Significance of erb-B2 immunoreactivity in cervical cancer.

C-erbB2 is over-expressed or amplified in many carcinomas. We assessed the relationship between erb-B2 immunoreactivity, and its predictive role in progression-free survival and treatment outcome in patients with cervical carcinoma. Sections from 65 cervical carcinoma were immunostained with antibody to p185 erbB2. Immunoreactive ErbB2 was found in 25 patients (38%) [+ 15 pts. (23%); ++ 10 pts. (15%)]. There were no correlation with age, performance status, grading and histology. Erb-B2 immunoreactivity significantly correlated with stage of the disease. Positive immunoreactivity was found in 63%, 44%, 14% and 0% of stage I, II, III and IV carcinomas, (p = 0.0045). Progression-free survival was longer in erb-B2 positive patients without reaching significance. No correlation was found between erbB2 and response to radiotherapy or chemotherapy. In conclusion, a significant proportion of stage I and II cervical cancer express erb-B2 compared to more advanced stages. Expression of the oncogene does not appear to be related to prognosis or treatment outcome.

Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors.

Fifteen analogues of the C-terminal CA1A2X motif were synthesized and evaluated for their inhibition potency against farnesyltransferase (FTase). Replacement of the A2 residue by phenylalanine or tyrosine-derived analogues, in which a different number of methyl groups were introduced on the aromatic ring, resulted in compounds less active than the reference compound CVFM against FTase except for compounds I and VI (IC50=1 microM and 2.5 microM, respectively) that were comparable to CVFM and compound IV (IC50=0.1 microM), which was 6-fold more active than the reference compound. Because pseudopeptidic derivatives I-IX were inactive in the cellular assays, the N-formyl- and methyl-ester derivatives (compounds X-XV) were synthesized and tested on different cell lines, showing, in some cases, activity and appreciable selectivity against transformed cells. To rationalize the obtained results, molecular modeling experiments were carried out suggesting the molecular basis of FTase inhibition by these products.

Synthesis and cytotoxic evaluation of novel spirohydantoin derivatives of the dihydrothieno[2,3-b]naphtho-4,9-dione system.

The synthesis and cytotoxic evaluation of 3-(alkyl)(alkyl-substituted)spiro[(dihydroimidazo-2,4-dione)-5,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)]derivatives are described. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines uncovered for most of the compounds a cytotoxic potency comparable to or greater than that of doxorubicin. Compound 15 exhibited remarkable cytotoxic activity against several other human solid tumor cell lines. Interestingly, only a partial cross-resistance to compound 15 in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx) was observed, whereas a total absence of cross-resistance in a tumor cell subline selected for resistance to cisplatin was found (A2780/DDP).

Thymosin beta-10 gene expression as a possible tool in diagnosis of thyroid neoplasias.

Overexpression of thymosin beta-10 (TB10) has been shown in rat thyroid transformed cell lines, and in human thyroid carcinoma tissues and cell lines. To investigate whether TB10 detection could be a valid tool in the diagnosis of human thyroid neoplasias, we extended the analysis of TB10 expression to a large number of thyroid hyperproliferative and neoplastic tissues using an immunohistochemical assay. Our analyses showed a TB10 positive staining in all human thyroid carcinomas particularly in the anaplastic histotypes, whereas no TB10 immunostaining was observed in normal thyroid, in adenomas and the majority of the goiters. These results suggest that the evaluation of TB10 gene expression may be considered a promising means of diagnosis of human thyroid hyperproliferative disorders.

Thymosin beta-10 protein synthesis suppression reduces the growth of human thyroid carcinoma cells in semisolid medium.

Beta-thymosins are structurally related, highly conserved acidic polypeptides, originally isolated from calf thymus. We have recently shown that the TB10 gene is overexpressed in human thyroid carcinoma cell lines and tissues, particularly in undifferentiated thyroid carcinomas, but expressed at an undetectable level in normal thyroid cells. The precise role of thymosin beta-10 (TB10) activity in maintaining the malignant phenotype of thyroid cell lines is unknown. To investigate TB10 function and relevance in a model system we used an antisense methodology to suppress TB10 protein synthesis in two human thyroid carcinoma cell lines (NPA and ARO). The growth in soft agar of NPA and ARO cells carrying a TB10 construct in an antisense orientation was significantly reduced. Conversely, anchorage-dependent growth was unchanged in NPA and ARO cells carrying the TB10 construct in a sense orientation or carrying the backbone vector. TB10 expression also affected actin organization. In fact, stress fibers were long and thick in ARO cells in which TB10 expression was suppressed by the antisense construct. Conversely, they were scarce and short in the vector-transfected ARO cells. These data suggest that TB10 plays a critical role in the regulation of anchorage-independent growth and assembly of actin filaments.