Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of gemcitabine are reviewed. Gemcitabine is a deoxycytidine-analogue antimetabolite with activity against some solid tumors. Gemcitabine is phosphorylated intracellularly to difluorodeoxycytidine triphosphate, which terminates DNA-chain elongation and competitively inhibits DNA polymerase and ribonucleotide reductase. After i.v. administration, gemcitabine is rapidly distributed into total body water. The drug is deaminated in the plasma to inactive difluorodeoxyuridine; both gemcitabine and difluorodeoxyuridine are primarily renally eliminated. In clinical studies, gemcitabine reduced pain and improved function in patients with advanced pancreatic cancer. Gemcitabine has shown some activity against non-small-cell lung cancer, particularly when combined with cisplatin or ifosfamide. The agent has also shown modest activity against advanced ovarian and breast cancer. Adverse effects include dose-limiting myelosuppression, flu-like symptoms, nausea, vomiting, and rash. Gemcitabine has FDA-approved labeling for use in the treatment of locally advanced and metastatic pancreatic cancer. The recommended dosage for this indication is 1000 mg/m2 (as the hydrochloride salt) i.v. given over 30 minutes weekly for seven weeks, followed after one week of rest by 1000 mg/ m2 i.v. given over 30 minutes weekly for three weeks every four weeks. Gemcitabine palliates symptoms in patients with advanced or metastatic pancreatic cancer. More study is needed to determine gemcitabine's role in the treatment of non-small-cell lung cancer, ovarian cancer, and breast cancer.
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PMID:Gemcitabine: a cytidine analogue active against solid tumors. 911 4

Symptomatic malignant pleural effusions should be treated systemic chemotherapy in chemo-sensitive tumors such as small cell lung cancer, breast cancer, lymphoma, or ovarian cancer. In other non-chemo-sensitive malignancies including non-small cell lung cancer, water-sealed tube drainage and pleurodesis is the standard treatment of choice in most of the cases. Drugs for instillation should be blomycin or OK-432 if commercially available. Instead of the former standard drug tetracycline, doxycycline has been frequently used. As we have no randomized trials, this drug awaits phase III trials. Talc slurry has been accepted and counted as one of the standard choices in the western countries, however, it usually needs general anesthesia and adverse effects are not negligible. As we have little experience on this modality, it should not be considered as a standard treatment. Other antitumor drugs instillation, thoraco-abdominal shunting, and pleuro-pneumonectomy should be considered experimental because of the lack of randomized trials. Symptomatic pericardial malignant effusion or cardiac tamponade is an oncologic emergency. We had better to treat the patient immediately by pericardiocentesis under the cardiac echographic guidance. It should be reserved to solve in randomized trials that the best method would be pericardiocentesis alone, percutaneous continuous drainage, pericardial fenestration, or pericardio-thoraco fenestration. Instillation of drug like doxycycline, OK-432, or bleomycin, lacks phase III comparison and it should be categorized as experimental.
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PMID:[State of the art: treatment of malignant pleural and pericardial effusions]. 936 17

The 4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine PD 158780 is a very potent in vitro inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (IC50 0.08 nM), and other members of the erbB family, by competitive binding at the ATP site of these signal transduction enzymes. A series of analogues of PD 158780 bearing solubilizing functions off the 6-methylamino substituent were prepared by reaction of the 6-fluoro derivatives with appropriate amine nucleophiles. These were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF-stimulated full-length EGFR enzyme and for inhibition of autophosphorylation of the EGFR in A431 human epidermoid carcinoma cells in culture. The most effective analogues were those bearing weakly basic substituents through a secondary amine linkage, which proved water-soluble (> 10 mM) and potent (IC50S generally < 1 nM). No clear SAR could be discerned for these compounds with respect to amine base strength or the distance of the cationic center from the chromophore, suggesting that 6-substituents are in a favorable area of bulk tolerance in the enzyme binding site. More distinct SAR emerged for the ability of the compounds to inhibit EGFR autophosphorylation in A431 cells, where analogues bearing lipophilic weak bases were preferred. Representative analogues were evaluated for antitumor effectiveness against four in vivo tumor models. Significant in vivo activity was observed in estrogen-dependent MCF-7 breast and A431 epidermoid tumors. Marginal activity was seen in an EGFR-transfected tumor model, suggesting that while this cell line requires EGF for clone formation in soft agar, other growth factors may be able to replace EGF in vivo. Also, no activity was seen against the SK-OV-3 ovarian cancer model, which is known to express other EGF receptor family members (although it is not clear whether these are absolutely required for growth in vivo). While substantial growth delays were seen in A431 and MCF-7 tumor models, the treated tumors remained approximately the same size throughout therapy, suggesting that the compounds are cytostatic rather than cytotoxic under these test conditions. It remains to be determined if more prolonged therapy has cytotoxic effects in vivo, resulting in net tumor cell kill.
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PMID:Tyrosine kinase inhibitors. 14. Structure-activity relationships for methylamino-substituted derivatives of 4-[(3-bromophenyl)amino]-6-(methylamino)-pyrido[3,4-d]pyrimidine (PD 158780), a potent and specific inhibitor of the tyrosine kinase activity of receptors for the EGF family of growth factors. 951 2

We measured mortality rates in a cohort of 20,508 aerospace workers who were followed up over the period 1950-1993. A total of 4,733 workers had occupational exposure to trichloroethylene. In addition, trichloroethylene was present in some of the washing and drinking water used at the work site. We developed a job-exposure matrix to classify all jobs by trichloroethylene exposure levels into four categories ranging from "none" to "high" exposure. We calculated standardized mortality ratios for the entire cohort and the trichloroethylene exposed subcohort. In the standardized mortality ratio analyses, we observed a consistent elevation for nonmalignant respiratory disease, which we attribute primarily to the higher background rates of respiratory disease in this region. We also compared trichloroethylene-exposed workers with workers in the "low" and "none" exposure categories. Mortality rate ratios for nonmalignant respiratory disease were near or less than 1.00 for trichloroethylene exposure groups. We observed elevated rare ratios for ovarian cancer among those with peak exposure at medium and high levels] relative risk (RR) = 2.74; 95% confidence interval (CI) = 0.84-8.99] and among women with high cumulative exposure (RR = 7.09; 95% CI = 2.14-23.54). Among those with peak exposures at medium and high levels, we observed slightly elevated rate ratios for cancers of the kidney (RR = 1.89; 95% CI = 0.85-4.23), bladder (RR = 1.41; 95% CI = 0.52-3.81), and prostate (RR = 1.47; 95% CI = 0.85-2.55). Our findings do not indicate an association between trichloroethylene exposure and respiratory cancer, liver cancer, leukemia or lymphoma, or all cancers combined.
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PMID:Mortality of aerospace workers exposed to trichloroethylene. 964 7

Topotecan, a water-soluble analogue of camptothecin, is a newly available cytotoxic agent which acts as an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. Topotecan is a semisynthetic product derived from camptothecin, which was discovered during a National Cancer Institute cytotoxic drug screening program almost 30 years ago. It acts by forming a stable covalent complex with the DNA/topoisomerase I aggregate, the so-called 'cleavable complex'. This process leads to breaks in the DNA strand resulting in apoptosis and cell death. Topotecan possesses a serum half-life of approximately 3 h, a high volume of distribution with high tissue uptake and a low protein binding. The chemical structure is based on a lactone ring. Topotecan undergoes reversible hydrolysis from its biologically active lactone form to the open ring inactive carboxylate form. It is also able to penetrate the intact blood-brain barrier. Since most of the agent is excreted by the kidneys, dose adjustment is necessary when renal function is impaired. In contrast, pharmacokinetic behavior is unchanged in patients with limited hepatic function. The principal toxicity of topotecan when administered at standard doses is neutropenia, but thrombocytopenia and anemia occur as well, while the nonhematological toxicities are usually mild. Alopecia is frequently observed and some patients may suffer from pronounced fatigue. Most clinical data available are based on the following schedule: 1.5 mg/m2 topotecan given as a 30-min infusion, days 1-5. There are currently only minimal data available regarding a dose-antitumor activity relationship. Other topotecan administration schedules are currently being investigated. Preclinical data suggest that continuous-infusion schedules may be a better application form in terms of both, toxicity and antitumor activity. However, clinical trials could not confirm these results to date. Results of phase II studies suggest considerable antitumor activity of single agent topotecan in small cell lung cancer and ovarian cancer patients. A randomized phase III trial of topotecan versus paclitaxel in ovarian cancer patients pretreated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Activity of topotecan was also observed in non-small-cell lung cancer, refractory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, etoposide, cytarabine and paclitaxel are potential interacting partners for combination chemotherapy regimens. However, the best combination regimen as well as the optimal combination schedule have yet to be conclusively determined. The potential of topotecan in a variety of solid tumors, as well as its use in combination regimens for ovarian and small cell lung cancer is currently being investigated.
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PMID:Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. 988 71

PURPOSE: Topotecan, a semisynthetic water-soluble camptothecin analog, was recently approved as a second-line treatment for women with ovarian cancer. In clinical trials, hematologic toxicity has been the predominant toxicity associated with its use. The purpose of this article is to provide guidelines on the clinical management of these toxicities. METHODS: The guidelines on the management of hematologic toxicities associated with topotecan therapy for advanced ovarian cancer patients were established through a review and analysis of phase I, II, and III clinical trials. RESULTS: In phase I studies, noncumulative neutropenia was the predominant toxicity associated with topotecan therapy. In subsequently conducted phase II trials, thrombocytopenia related to prior carboplatin and alkylating agent therapies has become a prominent toxicity, and neutropenia has been more severe than anticipated from phase I studies. The risk for both toxicities relates to the extent of prior myelosuppressive chemotherapy and to renal impairment. These toxicities can be managed through the identification of high-risk patients and implementation of appropriate prophylactic measures. Such measures include dose reductions or the use of hematopoietic growth factors. For patients with persistently low blood cell parameters, transfusion therapy remains a viable option. CONCLUSION: Hematologic toxicities associated with topotecan therapy are noncumulative. Consequently, once a dosing regimen is established, toxicity patterns are predictable. Pretreatment assessment of the nature and toxicities of prior therapy and renal function should assist the clinician in preventing complications caused by the myelosuppressive effects of topotecan therapy.
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PMID:Clinical Guidelines for Managing Topotecan-Related Hematologic Toxicity. 1038 79

Ovarian cancer is the fourth most common cause of death in women. Gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment has been successfully applied in the treatment of different cancers in experimental animals and in humans. In a recent report, we have demonstrated that the HSV-tk/GCV system can be used efficiently to kill human epithelial ovarian cancer cells (Gynecol Obstet Invest 1997;43:268-75). In this work, we wanted to test the ability of the HSV-tk/GCV to treat ovarian cancer in an animal model.The immune-deficient nude mice model was employed, and mice were injected intraperitoneally with the human epithelial ovarian cancer cell line OVCAR3, 10(8) cell/mouse. The mice were divided into three different groups, groups 1 and 2 were treated by intraperitoneal injection of adenovirus carrying the HSV-tk gene (ad-tk) on day 3 after cell implantation. Group 1 received 2 x 10(8) pfu/mouse; group 2 received 20 x 10(8) pfu/mouse. Group 3 did not receive any viral injection and served as our negative control. All mice received GCV 10 mg/kg IP bid for 6 days. All mice were hosted in the same facilities and had access to food and water ad libitum. Mice in group 3 started to show clinical manifestations of disease by day 10, and all mice were dead by day 21 (16 +/- 1.5). At this point mice in groups 1 and 2 appeared perfectly healthy. Autopsy done on group 3 mice demonstrated multiple cancer implants in the abdominal cavity plus hemorrhagic ascitis. In contrast, autopsy on sample mice from groups 1 and 2 at the same time point failed to demonstrate any macroscopic or microscopic cancer.On further follow-up, mice in groups 1 and 2 started to show cancer-related signs, eg, weight loss, movement difficulty, poor reflex response, and finally death. Survival varied between 50 and 101 days with a mean of 66 +/- 17 days for group 1 and 74 +/- 13 days for group 2. Autopsy done on treated mice demonstrated multiple cancer implants and ascitis. In conclusion, a single injection of ad-tk/GCV was able to improve survival in an ovarian cancer mouse model from an average of 16 days to 74 days. Trials with multiple injection in a novel immune-competent mouse model of ovarian cancer are underway in our laboratory.
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PMID:Gene therapy of epithelial ovarian cancer using adenoviral vectors. 1083 93

The results of studies on antiproliferative activity in vitro of nine new platinum(II) complexes against cells of eight human and six murine neoplastic cell lines are described. New complexes with the anionic rest originating from enantiomeric forms of hydroxydicarboxylic malic acid were synthesized to obtain agents with increased water solubility and decreased toxicity. Three compounds, coded 1-3, with ethylenediamine as a neutral ligand, showed cytotoxic activity against 12 out of 14 target cell lines. Their cytotoxic activity was similar or even slightly higher than that of the reference carboplatin. The remaining six compounds, coded 4-9, with 1-alkylimidazole as a neutral ligand, revealed rather low cytotoxic activity, and only against the cells of the human bladder cancer cell line Hu1703He, ovarian cancer cell line OAW-42 and mouse leukemia P388. Most of them appeared to be negative against all other cell lines. No compounds, including reference carboplatin, showed any cytotoxicity against the cells of the T47D human breast cancer cell line or B16F-10 mouse melanoma cell line. The results obtained are in accordance with common opinion, i.e. that the presence of neutral amine ligands with NH groups is required for the cytotoxic activity of platinum complexes. Compounds with a primary amine (ethylenediamine) showed higher cytotoxic activity in vitro than complexes with a tertiary amine (1alkylimidazole).
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PMID:Antiproliferative activity in vitro of new malatoplatinum(ll) complexes. 1091 52

Lysophosphatidic acid (LPA) is the simplest form of lysophospholipid. Molecular species of LPA have been identified as the potent components in the ovarian cancer activation factor. The elevated plasma LPAs may be used as potential biomarkers for the early detection of ovarian cancer. This paper is the first report on the quantitative analysis of molecular species of LPA using capillary electrophoresis. In this work, the separation of LPAs was achieved within 14 min in an adenosine monophosphate-borate-methanol-water solution, and the measurement was accomplished by indirect UV detection. With LPA (D) as internal standard, the method had linear calibration ranges for LPAs from 2.8 to 75 microM. The detection limits for various molecular species of LPA were from 1.2 to 2.3 microM by the pressure injection at 3.45 kPa for 5 s. The method had been applied to serum fortified with LPA (S), LPA (O), LPA (P), and LPA (M) and the recoveries ranged from 83 to 112%.
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PMID:Determination of lysophosphatidic acids by capillary electrophoresis with indirect ultraviolet detection. 1133 51

Topoisomerase I (topo-I) inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most, if not all, topo-I inhibitors are derivatives of the plant extract camptothecin. Topotecan is a derivative of camptothecin which has been structurally modified to increase water solubility. The pharmacokinetic profile of topotecan is usually characterised by a two-compartment model and is linear in the dose range of 0.5 - 3.5 mg/m(2). Current clinical trials suggest antitumour activity against a variety of human tumour types, including ovarian cancer, non-small cell lung cancer (NSCLC) and non-lymphocytic haematologic malignancies. The main dose-limiting toxicity (DLT) is non-cumulative myelosuppression. Non-haematologic toxicities are usually mild. Based on several Phase I studies, the recommended Phase II dose was 1.5 mg/m(2)/day iv. for 5 days. Current Phase I and Phase II trials are evaluating the combination of topotecan with other chemotherapeutic agents to increase the therapeutic benefits of topotecan. The DLT in these trials is mainly myelosuppression.
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PMID:Topoisomerase I inhibition with topotecan: pharmacologic and clinical issues. 1133 1


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