A novel NF-κB inhibitor improves glucocorticoid sensitivity of canine neoplastic lymphoid cells by up-regulating expression of glucocorticoid receptors.

Lymphoid neoplasms including lymphoma and leukemia are one of the most life-threatening disorders in dogs. Many lymphoid malignancies are well-treated with glucocorticoid (GC); however, GC resistance sometimes develops and its mechanism remains uncertain. Since constitutive activation of nuclear factor-κB (NF-κB) has been reported to play roles in lymphoid malignancies, we examined whether inhibition of NF-κB activity with a synthetic inhibitor IMD-0354 affected GC sensitivity of canine neoplastic lymphoid cells, CL-1 and GL-1. Dexamethasone failed to inhibit proliferation of these cells, in which low expression of glucocorticoid receptors (GR) was identified. In the presence of IMD-0354, GR expressions in CL-1 and GL-1 were increased, consequently dexamethasone inhibited their proliferation. These results indicated that GR expression might be down-regulated by spontaneous activation of NF-κB, resulting in GC resistance. Taken together, interference of NF-κB activity may have the synergistic effect in combination chemotherapy with GC for treatment against lymphoid malignancies.

Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways.

Despite being a well-characterized neurotrophic factor, nerve growth factor (NGF) influences survival, differentiation, and functions of mast cells. We investigated whether NGF was able to induce directional migration of rat peritoneal mast cells (PMCs). NGF clearly induced chemotactic movement of PMCs in a dose-dependent manner with the drastic morphological change and distribution of F-actin, which was completely blocked by pretreatment with Clostridium botulinum C(2) toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors specific for MAPK kinase and PI3K suppressed cell migration and these signals. In the coculture system with PMCs and fibroblasts, which produce biologically active NGF, directional migration of PMCs to fibroblasts was observed, and the addition of anti-NGF polyclonal antibodies significantly suppressed the migration of PMCs. These findings suggested that NGF initiated chemotactic movement of PMCs through both MAPK and PI3K signaling pathways following TrkA activation. Thus, locally produced NGF may play an important role in mast cell accumulation in allergic and nonallergic inflammatory conditions. (Blood. 2000;95:2052-2058)

Functional properties of murine macrophages promoted by nerve growth factor.

The stimulating effect of nerve growth factor (NGF) on phagocytosis, parasite killing, and interleukin-1beta (IL-1beta) production of murine peritoneal macrophages was assessed. In the presence of various doses of NGF, macrophages showed the increased phagocytosis of both nonspecific hydrophilic microspheres and sheep red blood cells (SRBC) opsonized with anti-SRBC antibodies (Ab) or complement in a dose-dependent manner. NGF also enhanced killing of Leishmania donovani promastigotes by macrophages, and its ability was comparable with that of an optimal dose of recombinant granulocyte-macrophage colony-stimulating factor or recombinant interferon-gamma. The addition of NGF to peritoneal macrophages and monocyte-macrophage J774A.1 cells led to a significant release of IL-1beta in a dose-dependent manner and expression of IL-1beta mRNA. Because pretreatment of peritoneal macrophages and J774A.1 cells with K-252a, a tyrosine kinase inhibitor, completely suppressed these NGF-mediated stimulating effects and p140trk phosphorylation and because flow cytometric analysis with specific Ab against two distinct NGF receptors showed the expression of p140trk, unlike p75LNGFR, on the surface of macrophages, the stimulating activity of NGF to murine macrophages may be mediated through p140trk. Thus, NGF may act as an activator for murine macrophages in the process of inflammatory and immune actions.

Clinical analysis of malignant lymphomas of tonsils.

Data of 38 patients with primary tonsil lymphoma, treated during the past 14 years was analysed. All cases were non-Hodgkin lymphomas. There were 11 patients with Stage 1, 14 with Stage II, 8 with Stage III, and 4 with Stage IV tonsillar lymphomas. The applied chemotherapies were CHOP or MACOP-B regimen. The overall 5-year survival rate was 64.4%. Further analysis of the intermediate grade group showed that 5-year survival rates were 72.7%) for patients younger than 60 years old, in contrast to 35.0% for patients aged 60 or older (p 0.0049). Five-year survival rates were 100%) for Stage I, 32.4% for Stage II, 55.6% for Stage III, and 100%) for Stage IV patients (p = 0.0878). In patients with Stage II tonsillar lymphomas, 5-year survival rates were below 100% for CHOP regimen, 100% for MACOP-B regimen, 66.7% for radiation alone, and 0% for radiation followed by chemotherapy (p = 0.1966). In patients with Stage III tonsillar lymphomas, 5-year survival rates were below 100% for MACOP-B regimen, and 0% for initial radiation followed by chemotherapy (p = 0.2568). The factors influencing survival were age, stage, and treatment modality. For Stage I patients without bulky mass, radiation therapy is sufficient. For Stage II patients or Stage I patients with a bulky mass, CHOP regimen (followed by radiation) is the choice of treatment. For Stage III or IV patients,, MACOP-B regimen is promising.

Clinical assessment of squamous cell carcinoma of the nasal cavity proper.

The subjects were 14 patients with squamous cell carcinoma or undifferentiated carcinoma of the nasal cavity treated at Nihon University Hospital between October 1984 and November 1991, who were followed for at least 3 years. The site of the tumor origin within the nasal cavity was the lateral wall in 8 patients, the nasal septum in three patients, and unknown in three patients. Histologically, there were 13 squamous cell carcinomas in (3 well differentiated, 7 moderately differentiated, and 3 poorly differentiated) and 1 undifferentiated carcinoma. Treatment was by a combination of radiotherapy, chemotherapy, and surgery in 8 cases, a combination of radiotherapy and surgery in 5 cases, and surgery alone in 1 case. The 3-year and 5-year Kaplan-Meier survival rates were 86 and 69%, respectively. A total of 6 patients suffered a recurrence, with local recurrence occurring in 4 patients and pulmonary metastasis in 2 patients. Tumor control was achieved in 3 of the 4 cases of local recurrence by reoperation, and by surgery in 1 of the 2 cases of pulmonary metastasis. The duration of the recurrence-free interval in the patients who developed local recurrences, 18 to 46 months after the completion of the initial course of therapy, was of considerable interest.

Cyclophosphamide, tetrahydropyranyl-adriamycin, and cis-platinum in the treatment of head and neck adenocarcinoma.

Twelve patients with advanced or relapsed head and neck adenocarcinoma received a combination chemotherapy regimen of either cyclophosphamide (C), tetrahydropyranyl-adriamycin (T), and cis-platinum (P) (CTP) or cyclophosphamide, adriamycin (A), and cis-platinum (CAP). Cyclophosphamide (300 mg/sq m), either etrahydropyranyl-adriamycin (30 mg/sq m) or adriamycin (30 mg/sq m), and cis-platinum (50 mg/sq m) were administered intravenously in a single day. Nine patients received the CTP regimen, and three patients, the CAP regimen. Prior to chemotherapy, five patients had received surgery or radiation therapy, and the other seven patients received no special treatment. A response rate 75% was achieved (9/12); there were 7 complete responses, whose duration was a mean 6.8 months, ranging from 2 to 18 months, and 2 partial responses, whose duration was 2 months. Virtually all patients experienced nausea and vomiting. Alopecia developed in 7 patients; however, the patients with the CTP regimen experienced less alopecia, if any. Leucopenia and anemia of either a slight or moderate degree were observed, but there was no patient for whom it was necessary to discontinue the treatment. Both CTP and CAP regimens appear to be of significant value in controlling head and neck adenocarcinoma.

Indication of cryosurgery on tonsillar diseases.

The present studies are concerned with the reconfirmation of cryo-effects on the tonsil, such as advantages of cryosurgery on habitual tonsillitis, on expansive growth of tonsillar haemangioma and papilloma, and on malignant lymphoma. The present results revealed that post-operative healing of the wounds was satisfactory with minimum scar formation. Recurrence of habituere tonsillitis within three years after cryosurgery was 17%. Cryosensitivity was extremely high on patients with haemangioma and papilloma, even in cases of malignant lymphoma.

Slow-release local chemotherapeutic regimen for maxillary sinus cancer.

Silicone foam containing BLM and implanted in the cavity resulting from the resection of a tumor seemed to act against any tumor cells remaining in the resection site in microscopic amounts by slowly releasing this carcinostatic agent. The silicone foam is molded in precise accordance with the shape of the wound surface as it foams and hardens, leaving no space between the material and the wound surface. The carcinostatic agent released can, therefore, act on the entire surface of the wound, and the implantation also has a hemostatic effect. High tissue concentrations of the agent can be maintained for a long time due to the slow-release properties of the silicone foam. Systemic side effects of the procedure seem to be negligible. Local recurrence of cancer was observed in 11 (33.4%) of our 32 patients. Three-year survival was seen in 1 (50%) of the 2 patients with T2 lesions, 11 (68.7%) of the 16 with T3 lesions and 4 (66.6%) of the 6 with T4 lesions.

Combination chemotherapy with CDDP, 5-FU and PEP in head and neck malignant tumors.

Multi-drug combination therapy with CDDP, 5-FU and PEP was performed in 23 patients with malignant tumors in the head and neck region, and 2 CR patients and 9 PR patients were obtained with a response rate of 47.8%. The present therapy (CFP therapy) is considered to be especially effective against patients at low performance status grades with poorly differentiated squamous cell carcinoma which is located in regions receiving an abundant blood supply like the oral cavity. It is advisable to perform more than 2 courses of treatment as an induction chemotherapy. With respect to the method of administration of PEP, further study will be made in the future.

Combination chemotherapy with CDDP and 5-FU in head and neck cancer.

Combination chemotherapy with CDDP and 5-FU was performed in 19 patients with evaluable head and neck cancer and 2 CR patients and 7 PR patients were obtained; thus the response rate was 47.4%. Histologically, the present therapy is considered to be especially effective against well differentiated squamous cell carcinoma (83.3%). The present therapy is considered to be useful as a neo-adjuvant chemotherapy (75.0%), but it is desirable to perform at least 2 courses of treatment. The side effects observed were nausea, vomiting, anemia, leukocytopenia and alopecia, etc., and most of them were reversible. However, there were 2 patients in which the continuation of chemotherapy was impossible due to renal disorders.

CAP therapy for advanced, recurrent and/or metastatic malignant tumors of the head and neck.

One-day CAP therapy utilizing CPM, THP-ADM and CDDP was performed on 33 patients with malignant tumors in the head and neck region which were able to be evaluated. As a result, CR was obtained in 6 patients and PR in 11 patients; thus the overall response rate was 51.5%. The present therapy is worthwhile as a neo-adjuvant chemotherapy and it was effective in patients with relatively severe systemic condition or those with lung metastasis. When the tissues were classified histologically, the present therapy was effective against anaplastic carcinoma and adenocarcinoma. Since agents significantly effective against adenocarcinoma have not been available so far, the present therapy is considered to be a useful method especially for the treatment of adenocarcinoma. Moreover, because irreversible side effects scarcely appeared and because the period for 1 course of treatment is short enough, the present therapy is considered to be a method with little burden on patients.

T-lymphocyte subsets in patients with squamous cell carcinoma of the head and neck.

T-lymphocyte subsets in the peripheral blood of patients previously untreated for squamous cell carcinoma of the head and neck were investigated using monoclonal antibodies under flow cytometry before starting treatment. T-lymphocyte subsets in the peripheral blood of patients with squamous cell carcinoma did not significantly differ from those in the peripheral blood of healthy subjects, patients with benign tumors of the head and neck, patients with chronic sinusitis and patients with benign otolaryngological diseases. The necessity to investigate the function of T-lymphocyte subsets was suggested. It was furthermore suggested that T-lymphocyte subsets in cancerous tissues should be investigated.

Serum immunosuppressive acidic protein (IAP) in patients with malignant head and neck tumors.

Measurements were carried out on the serum immunosuppressive acidic protein (IAP) level of patients with malignant head and neck tumors. The serum IAP value in patients with malignancies was significantly higher than that in healthy subjects and those with benign tumors. Following treatment, in cases with favorable progress the high IAP values prior to treatment showed a decline, becoming normal. Whereas in cases showing poor progress, there was a delay in reverting to normal values and some were observed to retain the same high values.