Neuropeptide growth factors and small cell lung cancer

Quiescent cultures of Swiss 3T3 cells are a useful model system for elucidating the mechanisms of mitogenesis. Here, Swiss 3T3 cells were used to test novel mitogens and characterise bombesin antagonists. Bradykinin was identified as a potent mitogen, acting in synergy with insulin. Two groups of antagonists were characterised: the substance P analogues [DArg1, DPro2, DTrp7,9, Leu11]- substance P (antagonist A), [DArg1, DPhe5, DTrp7,9, Leu11]- substance P (antagonist D) and [Arg6, DTrp7,9, Leu11] substance P(6-11) (antagonist G); and the bombesin-specific antagonists (Leu13-psi(CH2NH)Leu14]bombesin and N- acetyl-GRP(20-26). The substance P antagonists appear to interact with a common domain on the receptors for three mitogenic neuropeptides in Swiss 3T3 cells: bombesin, vasopressin and bradykinin. The bombesin-specific antagonists did not interact with other receptors. Small cell lung cancer (SCLC) is an aggressive form of lung cancer. The bombesin-like peptides, including gastrin- releasing peptide (GRP), have been postulated to act as autocrine growth factors for these tumours. In SCLC cell lines, all the antagonists were shown to block the early effect of bombesin, mobilisation of cytosolic Ca2+. The substance P antagonists also inhibited SCLC growth in liquid and semisolid media, in a reversible, dose-dependent fashion. The bombesin-specific antagonists did not inhibit SCLC growth, suggesting that other growth factors blocked by the substance P antagonists may be more important for regulating SCLC growth. A variety of peptides and hormones were tested for their ability to mobilise cytosolic Ca2+ in SCLG cell lines. Ca2+ signals were induced by GRP, vasopressin, bradykinin, cholecystokinin, galanin and neurotensin, and all were blocked by antagonists D and G. These neuropeptides are suggested as possible growth factors for SCLC

Deaf and hearing children's picture naming Impact of age of acquisition and language modality on representational gesture

Stefanini, Bello, Caselli, Iverson, & Volterra (2009) reported that Italian 24-36 month old children use a high proportion of representational gestures to accompany their spoken responses when labelling pictures. The two studies reported here used the same naming task with (1) typically developing 24-46-month-old hearing children acquiring English and (2) 24-63-month-old deaf children of deaf and hearing parents acquiring British Sign Language (BSL) and spoken English. In Study 1 children scored within the range of correct spoken responses previously reported, but produced very few representational gestures. However, when they did gesture, they expressed the same action meanings as reported in previous research. The action bias was also observed in deaf children of hearing parents in Study 2, who labelled pictures with signs, spoken words and gestures. The deaf group with deaf parents used BSL almost exclusively with few additional gestures. The function of representational gestures in spoken and signed vocabulary development is considered in relation to differences between native and non-native sign language acquisition

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

Measurements of Surface Diffusivity and Coarsening During Pulsed Laser Deposition

Pulsed Laser Deposition (PLD) of homoepitaxial SrTiO3 was studied with in-situ x-ray specular reflectivity and surface diffuse x-ray scattering. Unlike prior reflectivity-based studies, these measurements access both the time- and the length-scales of the evolution of the surface morphology during growth. In particular, we show that this technique allows direct measurements of the diffusivity for both inter- and intra-layer transport. Our results explicitly limit the possible role of island break-up, demonstrate the key roles played by nucleation and coarsening in PLD, and place an upper bound on the Ehrlich-Schwoebel (ES) barrier for downhill diffusion

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

Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate

Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments