Bombesin and bombesin antagonists: studies in Swiss 3T3 cells and human small cell lung cancer.

Bombesins are potent growth factors for murine Swiss 3T3 cells. Using these cells in chemically defined conditions we have been able to characterise the bombesin receptor and the early signals preceding DNA synthesis. We describe two substance P analogues [DArg1, DPro2, DTrp7,9, Leu11] substance P and [DArg1, DPhe5, DTrp7,9, Leu11] substance P which competitively block the binding of bombesins to their receptor and all the events leading to mitogenesis. Bombesins are secreted by human small cell lung cancers (SCLC) and may act as autocrine growth factors for these tumours, so the development of peptide bombesin antagonists could have therapeutic implications. We demonstrate that the antagonists can reversibly inhibit the growth of SCLC in vitro, with relatively little effect on other lung tumours

Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer

Small-cell lung cancer (SCLC) can produce numerous mitogenic neuropeptides, which are not found in normal respiratory epithelium. Arginine vasopressin is detected in up to two-thirds of SCLC tumours whereas normal physiological expression is essentially restricted to the hypothalamus. This presents the opportunity to identify elements of the gene promoter which could be exploited for SCLC-specific targeting. A series of human vasopressin 5′ promoter fragments (1048 bp, 468 bp and 199 bp) were isolated and cloned upstream of a reporter gene. These were transfected into a panel of ten cell lines, including SCLC with high or low endogenous vasopressin transcription, non-SCLC and bronchial epithelium. All these fragments directed reporter gene expression in the five SCLC cell lines, but had negligible activity in the control lines. The level of reporter gene expression reflected the level of endogenous vasopressin production, with up to 4.9-fold (s.d. 0.34) higher activity than an SV40 promoter. The elements required for this strong, restricted, SCLC-specific promoter activity are contained within the 199-bp fragment. Further analysis of this region indicated involvement of E-box transcription factor binding sites, although tumour-specificity was retained by a 65-bp minimal promoter fragment. These data show that a short region of the vasopressin promoter will drive strong expression in SCLC in vitro and raise the possibility of targeting gene therapy to these tumours

Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer

Small cell lung cancer (SCLC) is characterised by early and widespread metastasis. However, SCLC cells have so far been found to produce low levels of known pro-angiogenic factors. We speculated that SCLC cells might produce alternative pro-angiogenic factors. Here, we report that a panel of SCLC cell lines constitutively secrete granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR+ chemokine. In contrast, none of the three tested NSCLC cell lines secreted GCP-2. Production of GCP-2 in vivo was also confirmed in seven out of nine specimens with SCLC. We demonstrate that expression of GCP-2 is mediated by NF-κB as ALLN, an NF-κB pathway inhibitor, almost completely abolished GCP-2 production in SCLC cell lines. We also demonstrate that GCP-2 can be significantly upregulated by IL-1β and hypoxia in SCLC cell lines. This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation. As SCLC cells express both GCP-2 and its receptors CXCR1 and CXCR2, their biological significance in SCLC progression was further studied. We demonstrate that GCP-2 is an autocrine growth factor. Cell proliferation was significantly inhibited by anti-GCP-2 neutralising antibody in two high-GCP-2-producing cell lines. In addition, expression of the proliferation marker PCNA was upregulated by exogenous GCP-2 in two low-GCP-2-producing cell lines. Taken together, these results suggest an important role for GCP-2 as an autocrine mitogen in the growth and metastasis of SCLC

Follow up after Primary Treatment of Soft Tissue Sarcoma: A Survey of Current Practice in the United Kingdom

Despite the clinical and financial implications, there is little evidence about how patients who have been treated for soft tissue sarcoma should be followed up. The purpose of this study was to determine current practice in the United Kingdom. 192 clinicians treating patients with soft tissue sarcoma were surveyed with a postal questionnaire enquiring about frequency and method of follow up and how patients would be followed up in each of 3 clinical scenarios: a patient with a trunk or extremity tumour at low risk of relapse; a patient with a trunk or extremity tumour at high risk of relapse; and a patient with a retroperitoneal or abdominal tumour. 155 (81%) clinicians responded. Clinic visits and X-rays were the most frequently used methods of follow up. Chest CT scans, local site imaging, and blood tests were used infrequently. The intensity and methods of follow up varied with each of the clinical scenarios. There was a seven-to-twenty fold variation in cost between the least and the most expensive regimes. Respondents were generally supportive of the development of the clinical trial in this area

Family Health Climate and Adolescents’ Physical Activity and Healthy Eating: A Cross-Sectional Study with Mother-Father-Adolescent Triads

The importance of the family environment for children’s and adolescents’ health behavior has been demonstrated, the underlying mechanisms of this influence remain unclear. Therefore, the aim of the study was to investigate the relationship between family environmental and individual determinants. It was hypothesized that the Family Health Climate (FHC) is associated with adolescents’ physical activity and dietary behavior and that intrinsic motivation mediates this association. Methods Cross-sectional data were collected from 198 families (mother, father, and child) using questionnaires. Perceptions of FHC of mothers, fathers, and their children were assessed using the FHC-scales for physical activity (FHC-PA) and nutrition (FHC-NU). The adolescents also rated their intrinsic motivation for exercise and healthy eating, their physical activity and consumption of healthful food. A structural equation model was analyzed and a bootstrapping procedure was used to test direct and indirect effects. Results The FHC-PA was related to the amount of weekly physical activity and the FHC-NU to the consumption of fruit, vegetables and salad. These effects were mediated by adolescents’ intrinsic motivation; the indirect effects were significant for both behaviors. Discussion These results emphasize the importance of the FHC in shaping adolescents’ physical activity and dietary behavior. Individual motivational factors are potential mediators of family and parental influences. Considering family-level variables and their interaction with individual factors contributes to the understanding of adolescents’ health behavior

Treatment of bone metastases from breast cancer with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).

Twenty-eight patients with progressive symptomatic bone metastases from breast cancer received (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) 30 mg in 500 ml of 0.9% saline infused over 2 h every 14 days. No other systemic therapy for breast cancer was prescribed. All patients had progressed on at least one previous systemic treatment. APD was continued until the disease progressed. Patients were assessed for objective response by the UICC criteria. In addition, subjective response was determined by a pain questionnaire. Radiological evidence of bone healing with sclerosis of lytic disease (UICC partial response) was seen in 4 patients. The median duration of response was 10 months. Eleven patients had stable disease for at least 3 months (median 5 months) and 9 progressed. Symptomatic response occurred in 9 patients and 12 reported an improvement in quality of life. Treatment was tolerated well with no significant toxicity. In conclusion, long-term inhibition of bone destruction is possible with APD therapy alone and both subjective and objective responses are seen

Aging and memory effects in beta-hydrochinone-clathrate

The out-of-equilibrium low-frequency complex susceptibility of the orientational glass methanol(73%)-beta-hydrochinone-clathrate is studied using temperature-stop protocols in aging experiments . Although the material does not have a sharp glass transition aging effects including rejuvenation and memory are found at low temperatures. However, they turn out to be much weaker, however, than in conventional magnetic spin glasses.Comment: 5 pages RevTeX, 6 eps-figures include

Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma.

Temozolomide, an imidazotetrazine derivative, was given to 18 patients with low-grade non-Hodgkin's lymphoma (NHL) at a dose of 750 mg m-2 orally, divided over five consecutive days, escalated to 1000 mg m-2 over 5 days (i.e. 200 mg m-2 day-1) if no significant myelosuppression was noted at day 22 of the 28 day cycle. Fifty-six treatment cycles were given to 18 patients. The drug was well tolerated. Only one partial tumour response was documented. The patients were heavily pretreated but had chemoresponsive disease, as shown by a response rate of 69% among 13 patients who went on to receive alternative cytotoxic regimens. We conclude that temozolomide given in this schedule is inactive in previously treated low-grade NHL

Phase II trial of raltitrexed ('Tomudex') in advanced small-cell lung cancer.

Raltitrexed, a thymidylate synthase inhibitor, was given to 21 patients with advanced small-cell lung cancer, at a dose of 3 mg m(-2) as a 15-min intravenous infusion at 21-day intervals. All of the patients had extensive disease and 17 had received prior therapy. Patients with disease refractory to primary chemotherapy were excluded. Forty-one treatment cycles were given (median two, range one to four). The drug was well tolerated. No objective tumour response was documented. The patients had chemoresistant disease, as shown by a response in only one of ten patients who went on to receive alternative cytotoxic regimens. We conclude that raltitrexed given in this schedule is inactive as second line therapy for small-cell lung cancer