Nitric oxide accelerates interleukin-13 cytotoxin-mediated regression in head and neck cancer animal model.

Receptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi's sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter N(omega)-monomethyl-l-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with N(omega)-monomethyl-l-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent.     

Efficacy of Zoladex LA (goserelin) in the treatment of girls with central precocious or early puberty

OBJECTIVE: To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS: Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2-5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS: Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1-6.6) compared with 6.5 cm/year (range, 3.8-9.6) before treatment in nine patients for whom data were available. CONCLUSIONS: Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9-12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment.     

Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2 integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O- tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta2 integrin protein compared with the lower levels of beta2 integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 microg anti-beta2 integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P < 0.01 anti- beta2 integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta2 integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8- OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2 integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as anti-promoting and anti-progression agents.      

Mutation of the p53 tumor suppressor gene in spontaneously occurring osteosarcomas of the dog

Inactivation of the p53 tumor suppressor gene has been implicated in the pathogenesis of numerous human cancers, including osteosarcomas. Appendicular osteosarcomas of the dog appear to be a good model for their human equivalent with regard to biologic behavior, epidemiology and histopathology. We individually screened exons 5-8 of the p53 gene for mutations in 15 canine appendicular osteosarcomas using 'Cold' SSCP to compare the role of this gene in human and canine osteosarcoma tumorigenesis. Seven of the tumors (47%) exhibited point mutations, with one tumor possessing two mutations within different exons. Of these, seven were missense mutations and the eighth was a 'silent' mutation potentially affecting the exon 6-7 splicing region. Five of the missense mutations were located in highly conserved regions IV and V, while another corresponded with the highly conserved codon 220 mutational hotspot located outside the conserved domains. The locations and types of mutations were nearly identical to those reported in human cancer. These findings provide strong evidence of the involvement of p53 mutations in the development of canine appendicular osteosarcomas. Canine osteosarcomas appear to be a promising model for their human equivalent on a clinical, pathologic, and molecular level.      

SOMATIC NEUROPATHY IN DIABETES MELLITUS

One hundred patients of Diabetes Mellitus (70 with and 30 without clinical somatic neuropathy) were studied to correlate clinical severity with the magnitude of nerve conduction abnormalities. Age range was 10-79 years (mean 49) with equal number of males and females. Incidence of neuropathy was more in patients over 40 years of age (60 out of 70 patients) with duration of disease over two years (78.33%). The grades of severity were mild in 22 (31.33%), moderate in 25 (35.71%) and severe in 23 (32.86%) patients. Nerve conduction studies were carried out in 48 (27 with and 21 without clinical neuropathy) patients, using the apparatus Dantec (Cantata TM). The nerves (median, peroneal and sural) were stimulated at two points and the recording of latency; amplitude (micro V) and motor and sensory nerve conduction velocities (m/s) were done under identical environmental conditions. Sensory nerve conduction velocity was more affected than motor velocity. In the 21 patients without clinical neuropathy, 14 showed abnormalities indicating early involvement of peripheral nerves. Reduction of motor nerve conduction velocity was more in patients with moderate and severe grades. The reduction was more in lower than in upper limbs. Nerve conduction abnormality helps in diagnosis in diabetic neuropathy even in preclinical state and correlates with severity, in clinical neuropathy.KEY WORDS: Diabetic neuropathy, Nerve conduction abnormality, Peripheral neuropathy     

Contralateral pleural effusion during chemotherapy for tuberculous pleural effusion

A 25 year old woman developed a right pleural effusion 6 weeks after commencement of short course chemotherapy for left sided tuberculous pleural effusion. Since the patient improved following continuation of the same treatment, it is presumed to be a case of paradoxical response to anti-tuberculosis treatment.