Investigation on the efficiency of lentinan for injection combining cisplatin on treating malignant pleural effusion based on systematic review and meta-analysis.

BACKGROUND: Malignant pleural effusion (MPE) is a frequently observed complication in advanced malignant tumors. Clinical studies have shown that lentinan for injection (LNT) is beneficial for improving patients' quality of life and prolonging their survival. The purpose of this meta-analysis is to evaluate the efficacy and safety of LNT combining cisplatin in the treatment of MPE. METHODS: Randomized controlled trials (RCTs) of LNT combining cisplatin in the treatment of MPE were searched in 6 literature databases from the establishment time of each database by 2 researchers. According to the inclusion criteria, 2 researchers independently screened studies, assessed the risk of bias and conducted subgroup analyses for different outcome indicators according to the specific characteristics of the included literature. Analyzing the data by Revman software, and evaluating the stability of the results by Stata software. RESULTS: A total of 52 RCTs were included. The results showed that combined use of LNT and cisplatin could improve the treatment effect, and the difference between groups was statistically significant (RR = 1.40, 95%CI: 1.33 ~ 1.46, P < .001). And the combined use of LNT could increase the quality of life (RR = 1.45, 95%CI: 1.35 ~ 1.56, P < .001). The using of LNT could significantly decrease the incidence of gastrointestinal reactions (RR = 0.86, 95%CI: 0.78 ~ 0.94, P < .001). Sensitivity analysis results showed that there were no qualitative changes in the indicator, and suggested the possibility of publication bias. CONCLUSIONS: Available evidence suggested the combined use of LNT and cisplatin showed better efficacy in treating MPE without increasing ADR incidence than using cisplatin alone. LNT is an ideal treatment for MPE, which has high clinical application value.

Lentinan confers protection against type 1 diabetes by inducing regulatory T cell in spontaneous non-obese diabetic mice.

BACKGROUND: Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes. OBJECTIVE: In the current study, we investigated whether an intraperitoneal injection of LNT can diminish the risk of developing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice and further examined possible mechanisms of LNT's effects. METHODS: Pre-diabetic female NOD mice 8 weeks of age, NOD mice with 140-160 mg/dL, 200-230 mg/dL or 350-450 mg/dL blood glucose levels were randomly divided into two groups and intraperitoneally injected with 5 mg/kg LNT or PBS every other day. Then, blood sugar levels, pancreas slices, spleen, PnLN and pancreas cells from treatment mice were examined. RESULTS: Our results demonstrated that low-dosage injections (5 mg/kg) of LNT significantly suppressed immunopathology in mice with autoimmune diabetes but increased the Foxp3+ regulatory T cells (Treg cells) proportion in mice. LNT treatment induced the production of Tregs in the spleen and PnLN cells of NOD mice in vitro. Furthermore, the adoptive transfer of Treg cells extracted from LNT-treated NOD mice confirmed that LNT induced Treg function in vivo and revealed an enhanced suppressive capacity as compared to the Tregs isolated from the control group. CONCLUSION: LNT was capable of stimulating the production of Treg cells from naive CD4 + T cells, which implies that LNT exhibits therapeutic values as a tolerogenic adjuvant and may be used to reverse hyperglycaemia in the early and late stages of T1D.

The inhibitory effect of oral administration of lentinan on DSS-induced inflammation is exerted by the migration of T cells activated in the ileum to the colon.

Oral administration of lentinan ameliorated dextran sulfate sodium (DSS)-induced colitis through Dectin-1 receptor on intestinal epithelial cells. However, it is unclear where lentinan affects in the intestine to prevent the inflammation. We found that the administration of lentinan has induced migration of CD4+ cells from the ileum to the colon by using Kikume Green-Red (KikGR) mice in this study. This result suggests that the oral lentinan treatment could accelerate the migration of Th cells in lymphocyte from ileum into the colon during lentinan intake. Then, C57BL/6 mice were administered 2% DSS to induce colitis. The mice were administered lentinan daily via oral or rectal route before DSS administration. Its rectal administration also suppressed DSS-induced colitis, but its suppressive effects were lower compared to when orally administered, indicating that the biological responses to lentinan in the small intestine contributed to the anti-inflammatory effects. In normal mice (without DSS treatment), the expression of Il12b was significantly increased in the ileum by the oral administration of lentinan, but not by rectal one. On the other hand, no change was observed in the colon by either administration method. In addition, Tbx21 was significantly increased in the ileum. These suggested that IL-12 was increased in the ileum and Th1 cells differentiated in dependence on it. Therefore, Th1 predominant condition in the ileum could influence immunity in the colon and improve the colitis.

Local delivery of biocompatible lentinan/chitosan composite for prolonged inhibition of postoperative breast cancer recurrence.

Postsurgical localized chemotherapy for breast cancer recurrence (BCR) still faces many problems which dampen researchers' enthusiasm and discounted prognosis. Simple strategies with controllable toxicities are expected to address these hurdles. Lentinan (LNT) has excellent biocompatibility and notable antitumor activity but rather low bioavailability after intravenous or oral administration. Here, a sponge-like LNT/chitosan composite (LNT/CS sponge) was prepared for efficient local delivery to prevent postoperative BCR. The obtained sponges exhibit uniform porosity and sustained release of LNT in vitro and in vivo. Furthermore, the sponges were implanted and showed significant reduction of postsurgical recurrence and suppression of long-term tumor regrowth with favorable biocompatibility in a subcutaneous postsurgical recurrence mouse model. Subsequent studies revealed that LNT can restrain the stemness of breast cancer cells, which may account for the long-term inhibition of tumor relapse. Therefore, LNT/CS sponge has a great potential as a promising alternative for postsurgical BCR.

Apaf1 nanoLuc biosensors identified lentinan as a potent synergizer of cisplatin in targeting hepatocellular carcinoma cells.

Liver cancer is one of the most common malignancies that is difficult to treat due to late diagnosis and chemo-resistance. In the present study, we developed and validated a cell based split nanoLuc biosensor to monitor the Apaf1-Apaf1 interactions in response to apoptosis-inducing drugs such as cisplatin. We showed that the activity of split nanoLuc is reconstituted only in response to apoptotic inducer, cisplatin and in a dose-dependent manner. Apaf1 mutants which were unable to oligomerize failed to recover nanoLuc activity while constitutively active variant increased the nanoLuc activity. Generation of Apaf1 knockout HepG2 and treatment with cisplatin showed dramatic reduction in cell death suggesting that cisplatin mainly targets liver cancer cells through apoptosis. As the natural products are potent sources of compounds for adjuvant therapy, we screened a collection of natural products and identified lentinan as an inducer of apoptosome formation, a key step for induction of apoptosis. Lentinan is a polysaccharide with antitumor, pro-apoptotic properties that functions with poorly understood mechanisms. Lentinan was shown to have cytotoxic effects with the IC50 of 650 µM. Sub-lethal lentinan concentration doubled the nanoLuc activity when co-treated with cisplatin. We also showed that lentinan hugely reduced the dose of cisplatin to induce certain amount of death and that lentinan co-treatment with cisplatin enhanced the Apaf1 transcription in HepG2 cells while lentinan or cisplatin alone failed to alter the transcription. In addition, lentinan and cisplatin co-treatment induced mitochondrial depolarization. This suggested that lentinan combinatorial therapy with cisplatin engaged a different signalling pathway to kill the liver cancer cells and that adjuvant therapy with lentinan can reduce the dose of cisplatin and thus reduce the possibility of chemo-resistance.

Lentinan as a natural stabilizer with bioactivities for preparation of drug-drug nanosuspensions.

Lentinan is a natural ß-glucan with various bioactivities and is combined with chemotherapy drugs for cancer treatment. Regorafenib is an oral multi-kinase inhibitor approved by FDA for treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors. Regorafenib has poor water solubility and multiple toxicities. We report drug-drug nanosuspensions of regorafenib and lentinan. Results of dynamic light scattering and scanning electron microscopy showed that the mean particle size of the regorafenib-lentinan nanosuspensions was approximately 200 nm and was uniformly distributed. Transmission electron microscopy findings indicated that lentinan stabilized the nanosuspensions by steric manner. Hydrogen bonds and hydrophobic interactions were found between regorafenib and lentinan by molecular dynamics simulation. The results of cytotoxicity assay and pharmacokinetics study in rats showed that the regorafenib-lentinan nanosuspensions reduced the toxicity and enhanced the in vitro anticancer activity and oral bioavailability of regorafenib. Lentinan as a natural stabilizer has the potential using for drug nanosuspensions. Drug-drug nanosuspensions are a new form of combination therapies that can reduce the number of drugs taken by patients and improve their compliance.

Immunomodulatory Effect of Lentinan on Aberrant T Subsets and Cytokines Profile in Non-small Cell Lung Cancer Patients.

As a purified active component from traditional Chinese medicine, lentinan administration can be applied as beneficial chemo-immunotherapy for anti-tumor. In this study, the immunomodulatory effects of lentinan on aberrant T subsets and cytokines profile were evaluated for non-small cell lung cancer (NSCLC). Of all NSCLC patients treated with NP chemotherapeutic protocol (combination of vinorelbin and cisplatin), 73 cases were recruited in this retrospective cohort trial study, of which 38 cases received additional lentinan. The changes of aberrant T subsets and cytokines profile were compared between two groups (chemotherapy in combination with lentinan vs. conserved single chemotherapy) by flow cytometry and molecular biology. Higher subset ratio of CD3+CD8+ cytotoxic T cells was confirmed in the peripheral blood of NSCLC patients. Chemo-immunotherapy of lentinan resulted in a significant increase of CD3 + CD56+ NKT cells (15.7 ± 3.1%), compared with 8.6 ± 1.4% of NKT cells in single chemotherapy group, and up-regulated CD3+CD8+ and CD3+CD4+ subsets as well, but caused the decrease of CD4+CD25+ Tregs induction, accompanied by significant alleviation of IL-10 and TGF-ß1, and elevation of IFN-γ, TNF-α, and IL-12 (P < 0.05). It could be confirmed that lentinan could not only enhance the cellular immunity and promote the beneficial of anti-tumor by associated immunotherapy, but also had the ability to inhibit the expansion of immune suppressive Tregs in the NSCLC patients, in whom there was a raised Tregs induction compared to health control. Lentinan-based chemo-immunotherapy is a promising strategy for anti-tumor via enhancing the proliferation of cytotoxic T cells, followed by the elevation of inflammatory chemokines/cytokines. Meanwhile, the percentage of CD4+ CD25+ Tregs is down-regulated, leading to a shift in the inflammatory status from Th2 to Th1 in NSCLC patients treated with lentinan.

Evaluation of Efficacy and Safety for Lentinan in the Control of the Malignant Pleural Effusions via Intrapleural Injection.

BACKGROUND: Many studies have investigated the efficacy and safety of lentinan combined with cisplatin versus cisplatin alone for controlling malignant pleural effusion (MPE). This study is a meta-analysis of available evidence. MATERIALS AND METHODS: Seventeen studies reporting lentinan combined with cisplatin versus cisplatin alone for controlling MPE were reviewed. Pooled odds ratios and hazard ratio with 95% confidence intervals were calculated using the fixed effects model of meta-analysis. RESULTS: The overall response rate (ORR) of lentinan combined with cisplatin for controlling MPE was significantly higher than that of cisplatin alone (P < 0.001). In addition, lentinan combined with cisplatin showed a better benefit of quality of life (QOL) compared with cisplatin alone (P < 0.001). The main adverse effects (AEs) found in the control plan were hematological reactions, nausea/vomiting, chest pain and fever. However, the presence of lentinan did not have an extra influence on the incidence of AEs (P > 0.05). CONCLUSIONS: Intrapleural injection of lentinan combined with cisplatin had a better benefit of ORR and QOL for controlling MPE, compared with cisplatin alone. Moreover, lentinan combined with cisplatin had a similar incidence of AEs with cisplatin alone.

Lentinan modulates intestinal microbiota and enhances barrier integrity in a piglet model challenged with lipopolysaccharide.

The intestinal microbiota plays a vital role in metabolism, pathogen resistance, and immune development in host cells, and is modifiable by dietary change. Lentinan (LNT), a type of mushroom polysaccharide, is known to ameliorate intestinal inflammation with the potential of therapeutic effect on digestive diseases. We hypothesized that LNT could alleviate Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury via regulating the composition and metabolites of intestinal microbiota in a piglet model. Twenty-four weaned piglets were used in a 2 × 2 factorial design, and the main factors included a dietary treatment (basal or LNT diet) and immunological challenge (LPS or saline). After feeding basal or LNT diet for 21 days, pigs were injected with LPS or saline. At 4 h post-injection, pigs were killed and jejunum, ileum and cecal digesta were collected. LNT improved intestinal morphology and barrier function. LNT also inhibited inflammatory signaling pathways (toll-like receptor 4 and nucleotide binding oligomerization domain protein) and pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß and interleukin-6) expression, as well as up-regulated the heat shock protein 70 expression in small intestine. In addition, LNT enhanced the concentrations of propionate, butyrate, isobutyrate and isovalerate in cecal digesta, resulting in a significant increase in histone acetylation without affecting the protein level of G protein-coupled receptor 41 (GPR41), a short chain fatty acid receptor. Bacterial 16S rRNA gene pyrosequencing showed that LNT had a great impact on gut microbiota composition at different taxonomic levels. Moreover, the correlation analysis revealed some potential relationships between cecal metabolites and certain intestinal microbiota. These results indicate that LNT promotes intestinal health, in part, through altering intestinal microbiota composition and increasing the short chain fatty acid synthesis, which subsequently lead to a reduction in inflammation and hyper-acetylation of histones.

Lentinan inhibits tumor angiogenesis via interferon γ and in a T cell independent manner.

BACKGROUND: Antiangiogenic agents are commonly used in lung and colon cancer treatments, however, rapid development of drug resistance limits their efficacy. METHODS: Lentinan (LNT) is a biologically active compound extracted from Lentinus edodes. The effects of LNT on tumor angiogenesis were evaluated by immunohistochemistry in murine LAP0297 lung and CT26 colorectal tumor models. The impacts of LNT on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR, and ELISA. Nude mice and IFNγ blockade were used to investigate the mechanism of LNT affecting on tumor angiogenesis. The data sets were compared using two-tailed student's t tests or ANOVA. RESULTS: We found that LNT inhibited tumor angiogenesis and the growth of lung and colon cancers. LNT treatments elevated the expression of angiostatic factors such as IFNγ and also increased tumor infiltration of IFNγ-expressing T cells and myeloid cells. Interestingly, IFNγ blockade, but not T cell deficiency, reversed the effects of LNT treatments on tumor blood vessels. Moreover, long-lasting LNT administration persistently suppressed tumor angiogenesis and inhibited tumor growth. CONCLUSIONS: LNT inhibits tumor angiogenesis by increasing IFNγ production and in a T cell-independent manner. Our findings suggest that LNT could be developed as a new antiangiogenic agent for long-term treatment of lung and colon cancers.

Efficacy of biological response modifier lentinan with chemotherapy for advanced cancer: a meta-analysis.

Lentinan is a common biological response modifier. This study was sought to evaluate the efficacy of adjuvant lentinan combined with chemotherapy for advanced cancer. A meta-analysis of published prospective controlled trials investigating the effects of lentinan for kinds of advanced cancer was performed. Sensitivity analysis, inverted funnel plots, and trial sequence analysis were conducted to explore the reliability and stability of results. Seventeen clinical studies were identified containing 1423 patients. Twelve trials included gastrointestinal cancer (GIC), three trials included lung cancer (LC), and two trials included the two cancers. There was a increase in survival rate in 1 year (risk ratios [RR], 1.46, P = 0.001) and overall response rate including both complete and partial response (RR, 1.28, P = 0.005). There was also a reduction in progressive disease (RR, 0.57, P = 0.0005), nonsevere adverse events (RR, 0.88, P = 0.004), and severe adverse events (RR, 0.73, P = 0.007). Similar results were shown in the two subgroups of GIC and LC. Limited trials reported the data of median overall survival and time to treatment failure, and the data were insufficient for quantitative analysis, and no significant difference were found in 2-year survival rate. Adjuvant lentinan used with chemotherapy achieved improvements in 1-year survival rate, response rate, and adverse events in advanced cancer. The effect seemed to be similar irrespective of cancer type. However, its sustained efficacy on survival was still unclear.

[Evaluation of immunity in elderly patients with unresectable gastric cancer receiving S-1/Lentinan combination chemotherapy].

PURPOSE: This retrospective study evaluated immunity in elderly patients with unresectable gastric cancer receiving S-1/ Lentinan combination chemotherapy. PATIENTS AND METHODS: This study included 10 patients aged≥70 years with unresectable gastric cancer who received S-1/Lentinan combination chemotherapy between October 2008 and December 2012. All patients gave written informed consent. Immune parameters for regulatory T cell(Treg)ratio, prostaglandin E2(PGE2), C3, CH50, and granulocyte/lymphocyte ratio were measured before chemotherapy initiation and at 7 weeks after it. Clinicopathological or immune parameters affecting overall survival(OS)were consequently evaluated. RESULTS: A high Treg ratio(p=0.02) and low PGE2(p=0.05)levels at 7 weeks after chemotherapy and a decrease in the Treg ratio(p=0.02)were found to be significant favorable factors affecting OS. CONCLUSION: The outcome of elderly patients with unresectable gastric cancer receiving S-1/Lentinan combination chemotherapy seemed to be correlated with the change in immunity.

Effect of lentinan combined with docetaxel and cisplatin on the proliferation and apoptosis of BGC823 cells.

We studied the inhibitory effects of lentinan alone or lentinan combined with docetaxel and cisplatin on growth of gastric cancer cell line BGC823. The cells were divided into lentinan group, docetaxel combined with cisplatin group, and lentinan combined with docetaxel and cisplatin group. Gastric cancer cell line BGC823 was treated with different concentrations of drugs in each group. Tetrazolium-based colorimetric assay (MTT), Annexin V/propidium iodide method and flow cytometry were used to determine the proliferation and apoptosis of the cells in each group. The inhibition ratio was positively related with the concentrations of drugs when BGC823 cells were treated with docetaxel combined with cisplatin from low to high dose. The inhibition ratio of each group further increased after lentinan was added into the medium. The apoptosis rate of 6.25 µg/ml lentinan on BGC823 cells was 19.84 %. The apoptosis rate of BGC823 cells was significantly increased from 50.22 % to 72.06 % after treatment with 6.25 µg/ml lentinan combined with 2.5 µg/ml docetaxel and 50 µg/ml cisplatin. Lentinan has an inhibitory effect on the proliferation of gastric cancer cell line BGC823. Lentinan combined with docetaxel and cisplatin increases the inhibitory effect on the proliferation of BGC823 cells mediated by docetaxel combined with cisplatin. Low concentration of lentinan combined with docetaxel and cisplatin has better therapeutic effects on the proliferation of BGC823 cells compared with high concentrations of docetaxel combined with cisplatin. Lentinan has the ability of inducing BGC823 cell apoptosis and this effect is enhanced when combined with docetaxel and cisplatin.

[A case of combined resection of multiple adjacent organs in a patient with locally advanced residual gastric cancer].

A 69-year-old man with a history of distal gastrectomy for early gastric cancer consulted our department concerning a possible diagnosis of sigmoid colon cancer. After detailed examination, he was diagnosed with type 3 advanced sigmoid colon cancer with colonic stenosis and large type 3 gastric cancer in the residual stomach with gross infiltration of the adjacent organs. The patient first underwent sigmoidectomy and then received a regimen of neoadjuvant combination chemotherapy with S-1, cisplatin( CDDP), and Lentinan( LNT)( S-1 80 mg/m2, CDDP 60 mg/m2, and LNT 2 mg/body twice weekly for 2 weeks) for gastric cancer( cT4b[ SI, liver, pancreas], N2M0H0, Stage IIIC). After 2 courses of treatment, the gastric tumor had reduced in size but had penetrated the transverse colon. We performed total resection of the gastric remnant, D2 lymph node dissection, and en bloc resection of the transverse colon, partial liver, pancreas body and tail, partial diaphragm, and pericardium. S-1/CDDP (a total of 11 courses) followed by single-agent S-1 therapy was continued as adjuvant chemotherapy. With a follow-up time of 3 years and 10 months, no recurrence was noted following total resection of the gastric remnant.

[A case of advanced gastric cancer with para-aortic lymph node metastasis successfully treated with preoperative S-1/Lentinan chemotherapy followed by curative gastrectomy].

We report a case of advanced gastric cancer successfully treated with preoperative S-1/Lentinan (LTN)chemotherapy followed by curative gastrectomy. The patient was a 75-year-old man with right hypochondralgia. Endoscopic examination revealed a huge type 2 gastric cancer in the middle body of the stomach. Abdominal computed tomography (CT) revealed multiple perigastric lymph node metastases and bulky para-aortic lymph node metastases. The clinical diagnosis was cT 4N3M1( LYM) with cStage IV. We thought a complete resection would be difficult, so he was treated with S-1( 80 mg/m2 day 1-28/q6w) and LTN (2 mg weekly) in May 2010. After 3 courses, the primary lesion was markedly reduced, and gastric endoscopic biopsy showed no malignant lesion. After 4 courses, abdominal CT showed no lymph node swelling at the perigastric and para-aortic areas. After 5 courses, distal gastrectomy with D2 lymphadenectomy was performed. The histological diagnosis was ypT2( MP) N0M0, Stage IB. Histological features of the primary tumor and lymph nodes were judged to be Grade 2 and Grade 3, respectively. After surgery, S-1/LTN treatment was continued for 1 year. During this period, there were no serious adverse events. The patient has been in good health without recurrence for 28 months after surgery.

The effect of lentinan combination therapy for unresectable advanced gastric cancer.

BACKGROUND: Developed as a biological response modifier (BRM), lentinan mitigates patients' symptoms by boosting the immune system. In combination with S-1 (tegafur, gimeracil, oteracil), lentinan is reported to mitigate adverse reactions to therapy for unresectable recurrent gastric cancer and prolong survival. However, there are few reports from actual clinical practice, and precise methods of using lentinan have not yet been established. This study retrospectively examined the usefulness of lentinan in patients. PATIENTS AND METHODS: The subjects of this study were 39 patients who were diagnosed with unresectable gastric cancer, based on preoperative examinations or findings at laparotomy in our Department. These patients underwent S-1/paclitaxel therapy. Nineteen of the patients received lentinan while 20 did not, and these two groups of patients were compared. RESULTS: There were no significant differences in patients' characteristics such as the male:female ratio, age at the start of chemotherapy, and staging classification of the 19 patients receiving lentinan and the 20 patients not receiving lentinan. Comparison of the two groups revealed no significant differences in overall survival time, but comparison of the duration of therapy revealed that therapy tended to be longer for the group taking lentinan than the group not taking lentinan. Adverse events were noted in 61.5% (24 patients) of the total patients group; such events tended to occur less frequently in the group receiving lentinan. CONCLUSION: Lentinan inclusion in therapy did not seem to prolong survival. Nevertheless, the duration of therapy tended to be longer for patients taking lentinan. This may be due to the fact that adverse events tended to occur less frequently in these patients during therapy. A decline in the incidence of adverse events increases the duration of therapy and improves the patients' quality of life (QOL); it may also prolong survival. Optimal methods of using lentinan need to be established.

[A case study of advanced gastric cancer patient treated with S-1+paclitaxel/lentinan].

A 47 -year-old male presented with gastric cancer, with right cervical and para-aortic lymph node metastases. The patient had not undergone a curative operation, but was treated with immunochemotherapy in combination with S-1 60 mg/m2(2 weeks administration and 2 weeks rest), paclitaxel 60 mg/m²(day 1, 8, 15), and Lentinan 2mg/body(day 1, 8, 15). After 3 courses of this treatment, no hot-spots were identified on cervical and para-aorta lymph nodes by PET-CT examination. We decided to perform total gastrectomy with D3 lymphadenectomy and Roux-en Y reconstruction. On histopathological examination, no malignancy was seen in the lymph nodes and the main tumor was judged to be grade 2. With this combined immunochemotherapy, the patient had a favorable outcome without side effects, which proved effective for far advanced gastric cancer.

[Combination chemotherapy of S-1/low-dose CDDP/lentinan for advanced gastric cancer].

Eight patients with inoperable advanced gastric cancer were treated with combination chemotherapy of S-1, low-dose cisplatin(CDDP)and Lentinan. S-1 80 mg/ m² was orally administered for 2 weeks followed by 1-week rest, CDDP 15 mg/ m² and Lentinan 2 mg/body were given intravenously on day 1 and 8. One complete response and four partial responses were observed for an overall response rate of 63%(5 of 8 patients). Only one patient developed over grade 3 toxicity leukocytopenia. Many patients could be maintained by long-term continuous treatment. Since combination chemotherapy of S-1/low-dose CDDP/Lentinan for advanced gastric cancer was very tolerable, it could be used for a long time.

Effects of lentinan alone and in combination with fluoropyrimidine anticancer agent on growth of human oral squamous cell carcinoma in vitro and in vivo.

Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Lentinan, beta-(1-->3)-D-glucan, an extract from the edible mushroom, Lentinus edodes, has been reported to show direct antitumor effects and various immunomodulatory effects. S-1 is an oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with Lentinan and S-1 might exert dramatic antitumor effects on OSCC cells. In this study, the response of human OSCC cells to Lentinan alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (6.9 mg/kg/day, 7 times/week) was administered orally and Lentinan (0.1 mg/kg/day, 2 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The gene expression level of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) was determined using microdissection and RT-PCR, and their protein levels were determined using ELISA. Combined therapy of Lentinan and S-1 markedly exerted antitumor effects on human OSCC xenografts and significantly induced apoptotic cells in tumors treated with Lentinan plus S-1. Microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy. These findings demonstrate that the combination of Lentinan and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

[A case of advanced gastric cancer responding to S-1/paclitaxel/lentinan as neoadjuvant chemoimmunotherapy].

A 71-year-old man suffering from epigastric discomfort and dizziness was admitted to our hospital and diagnosed with advanced gastric cancer with bulky lymph node metastases and liver metastasis. We thought a complete resection would be difficult, so he was treated with neo-adjuvant immunochemotherapy in combination with S-1 80 mg/m2 (2 weeks administration and 2-week rest), paclitaxel (PTX) 50 mg/m2 (day 1, 8, 15) and Lentinan (LNT) 2 mg/body (day 1, 8, 15). After 5 courses of this treatment, swollen lymph nodes decreased in size and the metastatic liver tumor disappeared. Total gastrectomy with lymph node dissection was performed. The histological diagnosis was pT2 pN0, Stage I B. Histological effects of primary tumor and lymphnodes were judged to be grade 2 and grade 3, respectively. We considered that the combination of S-1, PTX and LNT can be effective and safe for advanced gastric cancer.