Biomedical subjects

G Soma

Publications and source records attributed to G Soma.

80 records · Page 5Linked to original sources

PubMedDate not supplied

Antitumor mechanism of intradermal administration of lipopolysaccharide.

We earlier demonstrated that 50% of the lethal dose of lipopolysaccharide (LPS) from Pantoea agglomerans given by the intradermal (i.d.) route is about 300 times greater than that given by the intravenous (i.v.) route, and that 400 micrograms/kg of LPS administered i.d. significantly suppressed metastasis whereas administered i.v., it did not. To learn the specific mechanism involved in this i.d. administration, the fate of LPS at the skin following administration and the concurrent production of endogenous tumor necrosis factor (TNF) in serum was examined. Histological observation following the i.d. administration of LPS (40 micrograms/kg) revealed neutrophiles in the skin 6 hours later. After 24 or 48 hours inflammatory cells were assembled at the site of injection. Endogenous TNF activity was found in the skin 24 hours after the injection and was significantly detectable even after 48 hours. Endogenous TNF was induced around tumor lesions of Meth A fibrosarcoma, MH134 hepatoma and Lewis lung carcinoma by treatment of LPS administered i.d. Taken together, these findings suggest that the antitumor activity of i.d. administered LPS results from the continuous supply of a small amount of this substance producing free TNF and activating inflammatory cells such as macrophages having membrane bound proTNF on their surface from the injected site to the tumor lesion for more than 48 hours.

Animals↗

PubMedDate not supplied

Anti-tumor effect of lipopolysaccharide by intradermal administration as a novel drug delivery system.

We examined the antitumor effect of lipopolysaccharide extracted from Pantoea agglomerans, a Gram-negative bacterium, using intradermal administration on murine syngeneic tumors, Meth A fibrosarcoma, MH134 hepatoma and Lewis lung (LL) carcinoma. The latter two tumors are known to be relatively low in immunogenicity, highly metastatic and to have low sensitivity to biological response modifiers. Although the intradermal administration of LPSp had a significantly suppressive effect on the growth of all tumors, including seventy-five percent of complete regression of mice bearing Meth A tumor, no complete regression was observed in MH134 or LL tumors. In combination with cyclophosphamide given once prior to the administration of LPS, however, the antitumor effects by intradermal administration of LPS were significantly augmented and there was complete regression in all types of tumors. Pretreatment by anti-tumor necrosis factor antibody reduced the effect exerted by LPS, suggesting that induced tumor necrosis factor might have a crucial role. Toxicity of intradermal administration of LPS was 230-380 times less than that by the intravenous route. Thus clinical application of LPS administered intradermally in combination with chemotherapeutics such as cyclophosphamide appears promising in terms of its antitumor effect as well as toxicity.

Animals↗

PubMedDate not supplied

Clinical experience of EET therapy for 75 advanced cancer patients.

BACKGROUND: Exogenous/endogenous TNF (EET) therapy has a strong effect which causes inflammation in the body. Together with the antitumor effect of a single administration, the complementary effect of immunotherapy based on specific immunostimulation of tumor cells is also expected. We studied the characteristics of EET therapy in cases of advanced cancer. PATIENTS AND METHODS: The patients were 75 cases with advanced cancer including 48 cases of colon cancer, 10 cases of urological cancer, and 9 cases of gynecological cancer. One course of therapy was composed of the intravenous administration of either IFN-gamma or TNF-SAM2 followed 3 hours later by OK-432. At least 2 courses were repeated during a 2 weeks period. RESULTS: As response cases, partial response (PR) was observed in 7 of the 42 cases of colon cancer (17%) which had an evaluable lesion. Objective responses of lung metastases were found in the patients with multiple organ metastases of cervical cancer, ovarian cancer and uterine rhabdomyosarcoma. The group of colorectal cancer patients with liver metastases which underwent more than 5 courses of the therapy showed a longer survival period compared to the control group. One of the side effects, transitory hypotension, was observed in 46% of the cases. CONCLUSION: In spite of restricted objective responses to date with EET therapy alone, anticancer effects observed in various kinds of tumors and activation of a cytokine network by which Th1 cells might be specifically activated suggest that a new biotherapy based on EET therapy may have potential.

Antineoplastic Agents↗

PubMedDate not supplied

Mechanisms by which chemotherapeutic agents augment the antitumor effects of tumor necrosis factor: involvement of the pattern shift of cytokines from Th2 to Th1 in tumor lesions.

BACKGROUND: The antitumor effect exerted by tumor necrosis factor (TNF) is characteristic in that it causes central necrosis of the tumor mass. Viable tumor cells surrounding the tumor mass remain, however, even after most of the mass is necrotized, and these cells gradually regrow and form tumors. To overcome this, we analyzed the combined effects of chemotherapeutic agents used with TNF. Alkylating agents such as cyclophosphamide altered the antitumor effect qualitatively, leading to complete regression which TNF alone could not achieve. The mechanism, behind the enhancement of endogenous TNF production and expression of mRNA of various cytokines by the combination of chemotherapeutic agents with TNF inducer was investigated in Meth A fibrosarcoma. METHODS: Seven days after the inoculation of Meth A fibrosarcoma into BALB/c mice, cyclophosphamide (CY, 100-150 mg/kg) was injected intraperitoneally, and 7 days later endogenous TNF was induced by the intradermal administration of lipopolysaccharide (LPS, 400 micrograms/kg) or intravenous injection of ONO-4007, a synthetic lipid A derivative (30 mg/kg). RESULTS: A combination therapy of LPS or ONO-4007 with CY showed the effect of complete regression in 50-100% of tested mice, while CY, LPSp or ONO-4007 alone did not cause complete regression. The amount of endogenous TNF induced by LPSp or ONO-4007 around a tumor lesion with CY was 4-5 fold higher than that without CY. The expression of mRNA of transforming growth factor-beta was suppressed by CY seven days after the injection, and expressions of mRNA of IL-1 beta and TNF-alpha were augmented by the administration of CY 1 to 3 hours after the administration of ONO-4007. CONCLUSION: Some chemotherapeutic agents thus appear to augment the antitumor effect of TNF around tumor lesions, leading to tumor regression through a mechanism in which the agent changes the host's immune status, especially around a tumor lesion and pattern shift of cytokines from Th2 to Th1.

Animals↗

PubMedDate not supplied

Treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2).

We present our experience with a combination chemotherapy regimen consisting of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for malignant astrocytomas. The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. Newly diagnosed patients were treated with up to four cycles of this regimen (TNF-SAM2, MCNU, and radiotherapy: TMR group). Seventeen patients (11 men and 6 women) aged 24 to 68 years (median 54.6 years) were eligible and evaluated for response and toxicity. The estimated median survival time was 354 weeks with anaplastic astrocytomas, and 76 weeks with glioblastomas. One- and 2-year survival rates were 100% and 100% with anaplastic astrocytomas, and 69.2% and 29.7% with glioblastomas. Grade 3 and 4 hematological toxicities were not experienced. None of the patients experienced a treatment delay due to toxicity. All other acute toxicities were anticipated and manageable. Twenty three patients (11 men and 12 women) aged 22 to 66 years (median 50.7 years) were evaluated as a historical control of patients who received chemotherapy with MCNU alone in conjunction with radiotherapy following standard surgical treatment (MCNU and radiotherapy: MR group). The estimated median survival time was 205 weeks with anaplastic astrocytomas, and 62 weeks with glioblastomas. One- and 2-year survival rates were 88.9% and 66.7% with anaplastic astrocytomas, and 71.4% and 7.1% with glioblastomas in this group. There were no significant differences in survival rates between patients in the TMR and MR groups with either anaplastic astrocytoma or glioblastoma. However, despite the small number of patients, those with anaplastic astrocytoma in the TMR group tended to survive longer than those in the MR group. These results suggest that combined chemotherapy with mutant TNF-alpha may benefit those with anaplastic astrocytoma, and thus warrants further evaluation. On the other hand, the lack of activity does not warrant any further study of this schedule of TNF-SAM2 for the treatment of glioblastoma.

Adult↗

PubMedDate not supplied

Preservation of metastatic ability of colorectal tumor cells stratified by inducibility of endogenous tumor necrosis factor after orthotopic transplantation in nude mice.

BACKGROUND: Inducibility of endogenous tumor necrosis factor (TNF) by colorectal tumor cells can be regarded as a novel prognostic factor in terms of distant metastasis or local recurrence following curative operation, especially at Duke's stage C. In this study, the metastatic ability of human colorectal tumor cells stratified by inducibility of endogenous TNF was analyzed by orthotopic transplantation in nude mouse. METHODS: Fifty three cases of freshly resected colorectal tumor specimens cut into about 50mg pieces were inoculated into the cecum wall of nude mice. Two to nine months after transplantation, tumor growth on this wall and metastases to the peritoneal wall as well as to the liver were assessed. RESULTS: Of forty one evaluable cases, successful transplantation was observed in twenty nine (70%), and metastases to the peritoneal wall or to the liver was found in thirteen (32%), or eight cases (20%), respectively. In the twenty nine cases with local tumor growth, incidence of the liver metastases in nude mice when tumor specimens from patients with liver metastases (4/8) were used was significantly higher than that from patients without liver metastases (4/21) (P = 0.096). Inducibility of endogenous TNF was separately analyzed in fourteen of the evaluable twenty nine cases. Seven cases belonged to the high group and seven to the low group in terms of the amount of endogenous TNF secreted by tumor cells. Incidence of metastases in mice was 1/7 in the high group and 6/7 in the low group, and there was a statistically significant difference between liver metastases in mice and inducibility of endogenous TNF by colorectal tumor cells (p = 0.0057). CONCLUSION: From these results, it is strongly suggested that inducibility of endogenous TNF by colorectal tumor cells can affect a patient's prognosis since it regulates metastatic ability to the liver.

Animals↗

PubMedDate not supplied

Endogenous TNF inducibility and prognosis of colorectal cancer.

BACKGROUND: We have demonstrated that the inducibility of endogenous TNF (en-TNF) by colorectal tumor cells is a factor in predicting a patient prognosis. The prognoses of colorectal tumor patients with the K-ras gene mutations in their tumors were poorer to those of patients with the wild type gene. Therefore, we analyzed the possible relationship between the inducibility of en-TNF by colorectal tumor cells during the follow-up of patients with K-ras mutations. MATERIALS AND PATIENTS: In 62 of 154 Dukes Stage C patients who received curative operation from June 1988 to June 1997, the prognoses in terms of the tumor-free rate and survival rate were compared with the inducibility of en-TNF by colorectal tumor cells, which were classified into three groups: grade 1: > or = 500 pg/ml, grade 2: 100-500 pg/ml, and grade 3: < 100 pg/ml. Regardless of the Dukes Stage of the patients, the K-ras gene was analyzed in 21 whose colorectal tumor cells were classified as grade 1: 8, grade 2: 4, and grade 3: 9. RESULTS: The tumor-free rate of the patients with grade 1 was significantly higher than that of the patients with grade 3, and the survival period of the patients with grades 1 and 2 was significantly longer than that of the patients with grade 3. Possible mutations disorder of K-ras were observed in 37.5% (grade 1), 50.0% (grade 2), and 88.9% (grade 3) of cases, respectively. CONCLUSION: The prognostic value of the inducibility of en-TNF by colorectal tumor cells from colorectal cancer patients who received curative operation at Dukes Stage C was confirmed. It is suggested that K-ras mutation may affect patient prognosis through modulation of the quality and/or quantity of cytokines such as TNF produced by tumor cells.

Colorectal Neoplasms↗

PubMedDate not supplied

A long-term survivor case of malignant mesothelioma treated by recombinant tumor necrosis factor-SAM2 (TNF-alpha mutein) and 5-fluorouracil (5-FU): a new therapeutic approach based on host-tumor relationship.

BACKGROUND: The prognosis of mesothelioma is very poor, and there is no established method to suppress tumor growth. Immunological approaches have recently been thought to be effective for mesothelioma and several studies using cytokines have been performed. We used a novel recombinant tumor necrosis factor-alpha (rTNF-alpha) we called rTNF-SAM2, in the treatment of a patient with this disease. PATIENT AND METHOD: A 48-year old male patient with ascites was diagnosed with malignant mesothelioma by cytological examination. TNF-SAM2 in an amount of 264 to 576 micrograms (1 to 2.2 x 10(6) U) was injected via a catheter several times. Five hundred mg of 5 fluorouracil (5-FU) was also given via catheter once a week and 5-FU derivative was given orally every day. RESULTS: No apparent tumor progression was observed for 6 years and 6 months and the patient led a normal life. During the therapy, the malignancy of tumor cells from the ascites changed from class V to class VI. CONCLUSION: TNF based therapy may be promising treatment for the suppression of malignant mesothelioma.

Antimetabolites, Antineoplastic↗