estramustine and Carcinoma--Small-Cell

Microtubules are one of the major filament of the cytoskelton and play a role in various biological functions such as mitosis, cell motility and intracellular transport. Therefore, microtubules are considered one of the most important molecular targets for cancer chemotherapy. Tubulin is one of the major microtubular components, and its polymerization and depolymerization regulate microtubular dynamics. Other microtubular components such as microtubule-associated protein (MAPs), actin, and intermediate and microfilaments have also been demonstrated to be involved in microtubular dynamics. Recent studies provide evidence that the functions of MAPs and filaments in microtubule assembly are regulated by phosphorylation, which is catalyzed by mitogenactivated protein kinase (MAP kinase) and cdc2 kinase. Antimitotic agents that disrupt microtubules can be classified in two categories according to the mechanism of action, vinca alkaloids and taxanes. Vinca alkoloids, estramustine, rhizoxin, and E7010 inhibit microtubule polymerization. In contrast, taxanes such as paclitaxel and docetaxel promote polymerization of microtubules and enhance microtubule stability. We have demonstrated that paclitaxel inhibits the catalytic activity of MAP kinase and cdc2 kinase in lung cancer cell lines. This biological effect may be responsible for the increased affinity between MAP2 and tubulins, resulting in promotion of microtubule assembly. Factors that contribute to the resistance to antimitotic agents include intracellular accumulation of the drugs, genetic or functional alternations in tubulin, and alternations in MAP kinase cascade. Antimitotic agents showed a broad spectrum of preclinical antitumor activity. Clinical trials of taxanes revealed that they were effective for several cancers which were advanced or resistant against other anticancer drugs, especially for breast cancers, ovarian cancers and non-small cell lung cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Small Cell; Drosophila Proteins; Estramustine; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lung Neoplasms; Mice; Microtubules; Ovarian Neoplasms; Paclitaxel; Vinca Alkaloids

A 52-year-old man presented to his urologist with hematuria and symptoms of frequency and incomplete voiding. The patient received antibiotics without symptom resolution. His prostate-specific antigen (PSA) level was 6.6 ng/ml and digital rectal examination revealed a normal-sized firm prostate gland. Biopsy obtained by transurethral resection revealed poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features. Pure small-cell cancer or poorly differentiated prostate cancer may secrete little or no PSA. One should be alerted to this phenotype in a patient with large volume disease on biopsy or examination and a low PSA or PSA not in proportion to tumor burden.. Digital rectal examination, laboratory tests, cystoscopy, prostatic chips obtained from transurethral resection, prostate biopsy, bone scan, CT scan of the chest, abdomen and pelvis.. Poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features.. Transurethral resection, androgen blockade with a gonadotropin-releasing hormone analog and antiandrogen flutamide, oral bicalutamide, docetaxel and oral estramustine. Total pelvic exenteration with ileal conduit urinary diversion and permanent end-colostomy formation, percutaneous nephrostomy placement, cisplatin combined with etoposide.

Topics: Adenocarcinoma; Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Docetaxel; Estramustine; Etoposide; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Nephrostomy, Percutaneous; Nitriles; Phenotype; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Tosyl Compounds; Transurethral Resection of Prostate; Urinary Diversion

Estramustine-binding protein has previously been demonstrated in normal rat prostatic tissue, in normal human prostate epithelium, and in prostatic carcinomas. It binds specifically estramustine and estromustine, the cytotoxic metabolites of estramustine phosphate (Estracyt), a drug which is used in the treatment of prostatic carcinoma. In this study we have examined the presence of an estramustine-binding associated protein in a panel of human cell lines, representing the major histopathological types of lung cancer. A mouse (murine) monoclonal antiserum developed against rat estramustine-binding protein was used for immunohistochemical detection. Fast protein liquid chromatography was used for biochemical characterization. As judged from the immunohistochemical investigation, estramustine-binding protein was present in large amounts in five of six non-small cell carcinoma cell lines, while seven of eight small cell carcinoma cell lines were essentially negative. Fast protein liquid chromatography analyses of lysated cells from the lung cancer cell lines, incubated with [3H]estromustine, concurred with the results from the immunohistochemical stainings. These data strongly indicate a convincing connection between the immunoreactivity and ligand-binding properties of estramustine-binding protein in the cell lines examined. The presence of an estramustine-binding associated protein in human lung cancer cell lines has implications for further investigations into the biological relevance and the potential for eventual therapeutic applications.

Topics: Antibodies, Monoclonal; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carrier Proteins; Chromatography, Liquid; Estramustine; Humans; Immunohistochemistry; Lung Neoplasms; Nitrogen Mustard Compounds; Prostatic Secretory Proteins; Tumor Cells, Cultured