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Biomedical subjects

S A Watson

Publications and source records attributed to S A Watson.

At least 73 records · Page 4Linked to original sources
PubMed1993

A hepatic invasive human colorectal xenograft model.

A hepatic invasive human colorectal xenograft model was derived in nude mice by selection through the liver of the parental cell line, C170. Following intraperitoneal injection, tumours selectively grew on the liver in > 80% of the animals within 15-20 days. The liver-invading xenograft line, renamed C170HM2, had a significantly greater expression of the Lewisx antigen compared to C170 (mean linear fluorescence per cell > 1000 compared with 500 for C170, P < 0.02). C170HM2 had significantly elevated proliferation (when compared with C170) in the presence of epidermal (P < 0.001) and basic fibroblast growth factor (P < 0.001). C170HM2 also mitogenically responded to type I collagen (derived from rat tails), unlike C170. C170HM2 tumours when invading the liver expressed both interstitial collagenase and gelatinase activity at the invading edge.

Animals↗
PubMed1993

Gastrin antagonists in the treatment of gastric cancer.

The polypeptide hormone, gastrin, is known to promote both the in vitro and in vivo growth of human gastric cancer. This proliferative activity has been shown to be mediated by high affinity, membrane-associated receptors. This has led to the development of agents with the ability to antagonise gastrin receptor binding, which have been evaluated for their potential clinical value. Other anti-gastrin therapies have been investigated. As gastrin may act as an autocrine mediator of gastric tumor cell proliferation, anti-secretory agents have been evaluated, as have agents which induce the production of neutralising anti-gastrin antibodies in situ.

Animals↗
PubMed1993

Effect of histamine on the growth of human gastrointestinal tumours: reversal by cimetidine.

The proliferative effects of histamine were examined on the human gastric tumour cell lines; MKN45, the gastrin producing subline, MKN45G, and the colorectal lines; LoVo and C170. The proliferation of MKN45 as assessed by 75[Se] selenomethionine uptake and cell counts was increased by histamine concentrations of 10(-7) and 10(-9) M. Histamine concentrations between 10(-6) and 10(-7) M maximally stimulated MKN45G proliferation which titrated out at lower histamine concentrations. The accumulation of cyclic adenosine 3',5' monophosphate (cAMP) in response to the same histamine concentrations was also increased in the two gastric cell lines. The histamine receptor antagonist, cimetidine (10(-5) M) reversed the histamine stimulated proliferation of both gastric cell lines despite having no effect on basal growth. The proliferation of the colorectal lines was unaffected by histamine. Histamine given locally at the subcutaneous implantation site of the tumour (1 mg/kg/day) increased the growth of MKN45G xenografts in nude mice. This was reversed by coadministration of cimetidine (100 mg/kg/day, given in the drinking water). Cimetidine also inhibited the basal proliferation of MKN45 xenografts. Histamine acting locally may enhance the proliferation of tumours arising within the stomach. Such effects may be blocked by administration of histamine receptor antagonists, such as cimetidine.

Animals↗
PubMed1992

Inhibition of gastrin-stimulated growth of gastrointestinal tumour cells by octreotide and the gastrin/cholecystokinin receptor antagonists, proglumide and lorglumide.

The rat pancreatic cell line, AR42J possessed high-affinity gastrin and somatostatin receptors and its growth was stimulated by physiological gastrin-17 concentrations between 5 x 10(-11) mol/l and 10(-9) mol/l as measured by [75Se]selenomethionine uptake. The somatostatin analogue, octreotide (2 x 10(-7) to 2 x 10(-11) mol/l), reduced this stimulated growth. Gastrin-stimulated AR42J growth was also inhibited by proglumide (3 x 10(-4) mol/l) and lorglumide (3 x 10(-5) mol/l) at maximal G17 concentrations of 5 x 10(-11) and 10(-10) mol/l, respectively, and the analogues competed with [125I] gastrin-17 (5 x 10(-10) mol/l) for binding to gastrin receptors on AR42J (50% inhibitory concentrations, less than or equal to 10(-3) mol/l and 4 x 10(-6) mol/l, respectively. Octreotide reduced the basal growth of the human gastric cell line, MKN45G, (which is associated with intracellular gastrin immunoreactivity) in serum-free medium to 73% of control at a concentration of 2 x 10(-8) mol/l, which was reversed by gastrin-17 (10(-10) mol/l). Lorglumide (3 x 10(-5) mol/l) also reduced the basal growth to 30% of control, which was reversed to 78% by 10(-5) mol/l gastrin. Proglumide had no effect on the basal growth of MKN45G.

Animals↗
PubMed1992

Therapeutic effect of the gastrin receptor antagonist, CR2093 on gastrointestinal tumour cell growth.

The gastrin receptor antagonist, CR2093, competed with 125I-gastrin-17 (5 x 10(-10) M) for binding to gastrin receptors on the rat pancreatic adenocarcinoma, AR42J (CR2093 concentration inducing 50% of 125I-gastrin-17 binding (IC50) was 8 x 10(-5) M), on the human gastric adenocarcinoma, MKN45 (IC50 5.5 x 10(-5) M) and the human colo-rectal adenocarcinoma C523 (IC50 greater than 10(-4) M). Intravenous administration of CR2093 (40 mg kg-1 day-1) reduced the gastrin-17 stimulated growth of AR42J xenografts in nude mice to below that of the original basal growth (P = 0.0166 from basal and P = 0.0109 from gastrin stimulated growth). CR2093 administration also reduced the gastrin-stimulated growth of MKN45 xenografts (P = 0.045) but failed to inhibit the gastrin enhanced proliferation of C523 xenografts. This may be related to the affinity (Kd) of the gastrin receptors present on the xenograft lines as the Kds of the two xenografts inhibited by CR2093 were 4.6 x 10(-10) M (AR42J) and 1.2 x 10(-9) M (MKN45) respectively whereas the Kd of C523 was of higher affinity (2.2 x 10(-10) M). GR antagonists may be a viable therapeutic option for gastrin receptor positive, gastro-intestinal tumours.

Amino Acids↗
PubMed1991

Intracellular gastrin in human gastrointestinal tumor cells.

Flow cytometry and immunohistochemical analyses of the human gastric adenocarcinoma cell line MKN45G identified an intracellular peptide recognized by an anti-gastrin-17 (G17) antiserum but not by an anti-cholecystokinin-specific antiserum. Staining was not associated with the parental line MKN45, of which MKN45G is a clonal variant. The MKN45G cell line had elevated in vitro growth in serum-free medium in which the proliferation of MKN45G cells but not MKN45 cells was reduced to 58% of the control value by treatment with a rabbit anti-G17 antiserum. This inhibition of proliferation was reversed by preabsorbing the antiserum with excess G17. Disaggregated primary human gastric and colorectal tumors were screened for gastrin immunoreactivity by flow cytometry, and 6 of 28 colorectal and 8 of 22 gastric tumors had greater than 20% positively staining cells.

Adenocarcinoma↗
PubMed1991

Co-stimulation of gastrointestinal tumour cell growth by gastrin, transforming growth factor alpha and insulin like growth factor-I.

Epidermal growth factor receptors and insulin like growth factor-I receptors were co-expressed on two gastric and three colorectal tumour cell lines. Previous studies have shown that gastrin receptors were also expressed at a low level or two of these cell lines. Both TGF alpha and IGF-I promoted cell growth in all of the cell lines tested. The cell doubling time of a colorectal cell line was reduced from 48 to 30-34 h. Furthermore the effects of the growth factors were additive. Each growth factor also increased the response of the cells to gastrin, but a combination of both growth factors and gastrin did not further increase growth.

Cell Division↗
PubMed1991

The effect of long acting somatostatin analogue SMS 201.995 therapy on tumour kinetic measurements and serum tumour marker concentrations in primary rectal cancer.

Twelve patients with rectal carcinoma were treated for 2 weeks with the somatostatin analogue SMS 201.995. Effects of this therapy were assessed using serum marker concentration, Ki67 and gastrin-immunoreactivity of the primary tumour. In four out of 12 patients, a significant decrease in Ki67 immunoreactivity was seen during SMS 201.995 treatment while in the remaining eight patients there was no significant change in Ki67 expression. Four patients had elevated pretreatment serum carcinoembryonic antigen (CEA) levels. In two of these four patients, serum CEA levels fell modestly during SMS 201.995 therapy. This is the first clinical evidence that a somatostatin analogue can inhibit the growth of some colorectal cancers.

Adenocarcinoma↗
PubMed1990

The effect of the E2 prostaglandin enprostil, and the somatostatin analogue SMS 201 995, on the growth of a human gastric cell line, MKN45G.

The effect of enprostil and the somatostatin analogue SMS 201 995 on the growth of a clonal variant of the human gastric adenocarcinoma cell line, MKN45, was studied. The derived cell line grew twice as fast as MKN45 when grown as a xenograft line in nude mice. However, it did not respond trophically to gastrin either in vitro or in vivo (unlike MKN45) although it possessed the same number of gastrin receptors as the parental line. Gastrin production by the cell line during in vitro culture was twice that of MKN45; thus, the cell line was denoted MKN45G. When MKN45G was grown as xenografts in nude mice (n = 10/group), enprostil (20 micrograms/kg/day) significantly inhibited tumour growth when administered continuously by an osmotic mini-pump from day 1 to day 7 of a 20-day experiment, and induced tumour regression when administered from day 7 to day 14. Enprostil reduced postprandial serum gastrin levels when administered from day 7 to day 14 and prevented gastrin release by MKN45 in vitro. SMS 201 995 at doses of 25 and 240 micrograms/kg/day induced tumour regression when administered from day 1 to day 7 and the former dose reduced post-prandial serum gastrin levels at day 5. Gastrin release by MKN45G was not affected by SMS 201 995 in vitro, thus its effect may not be mediated directly via gastrin, requiring interaction between other hormones or growth factors in the in vivo situation.

Adenocarcinoma↗
PubMed1990

An open multicentre study of the efficacy and safety of a single dose of fluconazole 150 mg in the treatment of vaginal candidiasis in general practice.

The efficacy and tolerability of fluconazole given as a single oral dose of 150 mg were assessed in 1,017 patients in general practice presenting with signs and symptoms of vaginal candidiasis. At the review visit 7-14 days after treatment, about 95 per cent of patients reported being either cured or improved. High vaginal swabs taken from 43 patients out of 50 who failed following treatment revealed Candida albicans in 17 (1.8 per cent). Efficacy in patients with predisposing factors (oral contraceptives, antibiotics and recurrent vaginal candidiasis - four episodes or more in previous year) was not significantly different from that in those without these factors. Of patients who had received previous intravaginal therapy for vaginal candidiasis, 88 per cent preferred fluconazole, 10 per cent previous therapy and two per cent had no preference. Investigators assessed efficacy after fluconazole as excellent or good in 91 per cent and tolerability as excellent or good in 91 per cent of patients. Significant adverse effects were reported in less than one per cent of patients.

Administration, Oral↗
PubMed1990

Postnatal development of the hair cycle in the domestic pig.

The postnatal patterns of hair follicle activity have been quantified in pigs born in summer and winter. Animals were skin sampled monthly during the first year of life and the stages of the hair cycle were identified from follicles in histological sections. Percentages of active follicles were used to determine hair cycle patterns and as a measure of how the hair cycle became synchronised with that of the adult. At birth, in excess of 95% of follicles were active in fibre production. Within the first 12 weeks of life, the proportions of active follicles were found to approach those found in adult skin, and thereafter the hair follicle population of the growing pig displayed cycles of activity and rest reminiscent of those of the mature animal.

Aging↗
PubMed1989

The in vitro growth response of primary human colorectal and gastric cancer cells to gastrin.

A series of 31 colorectal and 13 gastric primary human tumours were screened for their growth response to human gastrin-17 in vitro, as assessed by 75Se-seleno-methionine incorporation. Fifty-five percent of colorectal and 69% of gastric tumours showed a significant trophic response to the hormone. The responses were achieved at physiological gastrin concentrations (post-prandial circulating gastrin levels) in 35% of colorectal and 55% of gastric tumours. Lymphocytes from tumour-associated lymph nodes showed no response to the hormone and "normal" mucosal cells (obtained from the resection margin of the surgical specimen) showed lower mean levels of 75Se-seleno-methionine uptake (colorectal: 110%; gastric: 119%, expressed as a percentage of the control) when compared to tumours (colorectal: 151%; gastric: 147%). The small number of well differentiated and/or Dukes' stage A colorectal tumours examined were gastrin-responsive, but all the responsive gastric tumours were poorly differentiated. With respect to ploidy, 89% of diploid and 67% of aneuploid colorectal tumours responded trophically to gastrin. Patients with colorectal or gastric tumours may benefit from treatment with gastrin antagonists.

Animals↗
PubMed1988

Growth-promoting action of gastrin on human colonic and gastric tumour cells cultured in vitro.

The gastrointestinal hormone, gastrin, was examined for its trophic effect on the growth of colorectal and gastric tumour cells. All of the freshly disaggregated colorectal and gastric human adenocarcinomas responded to pentagastrin in 24 h cultures in vitro. Two newly established adenocarcinoma cell lines showed a response to pentagastrin at passage 2 but not at passage 6. Long-established cell lines did not respond to pentagastrin; however, upon synchronization of the human gastric cell line, MKN45, a trophic growth response with gastrin-17 was observed. This response was enhanced when the same cell line was grown as a xenograft in nude mice and then examined in vitro for gastrin dependence; this dependence was gradually reduced on further in vitro passaging. These results indicate that trophic responses to gastrin are lost during in vitro culture and may be underestimated by using long-established tumour cell lines. However, as all of the early cultures of colorectal and gastric tumours respond trophically to gastrin, perhaps gastrin-receptor blockers may be an important therapeutic modality for these patients.

Adenocarcinoma↗
PubMed1986

Epikeratophakia following previous refractive keratoplasty surgery: two case reports.

Epikeratophakia is becoming a significant and worthwhile surgical modality for selected cases of pediatric and adult aphakia, keratoconus, and myopia. Ultimately, it may also provide a safe and effective means of obtaining satisfactory surgical correction when the results from a previous refractive technique are insufficient. We present two successful cases of epikeratophakia following refractive keratoplasty: one following radial keratotomy for myopia and one following penetrating keratoplasty for keratoconus.

Adult↗