Anticancer Antitumor Effects

Lentinan isolated by Chihara and co-workers (7,20,26) resulted in complete regression of tumor induced from sarcoma 180 ascites cells implanted in Swiss albino mice with no cytotoxicity when given intraperitoneally. Lentinan was effective in limiting the tumor size, regardless of whether it was in an allogenic tumor-host system, syngenic tumor-host system, or autochthonous host system (31,32,36,37).

Other studies showed tumor regression in C3H/He mice when MM46 mammary carcinoma cells were subcutaneously inoculated (38). Complete regression of large Madison 109 lung carcinoma in syngeneic BALB/c mice was achieved. Evaluation of the effects of lentinan against Lewis Lung (LL) and Madison 109 (M109) lung carcinomas that were implanted in the footpads of syngeneic mice was carried out by Rose and co-workers (39). Intraperitoneal administration of lentinan was curative to mice bearing M109 lung carcinomas (50-70%) though it had no substantial effect on LL

carcinomas. This contradicted the findings of Suzuki et al. (40). Their study showed inhibition of pulmonary metastasis of LL carcinoma, also in mice.

Lentinan would also be effective for patients with advanced or recurrent breast cancer (41,42). Side effects have been transitional and not serious. Use of lentinan in a combined treatment of patients with advanced or recurrent gastric or colorectal cancer has also resulted in an increased life span (26,43). In addition, lentinan was able to prevent chemical oncogenesis as shown by its suppressive effect on 3-methylcholanthrene-induced carcinogenesis (36).

For all the above studies cited so far, lentinan was administered via injections. Studies (44-48) were carried out using oral administration of powdered, dried mushroom fruiting bodies. Oral administration may be important for eliminating the side effects of (1^3)-p-d-glucans, including the pain that accompanies parenteral administration. The tumor-growth-inhibitory activity increased with the concentration of the shiitake mushroom powder. When 10% L-feed (feed containing powdered shiitake fruit bodies) was used, the rate of tumor inhibition was 39.6%. Inhibition rates of 53.2% and 58.9% were achieved when 20% L-feed and 30% L-feed, respectively, were used. The degree of inhibition was proportional to the experimental diet. Administration schedule of the lentinan also influenced the rate of tumor inhibition.

In the most recent study on oral administration of lentinan conducted by Yap and Ng (22,49), male ARK mice (5-6 weeks old) were used. K36 cells (a murine lymphoma cell line) were used to induce the tumors. The mice were divided into three cohorts, namely, prefeeding for 7 days prior to inoculation of K36 cells, simultaneous feeding of the lentinan with inoculation of K36 cells, and postfeeding after 7 days of tumor induction with K36 cells. Three milligrams of lentinan were resuspended in buffer and force-fed to the mice daily.

Table 1 summarizes the data collected. It was clearly shown that lentinan feeding was very effective in preventing tumor development (between 83 and 94%). Prefeeding was the most effective regime when compared with simultaneous and postfeeding. The percentage of 83% from the postfeeding cohort indicated the regression rate of the developed tumors.

Crude mushroom homogenates also resulted in some degree of antitumor efficacy but at a much lower percentage (43-55%) The buffer-fed mice were controls (placebo). The mice with tumors are shown in Figure 1. Comparison of the sizes of the excised tumors is clearly shown.

In addition to the strong antitumor properties, the lentinan appeared to interfere with the morphogenesis of the murine lymphoma retrovirus (Fig. 2). The virus from the tumor cells of the control groups was electron-dense. However, in the lentinan-fed cohort, the virus particles from the tumor cells were empty. This indicated that the virus particles lacked the genomes and,

TABLE 1 Antitumor Properties of Lentinan

Average weight Tumor inhibition

TABLE 1 Antitumor Properties of Lentinan

Average weight Tumor inhibition

Pure lentinan

0.124 (prefeed)

94.44 (p

<

0.001)

0.265 (S/F)

88.59 (p

<

0.001)

0.398 (postfeed)

83.14 (p

<

0.001)

Crude mushroom

0.997 (prefeed)

55.20 (p

<

0.001)

homogenate

1.272 (S/F)

45.32 (p

<

0.001)

1.345 (postfeed)

43.06 (p

<

0.001)

Buffer solution

2.230 (prefeed)

0

2.386 (S/F)

0

2.362 (postfeed)

0

thus, were defective. This could be the reason that the induced tumors (if they occurred) were very small (Table 1) and well localized, unlike the control mice.

Past studies have shown that the efficacy of lentinan in the treatment of cancer is increased when used in conjunction with other therapies. The highest antitumor effect was achieved when bacterial lipopolysaccharide was used with lentinan (50,51). Lentinan could be used in combination with IL-2 for treating cancer (52-56). The combined administration of IL-2 and lentinan was effective against IL-2-resistant established murine tumors. Hamuro and co-workers (57) also investigated the antimetastatic effects of combined treatment with lentinan and IL-2 in spontaneous metastatic systems using murine fibrosarcoma and also showed the fruitful effects.

Marked antitumor effects were achieved when lentinan was used in conjunction with chemotherapy. The activity of pyrimidine nucleoside phos-phorylase (an enzyme that converts 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil) was induced by lentinan in tumors, but not in the spleen, thereby increasing the susceptibility of tumor cells to 5'-DFUR (58). Considerable improvement was seen in gastric and breast cancers when lentinan was used in combination with chemotherapy (59,60). Lentinan also enhanced the sensitivity of mouse colon 26 tumor to c's-diamminedichloro platinum

(61). An in vivo study in rats with peritonitis involving the combination of lentinan with gentamicin showed a significantly better survival rate than controls (13). The tumor-regressive effect of lentinan was markedly reduced by X-irradiation of mice. 6-Benzyl thioguanosine reduced the antitumor activity of lentinan when it was injected after sarcoma 180 implantation

(62). Such immunosuppressive agents should be avoided when lentinan is used to treat cancer patients.

Figure 1 Comparison of tumor sizes between lentinan-, crude-mushroom-homogenate-, and buffer-fed mice. K36 cells (a murine lymphoma cell line) were used to induce the tumors. It is clearly demonstrated that the tumor excised from the buffer-fed mouse is several times larger than that from mouse fed with lentinan. Crude mushroom homogenate also offers some antitumor properties as the tumor size is smaller than that of the buffer-fed cohort. This observation is statistically significant as presented in Table 1.

Figure 1 Comparison of tumor sizes between lentinan-, crude-mushroom-homogenate-, and buffer-fed mice. K36 cells (a murine lymphoma cell line) were used to induce the tumors. It is clearly demonstrated that the tumor excised from the buffer-fed mouse is several times larger than that from mouse fed with lentinan. Crude mushroom homogenate also offers some antitumor properties as the tumor size is smaller than that of the buffer-fed cohort. This observation is statistically significant as presented in Table 1.

The immunopotentiating ability of lentinan was postulated to play a key role in the antitumor process. Administration of lentinan to gastric cancer patients undergoing chemotherapy inhibited suppressor T-cell activity and increased the ratio of activated T cells and cytotoxic T cells in the spleen (63,64). Lentinan also increases peritoneal macrophage cytotoxicity against metastatic tumor cells in mice (65). Antimacrophage agents such as carra-geenan also inhibited the effect of lentinan (26,66-68). The antitumor effect of lentinan is abolished by neonatal thymectomy and decreased by the administration of antilymphocyte serum, supporting the concept that lentinan requires immunocompetent T-cell compartments.

Figure 2 Electron micrograph of murine retrovirus particles budding from tumor cells. (a) In the buffer-fed regime, electron-dense infectious virus particles (Vi) are seen budding out from the plasma membrane. (b) In contrast, the virus particles budding out from the lentinan-fed cohort exhibit empty core structures. This indicates that the virus particles are defective (dVi) and lack the virus genomes.

Figure 2 Electron micrograph of murine retrovirus particles budding from tumor cells. (a) In the buffer-fed regime, electron-dense infectious virus particles (Vi) are seen budding out from the plasma membrane. (b) In contrast, the virus particles budding out from the lentinan-fed cohort exhibit empty core structures. This indicates that the virus particles are defective (dVi) and lack the virus genomes.

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