estramustine and Lung-Neoplasms

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

Topics: Animals; Cytosol; Dogs; Drug Evaluation, Preclinical; Estradiol; Estramustine; Female; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Nitrogen Mustard Compounds; Receptors, Estrogen; Sex Factors; Uterus

To apply our preclinical findings of cytotoxic synergy with the combination of estramustine phosphate (EP) and docetaxel as the basis of treatment of hormone refractory metastatic prostate cancer in man. To determine the optimal dosage and the toxicities of these two agents for future trials.. Seventeen patients with hormone refractory metastatic prostate cancer who were ambulatory with performance status < or = 2, normal marrow, renal and hepatic function were entered. Prior exposure to EP or a taxane were exclusion factors. EP was given orally at a dose of 14 mg/kg of body weight daily with concurrent docetaxel administered every 21 days as an intravenous infusion over 1 hour with dexamethasone 8 mg. PO BID for five days. EP dosages were kept static; docetaxel dosages were explored in a minimum of three patients per level for dosages of 40, 60, 70, and 80 mg/m2. Patients were evaluated weekly. Prostate specific antigen (PSA) was measured every three weeks.. Five patients were entered at a docetaxel dose of 40 mg/m2, three at 60 mg/m2, six at 70 mg/m2, and three at 80 mg/m2. Only one patient had received prior chemotherapy. Grades 1 or 2 hypocalcemia and hypophosphatemia were seen at all dosage levels. Other grade 2 or less toxicities not related to dosage included alopecia, anorexia, stomatitis, diarrhea, and epigastric pain. Dose limiting toxicities (DLT) as grade 4 leukopenia and grade 4 fatigue were seen at 80 mg/m2. The phase II dose was defined at 70 mg/m2 with rapidly reversible leukopenia and minor liver function abnormalities. At this dosing level, dose intensity was 88% and 86% over consecutive cycles for docetaxel and EP, respectively. Two vascular events occurred at this dose level (70 mg/m2): one arterial and the other venous. PSA decreases greater than 50% from baseline were seen in 14 of 17 patients at all dosage levels. Four of the 17 patients demonstrated a complete biochemical response (PSA < or = 4 ng/ml). One patient had a partial response with measurable lung and liver lesions.. EP given continuously with every three-week docetaxel at a dose of 70 mg/m2 is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Prognosis; Prostatic Neoplasms; Survival Rate; Taxoids; Treatment Outcome

Prostate carcinoma is one of the most frecuent cancers in men. Significant numbers of patients have regional lymph node and bone metastases during the course of the disease. Mediastinal lymphadenopathy and cutaneous metastases are uncommon and signify well-advanced disease. We report the case of a patient with prostate cancer who develops mediastinal lymphadenopathy, pulmonary nodules and cutaneous metastases 8 years after the diagnosis.

Topics: Adenocarcinoma; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cyproterone; Diphosphonates; Estramustine; Fatal Outcome; Flutamide; Humans; Imidazoles; Ketoconazole; Lung Neoplasms; Lymphatic Metastasis; Male; Mediastinum; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Radionuclide Imaging; Skin Neoplasms; Triptorelin Pamoate; Zoledronic Acid

Docetaxel is an effective agent for the treatment of androgen-independent prostate cancer (AIPC). Its combination with estramustine phosphate (EMP) has shown promising results in AIPC but the toxicity remains considerable. In an effort to minimize toxicity, we designed an every-2-week docetaxel administration regimen with a 3-day low-dose EMP regimen. Patients with bone metastases also received zoledronic acid.. A total of 54 patients with AIPC received docetaxel at 45 mg/m2 and EMP (140 mg orally every 8 hours for nine doses) every 2 weeks. Zoledronic acid was administered at 4 mg every 28 days.. Of the 49 assessable patients, 22 (45%, 95% confidence interval [CI] 31% to 60%) had a prostate-specific antigen response. Of 24 patients with measurable disease, 9 (38%, 95% CI 19% to 59%) had a response to therapy (one complete response and eight partial responses). The median time to progression was 4.4 months (95% CI 2.7 to 6), and overall survival was 13.3 months (95% CI 9 to 17.6). Toxicity was mild, with only 5 cases of grade 3 or 4 toxicity. The pain score improved by 1 point in 21 (54%) of 39 symptomatic patients, and 14 (40%) of 38 patients who used analgesics discontinued analgesic consumption by the end of treatment.. The combination of an every-2-week regimen of docetaxel, EMP, and zoledronic acid is an effective, well-tolerated regimen that results in symptomatic improvement in a significant proportion of patients with AIPC.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Alopecia; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Combined Modality Therapy; Diphosphonates; Disease Progression; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Imidazoles; Life Tables; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Proteins; Neutropenia; Orchiectomy; Pain; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, High-Energy; Remission Induction; Survival Analysis; Taxoids; Treatment Outcome; Zoledronic Acid

The subjects for the present study were 270 patients with prostate cancer who underwent initial treatment at our hospital over the 14 years from 1986 to 1999. They were investigated to assess the relationship between their treatment and metachronous tumors. Sixteen patients (5.9%) developed cancer of other organs after starting treatment for prostate cancer. These metachronous tumors included gastric cancer in six patients as well as lung cancer, esophageal cancer, colorectal cancer, liver cancer, renal cancer, bladder cancer, skin cancer, leukemia, and mediastinal adenocarcinoma. Treatment for prostate cancer other than surgery included radiotherapy in eight patients, administration of estramustine phosphate sodium in nine patients, and LH-RH analogues in six patients. The chi-square test showed no significant difference in the incidence of metachronous cancer in relation to the presence/absence of these three therapies. The present study therefore ruled out the possible induction of other tumors by treatment for prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Estramustine; Gonadotropin-Releasing Hormone; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms, Second Primary; Prostatic Neoplasms; Stomach Neoplasms

We used 86Rb+ (K+ analogue) to study potassium influx during the interaction of highly specific 5-HT3-receptor antagonists, ondansetron and granisetron, with the effects of the anticancer drug, estramustine phosphate, on P31 mesothelioma cells. Estramustine phosphate (80 mg/l, 142 micromol/l) for 120 min. reduced 86Rb+ influx by 18.7%. The reduction was inhibited by ondansetron (0.1 micromol/l), but augmented by granisetron (0.1 micromol/l). Serotonin (1.0 micromol/l) antagonized ondansetron inhibition and restored granisetron-augmented reduction of estramustine phosphate-induced 86Rb+ influx to the level of the drug itself. Estramustine phosphate inhibited cellular Na+, K+, 2Cl- -cotransport activity whereas Na+, K+, ATPase activity was unaffected. Ondansetron blockade of estramustine phosphate-induced reduction of 86Rb+ influx was due to increased Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport whereas augmentation of estramustine phosphate-induced reduction of 86Rb+ influx by granisetron, or combination of 5-HT3 receptor antagonists with serotonin was due mainly to inhibition of cellular Na+, K+, ATPase activity Thus, ondansetron possesses a distinct ability to reverse K+ influx of tumour cells exposed to estramustine phosphate whereas granisetron does not, due to different effect on cellular Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport activity. Highly 5-HT3 receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs.

Topics: Antiemetics; Antineoplastic Agents; Biological Transport; Bumetanide; Chlorides; Drug Interactions; Estramustine; Granisetron; Humans; K Cl- Cotransporters; Lung Neoplasms; Mesothelioma; Ondansetron; Ouabain; Potassium; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sodium; Sodium-Potassium-Exchanging ATPase; Symporters; Time Factors; Tumor Cells, Cultured

The time from first diagnosis of primary multiple metastatic prostate carcinoma until progression and until death in patients less than 60 years old under two different therapeutic regimens was evaluated.. In the group with pure androgen deprivation (n = 21), the mean time until progression was 11.3 (6-55) months, the mean survival time being 21.4 (11-75) months. In the group with androgen deprivation plus cytostatic therapy (n = 10), progression was noted after 26.7 (15-77) months with a medium survival time of 26.2 (16-82) months.. The data argue in favor of changing the usual treatment strategy to combination therapy in "young' patients with primary metastatic prostatic cancer.

Topics: Adult; Androgens; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Castration; Cisplatin; Combined Modality Therapy; Doxorubicin; Estramustine; Gonadotropin-Releasing Hormone; Guidelines as Topic; Humans; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Prostatic Neoplasms; Retrospective Studies; World Health Organization

At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, as far as we know, not been studied in this respect. In the present study, the effects of the 5-HT3 receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10(-5) mol/l) had no effect on the survival of irradiated cells. Granisetron (10(-5) mol/l) significantly potentiated cytotoxicity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10(-7) mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT3 receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment.

Topics: Animals; Antibiotics, Antineoplastic; Antiemetics; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Bleomycin; Cells, Cultured; Cisplatin; Cricetinae; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Epirubicin; Estramustine; Fibroblasts; Granisetron; Humans; Lung Neoplasms; Ondansetron; Serotonin Antagonists; Tumor Cells, Cultured

We report a case of advanced prostate cancer in which an initial response to hormonal therapy with surgical castration and estramustine phosphate (EMP) was followed by disease progression, as shown by sequential elevations in serum prostate specific antigen (PSA) and prostate acid phosphatase (PAP) and the development of new symptoms, during maintenance endocrine and anti-cancer chemotherapy. Discontinuation of EMP resulted in sustained reductions in serum PSA and PAP levels and a sustained improvement in symptoms.

Topics: Acid Phosphatase; Adenocarcinoma; Biomarkers, Tumor; Bone Neoplasms; Castration; Estramustine; Humans; Lung Neoplasms; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms

Clinically-used drugs such as furosemide, bumetanide and cardiac glycosides, are modulators of transmembrane fluxes of cations. Recently, it has been suggested that the regulation of intracellular cation concentrations could be a primary target for anti-neoplastic drugs, and that the cytotoxic activity may be altered by inhibitors of cation fluxes at the level of the plasma membrane. Therefore, we investigated the mechanisms by which cations are translocated across the plasma membrane of malignant glioma (U251 MG), prostatic carcinoma (PC3) and pulmonary carcinoma (P31) cell lines. The interactions between cation flux inhibitors and the cytotoxicity of estramustine were also evaluated. Ouabain, the classical inhibitor of Na+, K+ATPase, markedly reduced 86Rb (K+) influx in all three lines, indicating that this ion transport system is present in the cells. Furosemide and especially bumetanide inhibited the 86Rb influx, indicating the presence of the Na+, K+, Cl- co-transport system. The potassium channel blocker, tetraethylammonium, but not apamin reduced the influx of 86Rb showing that high conductance K+ channels are present, but that channels of low conductance probably do not exist in these cell lines. The Na+, K+, Cl- co-transport inhibitors furosemide and bumetanide significantly reduced cytotoxicity of estramustine in P31 cells, whereas no interaction between other K+ flux inhibitors and the anti-neoplastic drugs were detected in any of the cell lines investigated. Thus, the data show that Na+, K+, ATPase and NA+, K+, Cl- co-transport systems and K+ channels of high conductance are present in malignant glioma (U251 MG), prostatic carcinoma (PC3) and pulmonary carcinoma (P31) cell lines, and that inhibition of the Na+, K+, Cl- co-transport system in P31 is associated with reduced cytotoxicity of estramustine. The results justify further studies evaluating the role of these cation flux pathways in terms of targets for anti-neoplastic therapy.

Topics: Bumetanide; Cell Division; Estramustine; Furosemide; Glioma; Humans; Ion Transport; Lung Neoplasms; Male; Ouabain; Potassium; Potassium Channels; Prostatic Neoplasms; Rubidium Radioisotopes; Sodium-Potassium-Exchanging ATPase; Tumor Cells, Cultured

A 69-year-old man initially came to our hospital with the chief complaint of dysuria and hematuria. On rectal examination, the prostate gland was found to be grossly enlarged and rock hard in consistency. Abnormal laboratory data included: lactate dehydrogenase, alkaline phosphatase, acid phosphatase and prostatic acid phosphatase. Chest X-ray revealed multiple nodular lesions in both lung fields. Pathologic findings of the prostate needle biopsy revealed moderately well differentiated adenocarcinoma. Early combined hormonal and chemotherapy (adriamycin, TGF, methotrexate, bleomycin) was performed. After two courses of this regimen, the pulmonary lesions vanished completely. In addition, partial disappearance of osteoblastic lesions on bone scans was recognized.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Estramustine; Humans; Lung Neoplasms; Male; Methotrexate; Orchiectomy; Prostatic Neoplasms; Proteoglycans; Tegafur; Uracil

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

The effects of estramustine phosphate (EMP) and diethylstilbestrol (DES) on natural killer (NK) cell activity, tumor growth, and artificial metastases were investigated in male C57BL/6 mice. Kinetic analysis and studies at the single-cell level indicated that EMP did not influence the number of NK cells but interfered with their lytic activity thereby reducing the actual killer capacity. NK cells from EMP-exposed animals responded normally to the interferon inducer Poly I:C which restored NK activity to control levels. Spleen cells from DES-treated animals had lytic activity comparable to that of control animals. However, more detailed analysis showed that DES reduced the number of lymphocytes able to recognize target cells, while the individual NK cell had an increased lytic activity and recycling capacity. Moreover, NK cells from DES-treated animals were refractory to poly-I:C stimulation, suggesting that they were prestimulated in vivo. The pertubations of the NK cell system induced by both EMP and DES were reversible and normalization of NK activity was reached within a week. The incidence of tumor takes after subcutaneous inoculation of the syngeneic Lewis lung carcinoma was increased in EMP as well as DES-treated animals. Artificial lung metastasis produced by intravenous injection of the same tumor was increased in EMP but not in DES-exposed animals.

Topics: Animals; Cytotoxicity Tests, Immunologic; Diethylstilbestrol; Disease Susceptibility; Estramustine; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Nitrogen Mustard Compounds; Spleen