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T Sethi

Publications and source records attributed to T Sethi.

34 records · Page 2Linked to original sources
PubMed1996

Replacement of hairpin and loop implants by optimised straight line sources.

Remote after loading is desirable for all forms of brachytherapy but is difficult in the oral cavity because the tight curvature at the top of implanted loops impedes passage of the source. For this reason we investigated differential loading of straight catheters to simulate a conventional loop or hairpin. Using a pulsed brachytherapy remote after loader the top four dwell positions of straight catheters were given two to four times the dwell time of other source positions. This raised the reference isodose to cover the surface mucosa without significantly changing either the total volume treated or the volume receiving > 150% of reference dose when compared with conventional loop implants of equivalent source length and separation. This optimised straight line implant should therefore be amenable to remote afterloading and have similar dose/volume characteristics to loops.

Brachytherapy↗
PubMed1996

Neuropeptides stimulate tyrosine phosphorylation and tyrosine kinase activity in small cell lung cancer cell lines.

Stimulation of small cell lung cancer (SCLC) cells with neuropeptides bombesin, bradykinin, gastrin, and neurotensin resulted in increased tyrosine kinase activity and tyrosine phosphorylation of a number of polypeptides including a p120 kDa polypeptide identified by immunoblotting as focal adhesion kinase (p125FAK). The neuropeptides stimulated a rapid, concentration-dependent phosphorylation of p125FAK (EC50 of 1 nM, 5 nM, and 2 nM for bombesin, bradykinin, and gastrin, respectively), which was receptor mediated and inhibited by both specific and broad-spectrum neuropeptide receptor antagonists. Specific inhibition of protein tyrosine kinase activity by tyrphostin-25 inhibited both basal and neuropeptide-stimulated SCLC cell growth. These results identify a novel neuropeptide-stimulated growth signaling event in SCLC cells.

Bombesin↗
PubMed1993

CCKA and CCKB receptors are expressed in small cell lung cancer lines and mediate Ca2+ mobilization and clonal growth.

Gastrin, cholecystokinin (CCK), and CCK-related peptides comprise a hormonal family characterized by an identical carboxy-terminal amino acid sequence, a domain critical for receptor binding. The addition of gastrin to small cell lung cancer (SCLC) cells causes a rapid and transient increase in the intracellular concentration of calcium ([Ca2+]i). Furthermore, gastrin acts as a direct growth factor through CCKB/gastrin receptors. We report here that the expression of the mRNA coding for CCKB/gastrin receptors correlates with the responsiveness of SCLC cells to gastrin in terms of Ca2+ mobilization and stimulation of clonal growth in semisolid medium. The GLC19 SCLC cell line had no detectable expression of CCKB/gastrin receptor mRNA. Accordingly, gastrin (1-100 nM) did not cause any measurable increase in [Ca2+]i. In contrast, the addition of cholecystokinin residues 26-33 (CCK-8) caused a rapid and transient increase in [Ca2+]i in this cell line. CCK-8 mobilized Ca2+ in a dose-dependent manner in the nanomolar range (half-maximal stimulatory concentration = 12 nM). Furthermore, the selective CCKA antagonist CAM-1481 inhibited the increase in [Ca2+]i induced by CCK-8 (half-maximal inhibitory concentration = 3 nM) in GLC19 but not in H510 cells. The selective CCKB/gastrin antagonist blocked the increase in [Ca2+]i induced by CCK-8 (half-maximal inhibitory concentration = 80 pM) in H510 but not in GLC19 cells. Thus, the effects of CCK-8 are mediated through CCKA receptors in GLC19 cells and via CCKB/gastrin receptors in H510 cells. CCK-8 markedly stimulated colony formation in GLC19 cells in a dose-dependent manner in the nanomolar range, whereas over the same concentration range, gastrin had no effect on clonal growth. CAM-1481 inhibited the CCK-stimulated colony formation in GLC19 but not in H510 cells. Our results show, for the first time, that CCKA receptors can mediate Ca2+ mobilization and growth in SCLC cells and that SCLC cells express two distinct functional CCK receptor subtypes.

Amino Acid Sequence↗
PubMed1992

Gastrin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer cells.

Gastrin has been postulated to be a physiological growth factor, but compelling in vitro evidence of this has been difficult to obtain. In the present study we investigated whether small cell lung carcinoma cell lines could provide a useful model system to study the effects of gastrin on signal transduction and cell proliferation in vitro. We found that the addition of gastrin to small cell lung cancer cells loaded with the fluorescent Ca2+ indicator fura 2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. The [Ca2+]i response was especially prominent in the small cell lung carcinoma cell line H510. In this cell line, gastrin I, gastrin II, cholecystokinin residues 26-33 (CCK-8), and unsulfated CCK-8 increased [Ca2+]i in a concentration-dependent fashion with half-maximum effects at 7, 2.5, 3, and 5 nM, respectively. The Ca(2+)-mobilizing effects of gastrin and CCK-8 were prevented by proglumide, benzotript, and the specific gastrin/CCKB receptor antagonist L365260. Gastrin stimulated the clonal growth of H510 cells in semisolid (agarose-containing) medium, increasing both the number and the size of the colonies. Gastrin and CCK agonists were equally effective in promoting clonal growth. The broad-spectrum neuropeptide antagonists [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P and [Arg6,D-Trp7,9,MePhe8] substance P (6-11) markedly inhibited gastrin-stimulated Ca2+ mobilization and clonal growth. These results show that gastrin acts as a direct growth factor through gastrin/CCKB receptors and demonstrate, for the first time, that these peptides can stimulate the proliferation of cells outside the gastrointestinal tract.

Benzamides↗
PubMed1992

Broad spectrum neuropeptide antagonists inhibit the growth of small cell lung cancer in vivo.

The proliferation of small cell lung cancer (SCLC) cells appears sustained by multiple autocrine and paracrine circuits involving Ca2+ mobilizing neuropeptides. Consequently, broad spectrum neuropeptide antagonists which inhibit SCLC growth in vitro have been suggested as potential anticancer agents. Here we evaluated this hypothesis using xenografts of WX322 cells, a SCLC cell line that responds to multiple Ca2+ mobilizing neuropeptides. The broad spectrum neuropeptide antagonists [Arg6,D-Trp7,9,MePhe8]substance P(6-11) and [D-Arg1,D-Phe5,Trp7,9Leu11[substance P were shown to inhibit the growth of WX322 xenografts in nude mice. Similar results were obtained with xenografts of the SCLC cell line H69. The results indicate that broad spectrum neuropeptide antagonists can inhibit the growth of SCLC in vivo and suggest that these antagonists could be useful in the treatment of SCLC.

Animals↗
PubMed1992

Growth of small cell lung cancer cells: stimulation by multiple neuropeptides and inhibition by broad spectrum antagonists in vitro and in vivo.

Neuropeptides are increasingly implicated in the control of cell proliferation and their mechanisms of action are attracting intense interest. The early complex cascade of events initiated by peptides of the bombesin family including gastrin-releasing peptide is increasingly understood. The cause-effect relationships and temporal organization of these early signals and molecular events provide a paradigm for the study of other growth factors and mitogenic neuropeptides and illustrate the activation and interaction of a variety of signaling pathways. These peptides may also act as autocrine growth factors for certain small cell lung cancer cells. The results discussed here strongly suggest that the autocrine growth loop of bombesin-like peptides may be only a part of an extensive network of autocrine and paracrine interactions involving a variety of Ca(2+)-mobilizing neuropeptides in small cell lung cancer including bradykinin, cholecystokinin, galanin, neurotensin, and vasopressin. In this context, broad spectrum antagonists that prevent the function of multiple Ca(2+)-mobilizing receptors are of special interest. These antagonists block neuropeptide mediated signals and inhibit small cell lung cancer growth in vitro and in vivo. Thus, broad spectrum neuropeptide antagonists constitute potential anticancer agents.

Amino Acid Sequence↗
PubMed1992

Radiation therapy of esophageal cancer: role of high dose rate brachytherapy.

Fifty untreated cases of squamous cell carcinoma arising from the middle one-third of the esophagus, with no apparent extraesophageal spread on a computed tomography (CT) scan and with a Karnofsky performance status of over 70, were treated by external beam irradiation to a dose of 3500 cGy/15 fractions/3 weeks. Twenty-five patients (Group A) received treatment with further external beam irradiation to a dose of 2000 cGy/10 fractions/2 weeks. Another group of 25 patients (Group B) received treatment with high dose rate intracavitary irradiation to a dose of 1200 cGy delivered in two sessions of 600 cGy each a week apart. All patients were assessed symptomatically, endoscopically, and radiologically every 3 months. There was marked difference at the end of 1 year in relief of dysphagia (37.5% in Group A vs. 70.6% in Group B), local control (25% in group A vs. 70.6% in group B) although the results were statistically insignificant (p greater than 0.05) and actuarial survival (44% in group A vs. 78% in group B) which was, however, significant statistically (z = 2.83). The cumulative radiation effect (CRE) by external beam irradiation was 1729 reu and by external beam and intracavitary irradiation 1741 reu, but the biological dose effect was better with external beam and intracavitary irradiation. Eight percent of patients treated by external beam and intracavitary irradiation had strictures in contrast to 4% treated by external beam irradiation alone. Moderate doses of external beam and intracavitary irradiation can give a better local response than external beam irradiation alone for the same biological dose in the treatment of esophageal carcinoma.

Brachytherapy↗
PubMed1991

Multiple neuropeptides stimulate clonal growth of small cell lung cancer: effects of bradykinin, vasopressin, cholecystokinin, galanin, and neurotensin.

We tested whether Ca(2+)-mobilizing neuropeptides can function as growth factors for small cell lung carcinoma cells. The neuropeptides bradykinin, neurotensin, cholecystokinin, and vasopressin at nanomolar concentrations stimulated a rapid and transient increase in the intracellular concentration of Ca2+. Crucially, these peptides in the same concentration range also caused a marked increase in colony formation in semisolid medium in responsive small cell lung carcinoma cell lines. At optimal concentrations bradykinin, neurotensin, cholecystokinin, vasopressin, galanin, and gastrin-releasing peptide were equally effective in promoting clonal growth. These findings support the hypothesis that small cell lung carcinoma growth is sustained by an extensive network of autocrine and paracrine interactions involving multiple neuropeptides.

Bradykinin↗
PubMed1991

Galanin stimulates Ca2+ mobilization, inositol phosphate accumulation, and clonal growth in small cell lung cancer cells.

Addition of the neuropeptide galanin to small cell lung cancer (SCLC) cells loaded with the fluorescent Ca2+ indicator fura-2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. Galanin increased [Ca2+]i in a concentration-dependent fashion with half-maximum effect (EC50) at 20-22 nM in H69 and H510 SCLC cells. Galanin mobilized Ca2+ from intracellular stores since its effects on [Ca2+]i were not blocked by chelation of extracellular Ca2+. Pretreatment with pertussis toxin (200 ng/ml for 4 h) did not prevent galanin-induced Ca2+ mobilization. In contrast, direct activation of protein kinase C with phorbol esters attenuated the Ca2+ response induced by galanin. The effects of galanin could be dissociated from changes in membrane potential: galanin did not increase membrane potential in SCLC cells loaded with bis(1,3-diethyltiobarbiturate)-trimethineoxonol and induced Ca2+ mobilization in depolarized SCLC cells, i.e., in cells suspended in a solution containing 145 mM K+ instead of Na+. Galanin also caused an increase in the formation of inositol phosphates in a time- and dose-dependent manner (EC50 10 nM). A rapid increase in the inositol trisphosphate fraction was followed by a slower increase in the inositol monophosphate fraction. Galanin stimulated clonal growth of both H69 and H510 cells in semisolid (agarose-containing) medium. This growth-promoting effect was sharply dependent on galanin concentration (EC50 20 nM) and markedly inhibited by [Arg6,D-Trp7,9,MePhe8]substance P, a recently identified broad spectrum neuropeptide antagonist. The results show for the first time that galanin receptors are coupled to inositol phosphate and [Ca2+]i responses in SCLC cells and, in particular, that this neuropeptide can act as a direct growth factor for these human cancer cells.

Calcium↗
PubMed1988

Characterization of leukotriene B3: comparison of its biological activities with leukotriene B4 and leukotriene B5 in complement receptor enhancement, lysozyme release and chemotaxis of human neutrophils.

1. Leukotriene (LT) B3 was prepared by total chemical synthesis and its identity was confirmed by nuclear magnetic resonance analysis and proton homonuclear plot of connectivities and chemical shift assignments. The effects of LTB3 on complement receptor enhancement, chemotaxis and lysozyme release in human neutrophils (PMN) were compared with those of LTB4 and LTB5. 2. LTB3 and LTB4 elicited a virtually identical dose- and time-dependent enhancement in complement receptors type 1 (CR1) and type 3 (CR3) and release of lysozyme. LTB5 was approximately 100 times less potent than LTB4 in enhancing CR1 and CR3, whereas it was 10,000 times less potent than LTB4 in releasing lysozyme from human PMN. 3. LTB3 and LTB5 were respectively 5- and 100-fold less potent than LTB4 in eliciting chemotaxis. 4. These findings indicate that the pro-inflammatory potential of LTB3 and LTB4 are similar, whereas LTB5 is substantially less potent as an inflammatory mediator. 5. The finding that LTB5 is a weak and partial agonist relative to LTB3 and LTB4 could be due to the rigidity of the C-17-C-18 double bond in LTB5. This may interfere with the active site specificity of LTB5 to a substantial extent. 6. One approach to the development of antagonists to the LTB4 receptor may be to establish a rigid structure in the C-17-C-18 region of the LTB4 molecule.

Chemical Phenomena↗