host defence mechanisms is also discussed.

Lentinan and other antitumoral polysaccharides

Despite a great deal of effort made by many researchers throughout the world, chemotherapeutic agents that attack cancer cells directly do not seem to have the expected effects except on some leukaemias. Besides, these agents show strong toxicity to the host, and reduce the host defense against infections, especially destroying lymphocytes and bone marrow cells. To find a new cancer drug that can activate or restore host defense mechanisms, we examined fungi, which had traditionally been said to be effective against cancer in Japan and other Asian countries, such as Ganoderma applanatum (Pers.) Pat. and Coriolus versicolor (Fr.) Quel., and several kinds of Japanese edible mushrooms. Test substances were administered intraperitoneally and screened for their ability to inhibit the growth of sarcoma 180 cells subcutaneously transplanted into swiss or ICR mice. This method, reported by Nakahara et al. [1], has been proven to be simple and suitable for screening of host-mediated anticancer drugs. Table 1 shows various antitumoral polysaccharides including lentinan that were isolated from fungi, basidiomysetes and yeast. Lentinan, a (1→3)-β-D-glucan with (1→6)-β-D-glucopyranoside branches isolated from an edible mushroom, Lentinus edodes (Berk.) Sing., exhibits a marked antitumor effect against sarcoma 180 cells transplanted subcutaneously at a dose of 1 mg/kg/day for ten days (Fig. 1) [2–4]. Its chemical and physical characteristics are listed in Table 2.

Effect of lentinan on the chemiluminescence produced by human neutrophils and the murine macrophage cell line C4Mφ

Lentinan, an immunopotentiating polysaccharide, stimulates the production of chemiluminescence (CL) by human neutrophils and the murine macrophage cell line C4M phi. The CL enhancing effect of lentinan opsonized in human serum is greater than that of lentinan itself. Lentinans stimulation of neutrophil CL was increased by 1/2 when opsonized in human serum inactivated at 56 degrees C to remove complement, while the CL was increased two fold by lentinan opsonized in whole serum. This indicates that C3b and immunoglobulin contribute separate signals in the activation process mediated by opsonized lentinan. The distinct roles of the C3b and Fc receptors was further illuminated by the finding that an Fc receptor-negative cell line was unresponsive to lentinan opsonized in heat inactivated serum (56 degrees C), whereas it exhibited a five fold increase in CL in response to lentinan opsonized in serum containing complement. Lentinan in an opsonized form can stimulate the production of CL via C3b and Fc receptors. This mechanism may be considered as one mode of action of lentinan and other similar immunopotentiating and antitumour glucan-type polysaccharides.

Lentinan: Rationale for Development and Therapeutic Potential

........ . 1. Biological Activities of Lentinan 1.1 Antitumour Activities . . . . 1.2 Antimetastatic Activities . . 2. Mode of Action of Lentinan in Tumour Destruction 2.1 Vascular Activities of Lentinan .. . 2.2 Immunological Activities of Lentinan ... 2.3 Effects of Lentinan on Tumour Progression. 3. Clinical Studies with Lentinan .... . .. . 3.1 Effects on Survival . . . . ..... . 3.2 Mechanisms of Clinical Effects of Lentinan 3.3 Quality of Life 4. Conclusions ....... .. ... . 121 122 122 123 124 124 124 127 130 130 130 131 131

Effect of lentinan on pinocytosis in mouse peritoneal macrophages and the murine macrophage cell line C4MØ in vitro

Lentinan, an immunopotentiating polysaccharide, stimulated the pinocytosis of horseradish peroxidase (HRP) or FITC-dextran by resident or thioglycollate-elicited mouse macrophages from 10 to 50% in a dose dependent manner. Pinocytosis of HRP and FITC-dextran by C4M phi cells, a murine macrophage cell line, exhibiting a lower basic pinocytic activity than peritoneal cells, was augmented up to 310 and 120%, respectively, by lentinan. Mannan inhibited the HRP uptake by peritoneal macrophages via specific mannose receptors. This inhibitory effect was partly abolished, when lentinan was also added to the cells. Mannan was not able to inhibit pinocytosis of HRP by C4M phi macrophages, indicating little or no mannose receptor activity on these cells. Pinocytosis of FITC-dextran was not affected by mannan. Lentinan, opsonized in mouse sera inhibited the uptake of HRP by peritoneal macrophages by 30-35%. Opsonized lentinan and mannan added together caused 60% inhibition of HRP uptake in peritoneal macrophages indicating a possible functional relationship between the mannose and C3b receptors. The results demonstrate that lentinan activates the pinocytic function of macrophages predominantly via specific beta-glucan receptors. These mechanisms may contribute to the antitumor and immunopotentiating action of lentinan and other glucan-type polysaccharides.

Immunopotentiation by the Antitumor Polysaccharide Lentinan

Despite the enormous efforts of researchers around the world, promising cancer chemotherapeutics do not as yet exist, excluding some agents acting against certain cancer types with special characteristics and against certain leukemias. Chemotherapeutic agents possessing direct cytocidal activities on target cancer cells intend to kill the total mass of cancer, but they clearly also have accompanying detrimental toxic side effects on various lymphoid cells and bone marrow cells which have recently been considered to have relevant roles in host defense-surveillance mechanisms against cancer and they, therefore, limit the effectiveness of immunotherapy.

A Possibility of Synergism between Corynebacterium parvum and Lentinan, Serotonin, or Thyroid Hormone in Potentiation of Host Resistance against Cancer

There is some reliable evidence that shows the presence of a resistance to cancer intrinsic in a human body, such as the correlation between senility and cancer incidence, the low metastatic rate against the number of tumor cells in blood flow, and the spontaneous cure of cancer observed in some cases. To clarify the mechanism of this resistance and to find a substance that would increase this resistance seems to be one of the important means in opening a way for new therapy in the treatment of cancer.

Medical and Biochemical Application of Infrared Absorption Spectra. III. Studies on Biological Lipids by Infrared Spectra. (1). Infrared Spectra of Total Lipids in Diabetes Serum

1) About 700 infrared spectra were examined of total lipids in the sera of diabetes patients, and a new and simple classification of these spectra was devised from the ratio of relative intensities of their absorptions. 2) It was found that there is a close relationship between the quantity of total lipids and their spectral types, and between the spectral types and serum lipoprotein index values. 3) It was found that diabetes is classified into several types from the type of these spectra and that infrared spectra would be valuable means in diagnosis and in judging therapeutic effect of pharmaceutics.