Relationship between insulin receptor tyrosine kinase activity and internalization in monocytes of non-insulin-dependent diabetes mellitus patients.

Reduced insulin receptor tyrosine kinase activity and internalization have been reported in non-insulin-dependent diabetes mellitus (NIDDM) patients. To clarify whether in NIDDM the defective internalization is caused by the defective kinase activity, we studied receptor tyrosine kinase activity and internalization in monocytes from eight lean control and six obese subjects and 10 obese NIDDM patients. Receptor internalization was also stimulated by an anti-insulin receptor antibody (MA-10) that is unable to stimulate receptor kinase activity. Basal exogenous tyrosine kinase activity was not different in monocytes from the three groups of subjects. As compared with control subjects (2,690 +/- 637 fmol 32P incorporated), insulin (100 nmol/L)-stimulated tyrosine kinase activity was lower in NIDDM patients (1,262 +/- 318, P < .05), but not in obese subjects (2,640 +/- 731). Basal receptor autophosphorylation did not differ between the three groups, whereas insulin-stimulated autophosphorylation in comparison to that in control subjects was reduced in NIDDM patients (P < .05), but not in obese subjects. In NIDDM patients, receptor internalization induced by both insulin and MA-10, was lower (P < .05) than that in control and obese subjects. No correlation was found between receptor internalization and exogenous tyrosine kinase activity (r = .30, NS) or autophosphorylation (r = .08, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

A study of endometrial adenocarcinoma treated with tamoxifen by scanning and transmission electron microscopy.

By scanning and transmission electron microscopy the Authors studied four cases of endometrial adenocarcinoma (stage I, G1) after 15-days treatment with Tamoxifen (20 mg X 2) before surgery. The ultrastructural findings, similar to those observed in untreated adenocarcinomas but quite different from those obtained in MAP-responsive cases - as other Authors reported too - seem to indicate an almost complete absence of secretory or cytotoxic induction at least as far as 15-days treatment is concerned. According to the Authors this study raises many doubts about the usefulness of a first-instance therapeutical protocol based on Tamoxifen alone. However they believe that Tamoxifen can be utilized combined with a progestational agent in a simultaneous or sequence treatment.

[Behavior of serum sialic acid levels at various stages of neoplastic disease]. / Comportamento del livello sierico dell'acido sialico in momenti diversi della malattia neoplastica.

Serum sialic acid levels were measured at two different stages of neoplasia (active and non-active phases). CEA levels were also assayed at the same time. 98 patients suffering from different neoplastic diseases and a group of healthy controls were studied. Serum sialic acid levels were always significantly higher in the neoplastic patients. When neoplastic disease were divided into active and non-active groups, it was observed that the level of this glycoprotein was specific in the non-active (NA) phase only for breast tumours and lymphomas. Correlation with CEA levels was also significant in these cases. It is concluded that serum sialic acid assay may be useful only for melanomas, breast tumours and lymphomas where the level of this membrane protein undergoes significant changes according to the stage of the tumour.

The treatment of recurrent and metastatic cervical carcinoma. Evaluation of an antiblastic combination of methotrexate-adriamycin-bleomycin (MAB).

Thirty patients with local recurrent and/or distant metastatic cervical carcinoma were treated by combined chemotherapy with methotrexate, adriamycin and bleomycin (MAB). Among the 25 evaluable patients 1 CR (4%), 5 PR (20%), 9 SD (36%) and 10 PD (40%) were obtained. A high incidence of cardiotoxicity (20%) and alopecia (32%) was observed. Both phenomena are linked to the anthracyclinic component of the regimen. As the results are not better than those reported by using only methotrexate and bleomycin, the authors did not find it useful to insert adriamycin in this regimen.

Endocytosis, recycling, and degradation of the insulin receptor. Studies with monoclonal antireceptor antibodies that do not activate receptor kinase.

The endocytosis, recycling, and degradation of the insulin receptor were studied in IM-9 cells and U-937 cells by employing two monoclonal antibodies directed at the alpha subunit of the human insulin receptor, antibodies MA-5 and MA-10. Antibody MA-5 is an insulin agonist and MA-10 is an insulin antagonist (Forsayeth, J., Caro, J.F., Sinha, M.K., Maddux, B.A., and Goldfine, I.D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3448-3451). Both monoclonal antibodies, like insulin, induced the endocytosis of the insulin receptor within 15 min. Upon removal of extracellular ligand the internalized receptor recycled to the cell surface. At this time there was no degradation of the receptor as measured by a sensitive insulin receptor radioimmunoassay. After 20 h of incubation, insulin and MA-5, but not MA-10, induced significant receptor degradation as measured by both insulin receptor radioimmunoassay and metabolic labeling studies. These studies demonstrated, therefore, that: 1) internalization and recycling of the receptor can be induced by antireceptor monoclonal antibodies that are either insulin agonists or insulin antagonists; 2) enhanced receptor degradation can be induced by monoclonal antibodies that are insulin agonists; and 3) the process of receptor internalization does not necessarily lead to enhanced receptor degradation. Since prior studies have indicated that neither MA-5 nor MA-10 enhance insulin receptor kinase activity, the present studies also suggest that insulin receptor endocytosis and degradation induced by ligands different than insulin can occur without activation of this process.