Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few chemotherapy agents have demonstrated activity in patients with myelodysplastic syndromes (MDS) and supportive management remains the standard of care. An increasing number of new drugs in development are being directed at specific molecular or biological targets of these diseases. Topotecan, a topoisomerase I inhibitor, has shown single-agent activity and is now being combined with other agents, including cytarabine. The aminothiol amifostine induces responses in about 30% of patients; however, its role is still being clarified. Agents that inhibit histone deacetylase and target DNA hypermethylation, thus permitting derepression of normal genes, include 5-azacytidine, decitabine, phenylbutyrate, and depsipeptide. Arsenic trioxide has demonstrated impressive activity in acute promyelocytic leukemia and preclinical data suggest the potential for activity in MDS. UCN-01 is a novel agent that inhibits protein kinase C and other protein kinases important for progression through the G1 and G2 phases of the cell cycle. Dolastatin-10 has extremely potent in vitro activity against a variety of tumor cell lines. Since its dose-limiting toxicities include myelosuppression, it is being studied in acute myelogenous leukemia (AML) and MDS. Ras may play a role in MDS, and activation of this gene and its signaling pathways may require farnesylation. Several farnesyl transferase inhibitors are now available for study in patients with MDS. An increasing body of data suggests a possible role for angiogenesis in MDS, and several antiangiogenesis agents are in clinical trials, including thalidomide, SU5416, and anti-vascular endothelial growth factor (VEGF) antibodies. Development of new drugs and regimens will be facilitated by recently developed standardized response criteria. Future clinical trials should focus on rational combinations of these agents and others with the goal of curing patients with MDS.
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PMID:Novel therapeutic agents for the treatment of myelodysplastic syndromes. 1104 23

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

Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m2 by 30-min intravenous (i.v.) infusion on days -8, -7, -6, -5, -4; thiotepa 300 mg/m2 by 3 h i.v. infusion on days -8, -7, -6; and carboplatin by 4 h i.v. infusion on days -5, -4, -3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min ( approximately 500 mg/m2/day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post-transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain.
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PMID:Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. 1160 67

We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan-filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization.
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PMID:Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells. 1160 69

The comparative saliva/plasma pharmacokinetics of topotecan were investigated in 13 patients with metastatic epithelial ovarian cancer receiving topotecan (30-min intravenous (i.v.) infusion) on a five consecutive day schedule every 3 weeks. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Quantitation of the total topotecan (lactone plus carboxylate form) was assessed by a highly specific high-performance liquid chromatographic (HPLC) method. Large patient-to-patient variations in the plasma and saliva concentrations were observed. Plasma and saliva pharmacokinetics could be described using a biexponential pattern. From the saliva data, the half-life of the terminal part of the curve was 2.64 h, it was of the same order of magnitude as the topotecan elimination half-life determined from the plasma data, 3.18 h. Topotecan concentrations were higher in the saliva than in the plasma, the saliva/plasma concentration ratio averaged 2.31 and the ratio area under the parotid saliva (AUC(s)) over plasma (AUC(p)) concentration-time curve (AUC(s)/AUC(p)) averaged 2.11. For each individual, a significant relationship was found between topotecan concentrations in the saliva and in the plasma, the coefficients of correlation ranged from 0.75 to 0.92 according to the patient. Myelosuppression, especially granulocytopenia was the most frequent toxicity encountered during the trial. The percent decrease in the leucocyte count, absolute neutrophil count and platelet count were related to the AUCp/day using sigmoidal E(max) models. The high values of the Hill constant found reflect the very steep AUC-haematoxicity relationship observed. In most cases, abdominal pain occurred in patients presenting high saliva concentrations. One patient with high salivary concentrations (mean S/P ratio=4.60) had grade 1 mucositis. In conclusion, the concentration of topotecan in saliva appeared to be useful as an indirect, non-invasive estimation of the levels of topotecan in the plasma; thus, saliva concentrations could be a good predictor of the behaviour of topotecan in the body.
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PMID:Salivary and plasma pharmacokinetics of topotecan in patients with metastatic epithelial ovarian cancer. 1172 Aug 28

Topotecan (Hycamtin, SmithKline Beecham, Philadelphia, PA) was approved by the U.S. Food and Drug Administration in 1996 for use in relapsed ovarian cancer and in 1999 for platinum-sensitive small-cell lung cancer. Hematologic toxicity has been the predominant side effect associated with its use. Patients who have had extensive platinum-based therapy have exhibited increased degrees of thrombocytopenia and more severe neutropenia. These adverse events can be managed by identifying high-risk patients (i.e., those with more than six cycles of chemotherapy containing an alkylating agent or radiation to more than 25% of marrow-bearing bones, patients with a history of myelosuppression or renal impairment) and by recommending appropriate dose modifications based on the creatinine clearance measurement. By reducing the topotecan dose, myelosuppressive effects, as evidenced by neutropenia and thrombocytopenia, may be lessened or prevented without reducing the antitumor response.
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PMID:Nursing considerations for managing topotecan-related hematologic side effects. 1189 7

Topotecan has demonstrated efficacy in the treatment of both platinum-sensitive and platinum-resistant recurrent ovarian cancer. However, the optimal dosing for topotecan has not been established. The standard dosing regimen is 1.5 mg/m(2)/day on days 1-5 of a 21-day cycle, with response rates ranging from 13%-33%. Although the resulting hematologic toxicities are reversible and noncumulative, this schedule is associated with significant myelosuppression. Ongoing clinical phase I and II trials have evaluated alternative dosing schedules such as the 21-day 24-hour continuous intravenous (c.i.v.), the 3-day i.v. bolus, the weekly 72-hour c.i.v., the weekly 24-hour c.i.v., and the weekly bolus i.v. regimens. Prolonged exposure to topotecan has been shown to increase the efficacy of topotecan, whereas shorter regimens decrease exposure to the drug and therefore decrease toxicity. Preliminary studies investigating the weekly bolus i.v. regimen have demonstrated response rates comparable with those achieved with the standard dosing regimen, with a lower frequency of severe toxicity. Although randomized, controlled comparative trials are necessary to determine relative efficacy, results from studies utilizing other alternative regimens are less encouraging, especially for lower-risk patients with platinum-sensitive ovarian cancer who are likely to tolerate higher doses of topotecan. Optimizing the dosing regimen will also increase the quality of life for the patient through increased efficacy, decreased toxicity, and increased convenience of administration. Continued investigation of the weekly i.v. bolus is needed to fully elucidate the contribution of this regimen to the current armamentarium used in the treatment of patients with relapsed ovarian cancer.
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PMID:Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer. 1232 31

Topotecan is an established therapy for the treatment of recurrent ovarian cancer and has demonstrated significant antitumor activity in both platinum-sensitive and platinum-resistant patient populations. The main toxicity associated with topotecan when used in the standard 5-day dosing schedule is myelosuppression, which is generally predictable, reversible, noncumulative, and manageable. Comparative trials have shown that topotecan is as effective as paclitaxel and pegylated liposomal doxorubicin in achieving tumor response, disease stabilization, and improved overall survival. Follow-up data extending to 4 years indicate that the survival benefit persists in long-term therapy without cumulative toxic effects. There appears to be little cross-resistance between topotecan and paclitaxel, indicating that the use of concurrent or sequential combination therapy could be a valuable option. Encouraging preliminary data suggest that alternative dosing schedules may improve the therapeutic index of topotecan and that topotecan may also be active as first-line therapy in combination with taxanes and/or platinum agents. Optimization of the use of topotecan may offer potential opportunities for further improving the management of ovarian cancer.
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PMID:Clinical experience with topotecan in relapsed ovarian cancer. 1312 89

Topotecan is an established treatment for patients with relapsed ovarian cancer, with good antitumor activity in both platinum-sensitive and -resistant disease. However, the perception of dose-limiting myelosuppression may have limited its use. Myelosuppression with topotecan is noncumulative, reversible, and predictable and as such can be successfully managed. Dose reductions and/or delays in patients at elevated risk, for example, patients with preexisting bone marrow damage from earlier treatment and those with diminished creatinine clearance, are usually effective in preventing complications. Most patients recover without incident and the requirement for specific therapy is generally low. The therapeutic index of topotecan may be improved by its use at first relapse, when patients have sustained less bone marrow damage. Alternative dosing schedules also show promise. Preclinical data suggest that repeated exposure to topotecan may be as effective as prolonged exposure, supporting the idea of weekly dosing. Phase I/II studies have confirmed that weekly topotecan dosing, using either a 24-h or a 30-min intravenous infusion, produces substantially less myelosuppression than the standard schedule (1.5 mg/m(2) daily for 5 days every 21 days). Early results indicate that antitumor activity is maintained, although further data are required to confirm this. Weekly administration of topotecan is an exciting new therapeutic option in the treatment of relapsed ovarian cancer.
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PMID:Weekly topotecan in the management of ovarian cancer. 1312 94

Improvements in ovarian cancer management mean that it may now be a long-term disease for which treatment must be carefully considered. Optimal sequencing of chemotherapy may help to enhance patients' benefit of therapy and minimize toxicity. The response to retreatment with platinum or a platinum/taxane combination is strongly influenced by the treatment-free interval after initial therapy with a platinum combination. Response rates to platinum retreatment in platinum-resistant patients (relapse within 6 months) are lower than those in platinum-sensitive patients (relapse after 6 months). Increasing the platinum-free interval by using non-platinum-based chemotherapy for treatment after relapse appears to increase the likelihood of response to later rechallenge with platinum. Many alternative agents have been investigated for the treatment of patients with relapsed ovarian cancer, including single-agent topotecan, which has been shown to achieve favorable responses. Topotecan may cause myelosuppression, which is noncumulative but tends to increase in direct correlation with the number of prior chemotherapy courses. Therefore, the best use of topotecan may be early in the course of salvage therapy. The hematologic toxicities associated with topotecan can also be reduced by adjusting the dose and schedule. Prolonged use of topotecan may be feasible and potentially beneficial in some patients.
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PMID:Optimal sequencing in the treatment of recurrent ovarian cancer. 1312 95


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