Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian cancer is the fifth leading cause of cancer death in women. Most patients with ovarian cancer respond to first-line chemotherapy, but many relapse within 18 to 22 months. The development of efficacious salvage therapies that increase overall survival while maintaining quality of life is a great challenge in the treatment of this disease. Topotecan, a novel topoisomerase I inhibitor, is currently indicated for the treatment of recurrent metastatic carcinoma of the ovary. In patients with relapsed ovarian cancer, the overall response rates on treatment with topotecan range from 19%-33% in platinum-sensitive patients, 14%-18% in platinum-resistant patients, and 5%-11% in platinum-refractory patients. The proportion of patients achieving stable disease ranges between 17% in refractory and 48% in sensitive patients. In phase III studies, topotecan was shown to be equivalent in efficacy to both paclitaxel and liposomal doxorubicin as second-line therapy in patients with relapsed ovarian cancer. Further, non-cross-resistance between topotecan and paclitaxel was demonstrated in a third-line, phase III crossover study, suggesting that topotecan may be effective in the first-line setting with paclitaxel and/or platinum. Hematologic toxicities include neutropenia, thrombocytopenia, and anemia; however, these toxicities are usually short lived, noncumulative, and manageable with dose modifications, including low-dose topotecan regimens. Nonhematologic toxicities are usually mild to moderate in severity. These data support the use of topotecan for second-line therapy and suggest that topotecan may also be effective in first-line therapy. Further studies with topotecan alone and in combination with other agents are needed to fully characterize the role and sequencing of topotecan in the salvage and first-line settings.
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PMID:Update on the role of topotecan in the treatment of recurrent ovarian cancer. 1232 28

The standard treatment for advanced colorectal cancer (CRC) has been 5-fluorouracil (5-FU)-based chemotherapy. However, addition of irinotecan, a topoisomerase I inhibitor, to the combination of 5-FU and leucovorin (LV) has proven to be superior to treatment with 5-FU/LV alone in both chemonaive as well as previously treated patients. Oxaliplatin, a 1,2 diaminocyclohexane platinum compound, in combination with 5-FU and LV, has demonstrated superiority as first-line therapy over 5-FU and LV in terms of response rate and time to progression. The irinotecan/oxaliplatin combination showed synergistic activity in vitro, and the optimal dose safety profile has been explored in several phase I studies. Neutropenia and diarrhea were the dose-limiting toxicities. The recommended dose of irinotecan/oxaliplatin in every-2-week and every-3-week schedules ranged from 150-200 mg/m2 and 85 mg/m2, respectively. In the weekly schedule, the recommended doses of irinotecan/oxaliplatin were 65 mg/m2 and 60 mg/m2. Promising clinical efficacy in CRC was observed in all studies. A recent randomized phase II study revealed that the irinotecan/oxaliplatin combination has equivalent clinical activity to other 5-FU-based combinations and a manageable toxicity profile. The evaluation of irinotecan/oxaliplatin in phase III trials as well as in combination with 5-FU is ongoing.
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PMID:Irinotecan plus oxaliplatin: a promising combination for advanced colorectal cancer. 1245 Apr 27

A pilot study investigated topotecan (Hycamtin, GlaxoSmithKline, Philadelphia, PA), a topoisomerase I inhibitor, in treating uterine serous carcinoma, a typically unresponsive aggressive tumor. Fifteen patients were surgically staged, then treated with topotecan (1.5 mg/m2, Days 1-5 every 21 days) as first-line therapy (n = 12) or secondary to platinum failure (n = 3). Patients received topotecan through six courses, disease progression, or unacceptable toxicity. Grade 3/4 hematologic toxicity prompted dose adjustments. Thirteen patients exhibited no gross evidence of residual disease postoperatively. At topotecan initiation, one patient had 5-cm and one had < 1-cm residual disease. Seventy-eight courses (median, six) were administered; 12 (80%) patients completed the specified protocol. Common serious toxicities included grade 3 neutropenia (33%), anemia (13%), and thrombocytopenia (13%). Eight patients received erythropoietin and/or granulocyte colony-stimulating factor. Median follow-up for 14 evaluable patients was 26 months (range, 13-40). Of 11 evaluable first-line topotecan patients, nine were alive at follow-up; five were disease-free. Of three second-line topotecan patients, two died and one was alive with disease 31 months post-treatment. One patient with measurable disease achieved a complete and one a partial response as assessed by computed tomography scan. Median progression-free survival was 25 months; median survival has not been reached at 26 months. Although topotecan's antitumor activity cannot yet be quantified, disease-free interval and survival outcomes compare favorably with other therapies in uterine serous carcinoma. Further evaluation of topotecan in this population is warranted.
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PMID:A pilot study of topotecan in the treatment of serous carcinoma of the uterus. 1265 27

Preclinical data suggest that the combination of inhibitors of topoisomerases I and II may be synergistic when administered together. The optimal sequence of such combinations is uncertain, but initial administration of a topoisomerase I inhibitor upregulates topoisomerase II. Several combinations of these inhibitors have been evaluated, but have not clearly demonstrated synergy. Thus, we have started a phase I study of the combination of irinotecan (CPT-11, Camptosar) and epirubicin (Ellence). Typical eligibility criteria for phase I studies were employed. Patients with a history of congestive heart failure, > 240 mg/m2 of prior doxorubicin, or > 10% weight loss in the prior 4 weeks were excluded. Irinotecan and epirubicin were administered on days 1 and 8, every 28 days. Initially, patients were treated with irinotecan at 100 mg/m2 and epirubicin at 40 mg/m2 (dose level 1). After substantial toxicity at this level, the doses to be evaluated were changed to irinotecan: 50-->75-->100 mg/m2, and epirubicin: 20-->25-->30 mg/m2. Dose-limiting toxicities were noted in 2/4 patients (2 neutropenic fever, 1 thrombocytopenia) on dose level 1; 0/3 on dose level 1A; 1/8 (neutropenia) on dose level 2A; and 1/3 (neutropenia) on dose level 3A. This is the first combination of irinotecan and epirubicin to be evaluated in humans. The toxicity, primarily myelosuppression, noted to date has exceeded the expected toxicity for the doses of the irinotecan and epirubicin alone, suggesting the possibility of a synergistic interaction of the agents on this schedule, at least in the bone marrow. Other toxicities were acceptable and non-dose-limiting. Accrual of patients continues, at level 3A (irinotecan at 75 mg/m2, epirubicin at 25 mg/m2).
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PMID:Combined inhibition of topoisomerases: a phase I. Study of irinotecan and epirubicin. 1280 Jun 7

Topotecan, a novel topoisomerase I inhibitor, is an established treatment for patients with recurrent small-cell lung cancer (SCLC), with antitumor response rates of approximately 20% and median survival of approximately 32 weeks in patients with extensive-stage disease. Topotecan's comparable activity relative to other agents used in SCLC and its novel mechanism of action, noncumulative toxicity, and in vitro synergy with other active agents have provided the rationale for investigating topotecan in first-line therapy. Furthermore, topotecan penetrates the blood-brain barrier and is potentially useful for the relatively large subset of patients with SCLC and brain metastases. In early studies of topotecan in brain metastases, encouraging antitumor activity has been observed. In several feasibility and phase II studies of topotecan as single-agent therapy in patients with extensive- and limited-stage tumors and as part of novel first-line combination regimens, overall response rates have ranged from 42% to 100%. Complete responses of 3%-67% and partial responses of 33%-80% have been observed in first-line therapy. Furthermore, the median overall survival in patients receiving topotecan in first-line therapy has ranged from approximately 8 months (extensive-stage disease) to 20 months (limited-stage disease). The most frequent adverse events associated with topotecan-based regimens include grade 3/4 neutropenia and thrombocytopenia that often require the incorporation of growth factor support into the treatment regimen. Nonhematologic adverse events associated with topotecan-based combination regimens have been mild or primarily attributed to other agents in the combination. Alternative doses and schedules (3 consecutive days and weekly) are being explored because they appear to be associated with considerably less myelosuppression. Although several trials have established the feasibility and activity of topotecan in first-line therapy of patients with SCLC, randomized phase III studies with comparison to standard therapy will be required to confirm a potential role for this active agent and to determine the optimal dosing regimen.
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PMID:Emerging role of topotecan in first-line therapy of small-cell lung cancer. 1460 45

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid extracted from the Chinese plant Camptotheca acuminata. It bears a bis-piperidine moiety and was selected for its water solubility and promising preclinical antitumor activity in in vitro and in vivo models. The target of drugs of the camptothecin family is DNA topoisomerase I, a nuclear enzyme involved in the relaxation of the DNA double helix required for replication and transcription activities. They stabilize the enzyme-DNA complex and prevent the religation of the single-strand breaks created by the enzyme, which are converted to double-strand breaks upon the collision with a replication fork during the S-phase. Resistance to irinotecan appears not to be mediated by P-glycoprotein, but by qualitative and/or quantitative alterations of its target, topoisomerase I, or by alterations occurring downstream of this interaction. As with all camptothecin derivatives, irinotecan contains a lactone ring that can be spontaneously and reversibly hydrolyzed to a carboxylate open ring form, which predominates at neutral and alkaline pH and is inactive on topoisomerase I-DNA complexes. Irinotecan is, in fact, much less active than its metabolite SN-38 and is generally considered as a prodrug of this compound. The carboxylesterase which carries out this conversion is preferentially active on the lactone form of irinotecan and directly generates the lactone form of SN-38, which may explain the superiority of irinotecan over SN-38 in vivo. Further metabolism of SN-38 to a beta-glucuronide conjugate is a major pathway of detoxification and plays an important role in determining irinotecan toxicity in the clinical setting. Other metabolic pathways of irinotecan involve oxidations occurring on the bis-piperidine rings, which are carried out by cytochrome P450. Irinotecan has shown an important activity in advanced and metastatic colorectal carcinoma and is now used for this indication in several countries, with two different recommended schedules: weekly administration of 125 mg/m(2) with a 2-week drug-free interval every 4 administrations or 3-weekly administration of 350 mg/m(2), a dose that can be increased to 500 mg/m(2) with the support of antidiarrhetics. Other possible indications of irinotecan include lung and cervix cancer, which are presently under investigation. The dose-limiting toxicity of irinotecan is mainly diarrhea, which occurs 7-10 days after treatment and can be life-threatening when associated with neutropenia, another frequent side effect. High-dose loperamide has shown good efficacy for treating this diarrhea and has allowed an increase in irinotecan doses tolerated by patients. The pharmacokinetics of irinotecan are characterized by a 2- or 3-compartment decay, with a terminal half-life of about 10 h, a total volume of distribution of 150 l/m(2) and a total plasma clearance of 15 l/h/m(2). SN-38 AUC is only a small fraction of that of irinotecan (2-4%) and SN-38 is eliminated from plasma with a half-life of about 12 h. SN-38 glucuronide is present in plasma at higher concentrations than SN-38 and is eliminated at the same rate. APC, produced by the action of cytochrome P450, isoenzyme 3A4, is present in plasma at concentrations close to those of irinotecan itself. Only a small fraction of irinotecan and its metabolites is eliminated in urine and a higher proportion in the bile, with an enterohepatic cycle of SN-38 glucuronide and SN-38. Significant relationships have been established between the AUCs of both irinotecan and SN-38 and hematological and intestinal toxicities, suggesting a potential use for monitoring of this drug.
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PMID:Pharmacology of irinotecan. 1498 54

The objective of this study was to define the maximally tolerated dose (MTD) and response rate of a combination of two topoisomerase I inhibitors, topotecan and irinotecan, in patients with metastatic colon cancer. Eleven patients, the majority with previously progressive disease on 5-fluorouracil-based regimens, were enrolled onto a phase I/II dose escalation trial utilizing continuous infusion topotecan for 2 weeks and weekly irinotecan x 3 with cycles repeated every 28 days. Dosages of topotecan utilized included 0.2 and 0.25mg/m2/day. Irinotecan was administered at a dose of 62 mg/m2 by i.v. bolus. Patients were followed for toxicity and response. The MTD of the combination of agents was found to be 0.25mg/m2/day for topotecan and 62 mg/m2 for irinotecan. The most common serious toxicities were diarrhea and nausea/vomiting. Only one patient experienced grade III neutropenia. There were no complete or partial responses. However, four patients had prolonged disease stabilization (SD) of up to 324 days and this group remained on protocol therapy for an average of 227 days (p=0.0005 versus patients not achieving SD). We concluded that the MTD for this combination of topoisomerase I inhibitors, given on this particular schedule, has been defined. This combination cannot be recommended as a first- or second-line therapy for patients with metastatic colon cancer based on the responses observed. However, approximately one-third of patients achieved prolonged disease stabilization. Topotecan with irinotecan may be useful as a palliative regimen for a subgroup of colon cancer patients.
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PMID:Combined topoisomerase I inhibition for the treatment of metastatic colon cancer. 1520 98

Irinotecan exerts its cytotoxic activity through inhibition of the nuclear enzyme topoisomerase I. It has been approved in most countries worldwide for treatment of patients with advanced colorectal cancer (CRC). Activity is seen in previously untreated patients and in patients refractory to fluorouracil treatment, whether it is given alone or in combination with other cytotoxic drugs. Irinotecan was first developed in patients refractory to fluorouracil. Activity in terms of tumour responses and patient benefit was seen in several phase II trials that used either a weekly or a three-weekly schedule. In two randomised trials (irinotecan vs best supportive care, and irinotecan vs an infused fluorouracil-based regimen), irinotecan prolonged median survival by approximately 2.5 months without any deterioration in quality-of-life. It was later studied in previously untreated patients with advanced CRC in combination with fluorouracil/folinic acid (leucovorin). In three large randomised trials, median time to tumour progression was prolonged by approximately 2.5 months and overall survival by about 2.5 months compared with fluorouracil/folinic acid alone. Tumour responses were also seen more frequently in the irinotecan arm (35-40% vs 20%). Again, quality-of-life scores were not deteriorated by the addition of irinotecan. Irinotecan has many acute adverse effects. The most prominent and dose limiting being diarrhoea and neutropenia. With irinotecan monotherapy, diarrhoea was seen in 80% of patients and severe grade 3 to 4 diarrhoea occurred in 30-40% of the patients. The severity of diarrhoea can be diminished by preventive actions. Less risk of diarrhoea is generally seen when irinotecan is combined with fluorouracil. Neutropenia is generally short-lived, but may be severe if diarrhoea is also present. This has been noticed particularly when irinotecan has been given in combination with a bolus fluorouracil/folinic acid regimen. Other toxicities include acute cholinergic-like symptoms, nausea and vomiting, and alopecia. In spite of these adverse effects, irinotecan has been accepted as an important first-line treatment for patients with advanced CRC, in combination with, preferably, an infused fluorouracil-based regimen, and has been approved for use as monotherapy in the second-line indication.
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PMID:Benefit-risk assessment of irinotecan in advanced colorectal cancer. 1585 43

In the treatment of extensive disease of small cell lung cancer (ED SCLC) there is an urgent need for more effective and better-tolerated drug regimens. We report on a prospective phase II trial performed to evaluate the efficacy and safety of a platinum-free regimen--containing topotecan and etoposide--in the first-line treatment of ED SCLC. Between December 1999 and July 2001, 28 chemotherapy-naive patients with ED SCLC were recruited; 9 patients had stage IIIB disease and 19 patients had stage IV disease. Based on phase I results, patients received treatment with intravenous topotecan 1 mg/m2 (days 1-5) followed by intravenous etoposide 75 mg/m2 (days 8-10). Treatment courses were repeated every 28 days for a maximum of 6 cycles. A confirmed response rate of 46.4% with 1 complete response (CR) and 12 partial responses (PR) (95% CI=27.5-66.1%) was observed. Stable disease (SD) was observed in 18% of patients. The median time to response was 7.9 weeks (range: 7.7-15.1 weeks) and median survival was 29.9 weeks (range from 3.3 to 91.4 weeks). Main toxicities encountered were haematological with Grade III/IV neutropenia in 2.6/1.5% of courses and Grade III/IV thrombocytopenia in 1.8%/0.7% of courses. These toxicities were manageable and were not associated with clinical sequels. Non-haematological toxicities were generally mild with no Grade III/IV toxicities reported apart from Grade III alopecia. The combination therapy of topotecan and etoposide is active in first-line chemotherapy for patients with ED SCLC. The regimen showed a tolerable safety profile. Since drug scheduling plays a critical role in the combination of topoisomerase I and II inhibitors, concurrent administration of topotecan and etoposide might increase the efficacy.
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PMID:Topotecan and etoposide as first-line therapy for extensive disease small cell lung cancer: a phase II trial of a platinum-free regimen. 1589 10

Edotecarin (PHA-782615; formerly J-107088) is a derivative of NB-506, an indolocarbazole antitumor agent. It is a novel inhibitor of topoisomerase I that induces single-strand DNA cleavage more effectively than NB-506 or camptothecin (CPT) and at different DNA sequences. The DNA-topoisomerase I complexes induced by edotecarin are more stable than those occurring after exposure to CPT or NB-506. The antitumor activity of edotecarin is less cell cycle dependent than other topoisomerase I inhibitors. Being an indolocarbazole, it is structurally related to staurosporine but does not possess protein kinase inhibitory properties. In addition, edotecarin does not form active metabolites and is not a substrate for in vitro P450-mediated metabolism. The antitumor activity of edotecarin has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in breast, cervix, pharynx, lung, prostate, colon, gastric, and hepatic cancer models. Edotecarin is effective on cells that have acquired resistance related to P-glycoprotein. In vitro synergy has been demonstrated when edotecarin was tested in combination with cisplatin, 5-fluorouracil, etoposide, paclitaxel, doxorubicin, vincristine, CPT, and gemcitabine. Three phase I and 5 phase II studies have been carried out to date. Combination studies of edotecarin with other chemotherapeutic agents are in current clinical trials. The primary dose-limiting toxicities were grade 3/4 neutropenia and febrile neutropenia. Dose-limiting diarrhea was observed only with a twice-weekly administration schedule. Recent progress in preclinical and clinical studies of edotecarin is reviewed.
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PMID:Edotecarin: a novel topoisomerase I inhibitor. 1592 4


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