PubMed Health⌕ Search

Biomedical subjects

F Thomas

Publications and source records attributed to F Thomas.

At least 19 recordsLinked to original sources
PubMed1992

Antitumoral activity of bombesin analogues on small cell lung cancer xenografts: relationship with bombesin receptor expression.

Gastrin releasing peptide (GRP), the human homologue of bombesin (BN), is an autocrine growth factor for small cell lung cancer (SCLC) cells. The synthetic octapeptides [D-cpa1-beta-Leu8-des-Met9]litorin (BIM 26182) and [D-Phe6-Leu13-CH2NH-Cpa14]bombesin(6-14)NH2 (BIM 26189) are potent GRP/BN antagonists of the proliferation of 3T3 and rat pancreas cells. The effect of these analogues on the proliferation of four SCLC cell lines (SCLC 6, SCLC 41, SCLC 75, SCLC 74R) was tested in vitro and in vivo. Two of these SCLC lines (SCLC 41M and SCLC 75) had receptors for BN/GRP and expressed the prepro-GRP mRNA. BIM 26182 and BIM 26189 inhibited [3H]thymidine incorporation into the DNA of SCLC 41 cells, stimulated [3H]thymidine incorporation in SCLC 6, and had no effect on the two other cell lines. The SCLC implanted s.c. in nude mice were treated with either BIM 26182 or BIM 26189. BIM 26182 and BIM 26189 injected at the doses of 50 micrograms twice a day (s.c.) around the tumor for 10 to 21 days delayed the growth of SCLC 41 and of SCLC 75. The maximal effect was observed during the treatment period, after which the tumors regrew, suggesting a cytostatic effect of these peptides. No inhibitory effect of the peptides on SCLC 74R or SCLC 6 growth was observed. These data suggest that GRP antagonists are able to inhibit the in vitro and in vivo growth of BN/GRP receptors-positive SCLC.

Animals↗
PubMed1992

Stimulation of a membrane tyrosine phosphatase activity by somatostatin analogues in rat pancreatic acinar cells.

A phosphoryl protein tyrosine phosphatase (PTPase) activity has been characterized in rat pancreatic acinar membranes using 32P-labeled poly(Glu,Tyr) as substrate. Acinar membranes exhibited a high affinity for the substrate, with an apparent Km of 0.46 microM and an apparent Vmax of 0.9 nmol.mg protein-1.min-1. Acinar membrane PTPase activity displayed specific characteristics of other PTPases; it was inhibited by the inhibitors Zn2+, orthovanadate and by the divalent cations Mn2+ and Mg2+, and was stimulated by the reducing-agent dithiothreitol. It was also inhibited by soybean trypsin inhibitor and stimulated by trypsin. Gel permeation of pancreatic acinar membranes gave a single peak of enzyme activity with an apparent molecular mass of 70 000 Da. Further purification by HPLC on DEAE revealed two peaks of PTPase activity at 120 mM and 180 mM NaCl. These two peaks reacted in a Western-blot procedure with anti-(peptide) serum directed towards conserved domain of PTPase as a common 67-kDa form associated with lower-molecular-mass proteolytic fragments (31-56 kDa). Incubation of pancreatic acini with somatostatin analogues, SMS 201-995 or BIM 23014, resulted in a stimulation of membrane PTPase activity. The stimulation was rapid and transient, with a maximal level reached within 15 min of addition. The two analogs stimulated PTPase activity in a dose-dependent manner with half-maximal activation occurring at 7 pM and 37 pM and maximal activation at 0.1 nM and 0.1-1 nM for SMS 201-995 and BIM 23014, respectively. The stimulated-membrane PTPase activity also eluted at an apparent molecular mass of 70 kDa in gel-permeation chromatography. The two analogs inhibited the binding of [125I-Tyr3]SMS 201-995 to pancreatic acinar membranes with similar relative potencies to that observed on stimulation of PTPase activity. We conclude that pancreatic acinar membranes possess a low-molecular-mass PTPase which is stimulated by somatostatin analogs at concentrations involving activation of membrane somatostatin receptors.

Amino Acid Sequence↗
PubMed1992

Molecular heterogeneity of somatostatin analogue BIM-23014C receptors in human breast carcinoma cells using the chemical cross-linking assay.

Distinct proteins complexed with somatostatin and the somatostatin analogue BIM-23014C were revealed in human breast cancer cells using the cross-linking assay. One BIM-23014C-specific complex (Mr 57,000) was observed in MCF-7 (monolayer, nodule, and tumor) and T47D. Growth inhibition of MCF-7 tumor xenografts by BIM-23014C was dose related in the 6-day subrenal capsule assay. Three complexes (Mr 27,000, 42,000, and 57,000) were detected in MDA-MB-231, and no complex was visible in HBL-100. No correlation was found between receptors for BIM-23014C and epidermal growth factor in these lines. Twenty-seven of 30 human breast tumors (90%) had at least one BIM-23014C receptor. Sixteen had three complexes (Mr 27,000, 42,000, and 57,000). Six had the two complexes (Mr 27,000 and 57,000), two had Mr 42,000 and 57,000 complexes, two had just the Mr 27,000 complex, and one had just the Mr 42,000 complex. The presence of the three BIM-23014C receptors was positively correlated (P less than 0.05) to the low amount of sex steroid receptors (less than 20 fmol/mg) [seven of eight (estrogen receptor negative, progesterone receptor negative) versus four of 14 (estrogen receptor positive, progesterone receptor positive)]. Another positive correlation was established between the absence of progesterone receptors and the presence of these three complexes [12 of 16 (progesterone receptor negative) versus four of 14 (progesterone receptor positive)]. This high percentage of BIM-23014C receptor-positive biopsies and its inhibitory activity would support its clinical potential for the treatment of breast cancer.

Adult↗
PubMed1992

Level and diurnal variations of hormones of interest to the cardiovascular system in patients with heart transplants.

The lack of a nocturnal decrease in blood pressure in cyclosporine-treated cardiac transplant recipients may indicate abnormalities in the mechanism(s) responsible for circadian variability in other physiologic parameters such as in circulating hormones. This possibility was addressed through repeated determinations of circulating catecholamines, neuropeptide Y, pancreatic polypeptide, calcitonin gene-related peptide, plasma renin activity, aldosterone, atrial natriuretic factor and cortisol. The results from 10 patients with heart transplants were compared with those of 12 age-matched, healthy control subjects. Both groups were studied during 24-hour supine rest. There was no difference between patients and control subjects in mean levels of catecholamines, neuropeptide Y, pancreatic polypeptide and aldosterone. Patients had higher levels (+/- SD) of plasma renin activity (6.4 +/- 1.3 vs 2.6 +/- 0.4 ng/ml/hour, p less than 0.001), calcitonin gene-related peptide (47.7 +/- 9.9 vs 33.3 +/- 5.7 pmol/liter, p less than 0.01) and atrial natriuretic factor (93.0 +/- 56.7 vs 20.7 +/- 8.9 pg/ml, p less than 0.001) than control subjects, respectively. Cortisol was not detected in patients. Abnormal diurnal profiles in patients were found for calcitonin gene-related peptide, aldosterone and atrial natriuretic factor, and for pancreatic polypeptide, together with decreased levels, in patients with greater than 6 months follow-up. Except for hormones reflecting sympathetic nervous activity, all hormonal systems studied showed abnormalities in level or circadian rhythmicity, or both. The pancreatic polypeptide results suggest that parasympathetic neuropathy could develop in cyclosporine-treated heart transplant recipients.

Adrenal Cortex Hormones↗
PubMed1992

Therapeutic response to somatostatin analogue, BIM 23014, in metastatic prostatic cancer.

Metastatic prostate cancer is well known to respond to hormonal manipulations, but once progression occurs new treatment modalities are required. Specific and systemic antitumour therapy is preferable to local treatments such as radiotherapy in such patients. The finding that somatostatin analogue, BIM 23014, inhibits prostatic tumour growth in animal models is of great interest. We treated 25 poor risk patients with progressive metastatic prostate cancer. Sixteen had also failed to respond to 'total androgen blockade'. Two patients have achieved a partial remission, one of which is maintained at over 30 months, and three had stable disease for over 6 months. Side effects have consisted of mild diarrhoea and abdominal cramp in the first few days of treatment in a minority of the patients. These results are encouraging and further randomized studies are in progress.

Aged↗
PubMed1992

Phase II study of a combination of elliptinium and vinblastine in metastatic breast cancer.

Thirty nine patients with metastatic breast cancer, all previously treated with chemotherapy including anthracycline, were given Elliptinium acetate (80 mg/m2/day) and a continuous infusion of Vinblastine (2 mg/m2/day) for 3 consecutive days every 4 weeks. Twenty nine patients had measurable metastatic disease. Nine (31%) achieved a partial response. No complete response was observed. Median duration of response was 6 months. The response rate was dependent on the number of metastatic sites and independent of the number of previous chemotherapy regimes. Side effects were dry mouth (27 patients), vomiting (9), neutropenia (3 patients with grade IV, 2 with grade III), muscle cramps (5) and thrombosis (3). Xerostomia and vomiting contributed to weight loss and fatigue (8 patients). We conclude that Elliptinium-Vinblastine combination has moderate activity as second line treatment in metastatic breast cancer. This combination causes xerostomia and fatigue with moderate myelosuppression.

Adult↗
PubMed1992

Acute changes in growth hormone-releasing hormone secretion after injection of BIM 23014, a long acting somatostatin analog, in rams.

BIM 23014 is a somatostatin analog displaying an increased biological half life due to resistance to enzymatic degradation. This peptide inhibits GH release directly at the level of pituitary somatotrophs. In addition, an action of BIM 23014 at the level of the hypothalamus is possible since somatostatinergic fibers and receptors have been identified on GH-RH neurons. To evaluate the effect of BIM 23014 on GH-RH secretion, hypophysial portal blood (HPB) was continuously collected in conscious sheep. Twelve rams (40-45 kg, 9-month-old) with chronically implanted perihypophysial cannulae were i.v. injected with BIM 23014 (1 mg) or saline. HPB and jugular blood were collected for 3-5 hours before and after the injection for the determinations of GH-RH and GH concentrations respectively. The acute injection of BIM 23014 induced a rapid decrease of plasma GH within the first two hours. Simultaneously, GH-RH in HPB decreased significantly. After reaching a nadir, GH concentrations increased to values greater than baseline. A similar rebound in GH-RH levels in HPB was also observed. These data indicate that BIM 23014 acts at the level of GH-RH hypothalamic neurons, in addition to its well-know effect on the pituitary gland.

Animals↗
PubMed1992

De novo splice site mutation in the antithrombin III (AT3) gene causing recurrent venous thrombosis: demonstration of exon skipping by ectopic transcript analysis.

A single basepair substitution at conserved position -1 in the exon 3a donor splice site of the liver-expressed antithrombin III (AT3) gene was detected by PCR/direct sequencing in a patient with sporadic type 1 ATIII deficiency and recurrent venous thrombosis. The lesion, a heterozygous silent AAG----AAA transition at Lys 176 occurred de novo in the proposita. Ectopic transcript analysis of lymphocyte mRNA demonstrated the presence of an abnormally sized mRNA specific to the patient which was shown by cDNA sequencing to lack exon 3a. Oligonucleotide discriminant hybridization demonstrated the absence of any detectable transcript of normal length derived from the disease allele. These findings demonstrate the utility of ectopic transcript analysis in the characterization of defects of mRNA splicing.

Antithrombin III↗
PubMed1992

Prolongation of xenograft survival after combination therapy with 15-deoxyspergualin and total-lymphoid irradiation in the hamster-to-rat cardiac xenograft model.

Adequate immunosuppression remains a major obstacle to successful xenotransplantation, with early xenograft rejection appearing to be mediated by humoral factors. Total-lymphoid irradiation (TLI) and 15-deoxyspergualin (DOSP) have been shown to be effective immunosuppressive agents in allografs. In this study, TLI alone and in combination with DOSP and cyclosporine were evaluated in the hamster-to-rat heterotopic cardiac xenograft model. The animals were divided into four groups: group 1--control (n = 9); group 2--TLI alone, administered pretransplant at 125 cGy/day, four days per week, for three weeks (n = 12); group 3--TLI plus CsA at 10 mg/kg/day (n = 17); and group 4--TLI plus DOSP at 2.5 mg/kg/day (n = 10). Tissue sections were taken from rejected xenografts in all treatment groups for histological examination. Complement-dependent cytotoxicity assays were performed on the control group and also the TLI-DOSP group. The control animals were found to have a mean graft survival of 3.2 +/- 0.4 days. TLI alone (5.8 +/- 0.7 days) did not significantly improve graft survival in comparison with the control group. Combination of TLI with DOSP (26.3 +/- 5.9 days) results in significantly improved survival (P less than 0.05) in comparison with the control, TLI alone, and combination of TLI and CsA (13.6 +/- 8.6 days). Complement-dependent cytotoxicity assays revealed that control groups have low rat antihamster lymphocytotoxic antibody titer (1/1-1/10) prior to xenografting, and that these antibody titers show a precipitous rise to a level of 1/640-1/1280 by day 3, the time at which rejection occurred. This correlates with the histological findings of the rejected hearts showing a severe humoral type of rejection and no evidence of cellular rejection. In contrast, animals in the TLI-DOSP group had markedly lowered rat antihamster lymphocytotoxic antibody titers (1/20-1/40) on day 3, and these titers only increased to 1/160 at time of rejection. This correlates with the histological findings of a lesser degree of humoral rejection in the TLI-DOSP group. Combination therapy with TLI and DOSP results in a marked increase of survival in xenografts in this model not seen with any other drug combination studied in over 500 xenografts in our laboratory. This study indicates that TLI combined with DOSP results in prolonged suppression of the antixenograft antibody response. This combination of agents appears to have the potential to prevent early xenograft rejection.

Animals↗
PubMed1992

The development of a posttransplant TLI treatment strategy that promotes organ allograft acceptance without chronic immunosuppression.

The effectiveness of fractionated TLI in promoting allograft tolerance without chronic drug therapy is well established experimentally. TLI has not been widely applied in clinical transplantation, largely due to logistic and medical limitations of pretransplant TLI conditioning. Potential use of posttransplant TLI (PT-TLI) has not been critically evaluated. In this study we investigated PT-TLI in combination with rabbit antithymocyte globulin (RATG) in the absence of chronic immunosuppressive drugs as a strategy for inducing long-term kidney allograft acceptance. Recipients were studied with and without infusion of DR-CD3- donor bone marrow cells (DBMC). Normal rhesus monkeys, which received no pretransplant treatment, underwent bilateral intrinsic nephrectomy and splenectomy at the time of transplantation. RATG was administered daily for 3-5 consecutive days beginning on day 0. A total dose of 500-625 cGy of fractionated TLI was given in 4-5 treatments at 125 cGy per day beginning on day +1. Whereas neither PT-TLI nor RATG monotherapy induced long-term graft acceptance in splenectomized recipients, the combination of these modalities was remarkable in promoting long-term allograft acceptance without immunosuppressive drug therapy. Of 4 recipients given RATG x 5, splenectomy and PT-TLI, all were free of acute rejection. Of these, 3/4 had graft survivals greater than 100 days, 2/4 were greater than 150 days and 1/4 greater than 365 days. Of 5 recipients given this treatment plus an infusion of DR-CD3-DBMC, 4/5 grafts survived greater than 150 days and 3/5 still have normal functioning grafts at greater than 365 days. PT-TLI accentuated and prolonged changes in PBL subpopulations that were initially affected by RATG. Depressed levels of CD3+ cells were present for 4-5 months, with large numbers of circulating CD4+CD3- and especially CD8+ CD3- cells. In addition, antibody responses to RATG and alloantigens were suppressed in PT-TLI-treated recipients. Overall, the combination of PT-TLI, splenectomy, and RATG was found to be effective in promoting long-term allograft acceptance without chronic immunosuppressive drug therapy. The infusion of DR-CD3- DBMC in recipients treated with PT-TLI, RATG and splenectomy appeared to further increase the incidence of stable long-term survivors. If infectious complications can be improved, this approach may provide a clinically applicable posttransplant treatment strategy for inducing functional allograft tolerance.

Animals↗
PubMed1992

[The role of gastrin releasing peptide as a lung growth factor].

The proliferation of the bronchial epithelium and tumors associated with this tissue is controlled by various growth factors. The main factor is Gastrin Releasing Peptide (GRP), the human counterpart of the amphibian bombesin. These neuropeptides also act as neuromediators and gut hormones. All peptides of this family share a conserved C terminal sequence which is required for biological activity. The determination of this sequence has provided the basis for the design of specific agonist and antagonist peptides and for the generation of monoclonal antibodies (Mab). GRP interacts with a receptor coupled to a G protein and the signalling process leads to the activation of phospholipase C and kinases, and the mobilization of calcium. GRP promotes the proliferation of foetal and adult bronchial epithelium and of small cell lung cancer (SCLC) cells. GRP is also an autocrine growth factor for some SCLC cell lines. The growth of these lines is reduced in vitro and in vivo by MAb and specific antagonists. Hyperplasia of GRP producing cells has been shown in various lung diseases in adults and children. Pharmacological data on GRP suggest that its antagonists could be used in the treatment of SCLC (in addition to chemotherapy) and of interstitial lung disease. The cloning of the GRP receptor should facilitate the design of specific and potent antagonists of the peptide.

Adult↗