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Biomedical subjects

T Dawson

Publications and source records attributed to T Dawson.

26 records · Page 2Linked to original sources
PubMed1992

Effect of serum growth factors and phorbol ester on growth and survival of human thyroid epithelial cells expressing mutant ras.

We previously demonstrated a high incidence of ras mutation in thyroid follicular (epithelial) cell neoplasms and showed that expression of mutant ras is a potent mitogenic stimulus for normal human follicular cells in culture. Here we show that induction of cell proliferation in primary follicular cells by a mutant human Ha-ras (val 12) expressed from a retroviral vector was absolutely dependent on the presence of serum growth factors. Induction of DNA synthesis showed partial dependence. Mutant ras-induced growth was also inhibited by exposure to phorbol ester at concentrations sufficient to downregulate protein kinase C. More importantly, we observed an unexpected toxic effect of phorbol ester in this system that was specific to cells expressing mutant ras. This has potential significance both for elucidating the basic mechanism of ras action in epithelial cells and also as a pointer to a novel therapeutic strategy.

Animals↗
PubMed1992

Detection and partial purification of a potent mitogenic factor for human thyroid follicular cells.

Normal adult human thyroid follicular cells have an extremely limited proliferative capacity in vitro. No previously studied mitogen, including thyrotropin (TSH) or epidermal growth factor (EGF), has in our hands resulted in a significant improvement over the 3-4% nuclear [3H]thymidine pulse-labelling index (LI) obtainable with 10% fetal calf serum. Here we report the detection in the conditioned medium from a sub-clone of NIH3T3 fibroblasts of a mitogenic activity capable of increasing this response up to 10-fold, to an LI of over 20%, together with an even greater relative stimulation of mitotic activity. Preliminary characterisation has excluded EGF and TGF alpha, and demonstrated that the activity is bound reversibly by heparin-Sepharose, thus pointing to a member of the heparin-binding fibroblast- or hepatocyte-growth factor families. This material should have wide practical application in facilitating primary culture of follicular cells, and may reveal new mechanisms of stromal-epithelial interaction regulating normal and neoplastic thyroid growth in vivo.

Cell Division↗
PubMed1991

Correlated abnormalities of transforming growth factor-beta 1 response and p53 expression in thyroid epithelial cell transformation.

Using the thyroid follicular cell as a model for multi-stage carcinogenesis, we have investigated the role of two potential negative growth regulators ('anti-oncogenes') in epithelial tumour progression--transforming growth factor-beta 1 (TGF beta 1) and p53. Normal follicular cells, as expected, showed marked growth inhibition in response to TGF beta 1. Adenoma cells were equally inhibited. In contrast, spontaneously and SV40-immortalised follicular cell lines showing features of malignant transformation (notably loss of growth factor dependence) had lost all responsiveness to TGF beta 1, accompanied by a partial loss of its receptors. p53 protein was below detectable limits in normal and in adenoma cells but in contrast very high levels were observed in all three transformed lines. In the SV40-immortalised cells, this was expected in view of the known stabilising effect of the viral large T protein. In the spontaneous line we found strong evidence for point mutation of p53, which is known to have the same effect. Both mechanisms result in loss of p53 tumour suppressor function despite increased protein content. We conclude that loss of inhibition by TGF beta and inactivation of p53 are important steps in in vitro immortalisation and/or in vivo tumour progression in human thyroid follicular cells, and speculate that p53 may mediate or be required for the inhibitory signal normally induced by TGF beta 1.

Adenoma↗
PubMed1990

Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds.

Fifty-four patients with ovarian cancer who achieved a complete or partial remission with cisplatin or carboplatin were rechallenged with the same drug or crossed over to the other platinum compound at relapse. Fifteen of 43 (35%) crossover patients and 1/11 (9%) rechallenged patients responded; the difference was not significant and there was no difference in survival between the two groups. Responders survived significantly longer than nonresponders (P = 0.001) but there was no survival difference between those who responded to a rechallenge and those who responded to crossing over to the other platinum compound. The progression-free interval between the end of initial treatment and relapse was a significant prognostic factor for response to treatment and survival; 17% (6/35) of patients who relapsed before 18 months responded as compared to 53% (10/19) who relapsed after 18 months (P = 0.006) and median survival was 221 and 486 days, respectively, for these two groups (P = 0.026).

Antineoplastic Agents↗
PubMed1989

Cisplatin/carboplatin cross-resistance in ovarian cancer.

Forty-six patients who were treated with cisplatin or carboplatin for ovarian cancer developed resistant disease (no change in measurable disease or progressive disease) and 'crossed over' to the other platinum compound. Three patients (6.5%) responded to this second treatment but these patients had no survival advantage compared to the non-responders. One responder had progressive disease on cisplatin before crossing over to carboplatin.

Adult↗