Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small-cell lung cancer (SCLC) is highly chemosensitive but up to 70% of patients with limited disease and more than 90% of patients with extensive disease will relapse after first-line treatment. There are several standard chemotherapy regimens used for second-line treatment yet the prognosis for patients requiring this treatment remains poor. The topoisomerase-I inhibitor, topotecan, has achieved response rates of up to 22% in previously treated patients with SCLC and survival almost double that achieved with other single agents. Compared with cyclophosphamide/doxorubicin/vincristine (CAV), single-agent topotecan achieved a higher response rate, longer survival and statistically significant improvements in dyspnea, hoarseness, fatigue, anorexia and interference with daily activities. Brain metastases are common in SCLC. Topotecan crosses the blood-brain barrier and shows promise for the management of brain metastases.
 ...
PMID:The role of topotecan in treating small cell lung cancer: second-line treatment. 1456 8

Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-soluble salt camptothecin-sodium - introduced in early trials in the 1960s - was highly toxic in animals, whereas the semisynthetic derivatives irinotecan and topotecan did not cause haemorrhagic cystitis because of their higher physicochemical stability and solubility at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert's syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhoea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitising solubilisers. Leukopenia and thrombocytopenia occur in 65% and 80%, respectively, of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhoea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clinical pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concentration-time curve values and steady-state concentrations for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metabolism may be associated with a higher risk for secondary malignancies.
 ...
PMID:Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. 1652 21

Long-term survival is quite uncommon in refractory small cell lung cancer (SCLC) patients, with less than 25% of patients with limited-stage disease and 1%-2% of patients with extensive-stage disease remaining alive at five years. Recent clinical studies have demonstrated the promising efficacy of amrubicin for patients with relapsed SCLC. This review presents the results of clinical studies showing the efficacy and safety of amrubicin for the treatment of relapsed SCLC. Amrubicin is a synthetic anthracycline agent with a similar structure to doxorubicin, in which the hydroxyl group at position 9 in amrubicin is replaced by an amino group to enhance efficacy. It is converted to an active metabolite, amrubicinol, which is 5-54 times more active than amrubicin. Amrubicin and amrubicinol are inhibitors of DNA topoisomerase II, exerting their cytotoxic effects by stabilizing a topoisomerase II-mediated cleavable complex. The toxicity of amrubicin is similar to that of doxorubicin, although amrubicin shows almost no cardiotoxicity. In the relevant trials, amrubicin was administered intravenously at a dose of 35-40 mg/m(2) on days 1-3 every three weeks. The response rate was 34%-52% and median survival times were 8.1-12.0 months. Common hematologic toxicities included neutropenia, leucopenia, anemia, thrombocytopenia, and febrile neutropenia. Nonhematologic adverse events included Grade 3-4 anorexia, asthenia, hyponatremia, and nausea. The results of the studies which demonstrated the efficacy of monotherapy for relapsed SCLC involved mainly Japanese patients. Therefore, it is necessary to conduct more clinical studies in non-Japanese patients to confirm the efficacy of amrubicin.
 ...
PMID:Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer. 2118 10