Effects on tumors

The practical importance of complex carbohydrate therapy may rest on their use as immune stimulants in humans or animals suffering from neoplastic conditions.

Glucans

Although common polysaccharides such as starch (al —» 6 glucan), and inulin (fructan) do not have antitumor activity, there is abundant evidence that some mannans and glucans are very potent anticancer agents. The factors that determine this are unclear. The soluble D-glucans have antitumor activity if they are mainly linear, without excessively long branches, and provided they are relatively resistant to degradation by glucanases. Thus glycogen, starch and dextrans are inactive while compounds with long stretches of (31 —► 3 linkages are effective. Dextrans may be made active if derivatized with diethylaminoethyl groups. Studies on synthetic, pi —» 6 linked celluloses suggest that antitumor activity against sarcoma-180 in mice is greatest in molecules with a high degree of polymerization and homogeneous distribution of side-chains.

Intravenous glucan inhibits the growth of a murine allogenic adenocarcinoma and increases tumor macrophage populations. The glucan decreases the number of hepatic metastases as well as the size of the primary tumor. Enhanced Kupffer cell antitumor activity is correlated with this increased resistance to hepatic metastases. Intravenous administration of soluble glucans also results in a significant reduction in the growth of syngeneic murine mammary carcinoma and melanoma B16. Glucan from Saccharo-myces cerevisiae has been reported to reduce the size of malignant melanomas and adenocarcinomas in patients with advanced neoplastic disease when administered in and around selected lesions. This reduction in size is associated with necrosis, abscessation and liquefaction of the tumor and a monocytic infiltrate. Water-soluble glucan administered in combination with lymphokine-activated killer (LAK) cells to mice, significantly suppresses the growth and metastasis of a reticulum cell sarcoma. This therapy increased splenic natural killer (NK) cell activity as well as Kupffer cell tumoricidal activity.

Other investigators have failed to substantiate the antitumor activity of glucans in syngeneic systems. Thus when Saccharomyces glucan was tested in a guinea pig hepatoma, two murine fibrosarcomas, a murine melanoma and a murine adenocarcinoma and compared with BCG vaccine, no effect was noted. Intralesional, intraperitoneal or intravenous administration of glucan was also found to be inef fective in the murine system. The glucan had no significant effect on tumor size, tumor incidence or host survival. It was concluded that the effects of glucan, although impressive in allogeneic systems (such as the sarcoma-180 system), are much less effective in syngeneic tumor systems.

Saccharomyces glucan probably exerts its antitumor effects by activating macrophages. Its activity appears not to be T cell mediated since administration of glucan severely inhibits the growth of melanoma B16 cells in nude mice. This antitumor activity in nude mice was associated with enhanced macrophage phagocytosis. The glucan probably stimulates macrophages to produce cytokines such as interleukin 1 and tumor necrosis factors. Thus macrophages from glucan-treated animals have been shown to release factors cytotoxic for tumor cells. Glucan also increases serum lysozyme levels, suggesting increased macrophage function and stimulated in vivo and in vitro secretion of interleukin 1 (IL-1). IL-2 production by splenic lymphocytes is enhanced 6 h after glucan administration and remains elevated for 9 days, presumably in response to the IL-1. Peak plasma IL-1 and IL-2 activities are found 9 and 12 days, respectively, following glucan administration. Given the very short half-life of these interleukins, this sustained elevation of IL-1 and IL-2 suggests that there is a very high rate of production.

Lentinans

Lentinan is a glucan derived from Lentinus edodes, a common edible mushroom. It has been shown to be active against several different allogeneic and syngeneic tumors. Lentinan, like other glucans has no direct cytotoxicity on tumor cells. Nevertheless it shows an optimal dose for antitumor action. The antitumor activity of lentinan varies between mouse strains which may be classified as either high or low responders. In strong responder mice, lentinan will completely regress 3-methylcholanthrene-induced transplantable fibrosarcomas. Lentinan is very effective against mouse methylcholanthrene-induced primary tumors in combination with cyclophosphamide. When administered to cancer patients in phase I and II trials, encouraging results have been obtained.

The antitumor activity of lentinan, unlike that of glucan, does not occur in neonatally thymectomized mice or in mice treated with anti lymphocytic serum or by whole-body irradiation. It does not increase phagocytosis but it can stimulate macrophage cytotoxic activity in vivo. As a result, the antitumor effect of lentinan may be blocked by antimacrophage agents such as carrageenan or silica. Lentinan does not accelerate antibody formation, nor does it cause an increase in blood lymphocytes, accelerate allograft rejection or influence delayed-hypersensitivity reactions.

Mannans

Mannans with significant antitumor activity have been isolated from several species of yeast. They have been tested for activity against sarcoma-180 in Swiss albino mice. There appears to be no relationship between the amount of glucose in these mannans and their activity. The mannan from C. utilis that contains an a-linked glucose is poorly inhibitory while the mannan from C. albicans that contains a (3-glu-can component is highly active. Mannans from S. cerevisiae and from Candida utilis inhibit the growth, not only of sarcoma-180 but also of 3-methylcholanthrene-induced tumors, Ehrlich carcinoma and NF sarcoma. None of these mannans appear to be active against the ascites form of sarcoma-180.

When mannoglucan prepared from Magnaporthe grisea is administered intravenously to C3H mice bearing the solid MH134 hepatoma, the blood flow to the tumor is inhibited within 6 h and tumor growth retarded within 3 days. If the tumor mass is excised and extracted at various intervals after administration of mannan, a soluble cytotoxic factor is detectable in the tumor homogenate. This factor is probably a form of tumor necrosis factor (TNF) since its activity is inhibited by anti-TNF serum, it has the same molecular weight range as TNF (70-80 kDa) and the dose dependencies of the cytotoxin and TNF are similar.

Acemannan (polyacetylated mannan) obtained from Aloe vera stimulated a tenfold release of 51Cr from labeled tumor cells in the presence of macrophages. When injected intraperitoneally into female CFW mice subcutaneously implanted with murine sarcoma cells, acemannan reduces mortality from 100% of the control animals to 60-65% mortality in treated animals. Acemannan-treated animals exhibit characteristics of in vivo tumor necrosis, including development of concave liquefied areas on the tumor mass, and show visible evidence of necrotic toxemia. Necrotic tumors are found to exhibit central necrosing foci with hemorrhage and peripheral fibrosis. Similar effects have been observed in cats and dogs with spontaneous fibrosarcomas treated with acemannan.

Levans

The antitumor activity of levans, unlike that of the other polysaccharides described above, is a result of its ability to stimulate not only macrophages, but also B cells and T cells. For example, levan is a B

cell mitogen and can therefore stimulate a polyclonal B cell response. Inhibition of growth of Lewis lung carcinoma (3LL) by levan in mice is probably due primarily to macrophage activation. The site and timing of treatment with high molecular weight levan (2 x 104 kDa) significantly affects its activity against transplanted AKR lymphoma. Thus tumor growth is best inhibited by inoculation of levan directly into the primary tumor soon after tumor inoculation. It is ineffective if administered more than 2 days later. However, metastases are most effectively inhibited by intraperitoneal inoculation, suggesting that macrophage activation may be required for antitumor activity.

Pectin

Pectin, a galactose-rich carbohydate abundant in citrus, is also known to have an antitumor effect. Inhibition by pectin of the metastasis of prostate cancer cells has been shown in a rat model. It has been suggested that pectin blocks galectin-3, a galactose-specific lectin, on cancer cells so that they cannot interact with the cellular matrix and therefore cannot emigrate.

In conclusion, it is clear that many complex carbohydrates have immunostimulating activity which may be of use for the treatment of malignancies. However, all complex carbohydrates clearly do not have the same mode of action, but act on different components of the immune system. Further studies are clearly required to determine the optimal conditions for their use in humans and animals. Recent developments in understanding carbohydrate-lectin interactions in the mammalian system will certainly add to these efforts.

See also: Carbohydrate antigens; Immunopotenti-ation; Tumors, immune response to.

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