UMLS:C0027947 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0027947 (neutropenia)
17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CPT-11 (irinotecan) is a promising anticancer agent with a novel mechanism of action dependent on the inhibition of the DNA eukaryotic enzyme, topoisomerase I. The clinical utility of CPT-11 in advanced colorectal cancer has been documented in more than 400 patients recruited in phase II clinical trials in Europe, Japan, and United States. Among 178 eligible patients in a multicenter European study, the overall response rate to CPT-11 on a once-every-3-weeks regimen was 18%, and the median duration of response was 9.1 months. Thirty-two percent of the patients had no evidence of disease progression at 6 months. These results were similar in chemotherapy-naive and pretreated patients. These findings are consistent with the results of other studies conducted in Japan and the United States in which a weekly CPT-11 regimen was associated with response rates of 15% to 32% in chemotherapy-naive or pretreated patients. The principal adverse events of CPT-11 are neutropenia and delayed diarrhea, which in the European studies developed as grade 3 or 4 toxicity in 21% and 12% of the cycles (47% and 38% of patients), respectively. Neutropenia did not appear to be cumulative, with total recovery by day 22 in most cases. Loperamide was considered the most effective agent for controlling delayed diarrhea. Other adverse events included an early cholinergic-like syndrome (consisting of diaphoresis, early diarrhea, and abdominal cramps), nausea and vomiting, fatigue, and alopecia. In conclusion, CPT-11 has shown promising antitumor activity in the treatment of patients with advanced colorectal cancer, including those refractory to 5-fluorouracil (5-FU)-based regimens, suggesting no cross-resistance to 5-FU. CPT-11 appears to have activity similar to that of 5-FU in first-line treatment and, moreover, remains active after failure of 5-FU therapy. The specific gastrointestinal toxicity is manageable, and a better control of this type of toxicity is expected in the future. CPT-11 would therefore appear a welcome addition to the oncology armamentarium for this difficult-to-treat malignancy.
...
PMID:CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. 863 52

Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy.
...
PMID:[Taxotere (docetaxel) and CPT 11 (irinotecan): phase I trials]. 867 54

It has been reported that the antitumor effect of CPT-11 is manifested through the inhibition of topoisomerase I by SN-38 which is an active metabolite of CPT-11 produced by intracellular carboxylesterase, and that CPT-11 is effective against recurrent ovarian carcinoma. We investigated the antitumor effect and adverse reactions in the combined therapy with CPT-11 and CDDP in patients with prior chemotherapy for recurrent carcinoma, and in 7 patients without prior chemotherapy, consisting of 4 patients with postoperative adjuvant chemotherapy for clear cell carcinoma and 3 patients with metastatic ovarian carcinoma. CDDP was administered on day 1 and CPT-11 was administered three times on days 1, 8 and 15. The dose of both CDDP and CPT-11 was 50 mg/m2 or 60 mg/m2. Adverse reactions were investigated in all patients and the antitumor effect was assessed in 12 patients with recurrent carcinoma who had measurable lesions. (1) The DLF was neutropenia. The neutrophil count nadiar occurred on day 18 or 19. Grade 3 or 4 adverse reactions were observed in 60% or more of the patients, but they disappeared following short term administration of G-CSF. In patients with recurrent carcinoma given CDDP and CPT-11 at 60 mg/m2, the incidence of grade 3 or 4 adverse reactions and number of occasions on which CPT-11 administration had to be postponed were higher than those in patients given 50 mg/m2. (2) Mild platelet reduction was observed. (3) Grade 3 or 4 diarrhea was observed in 3.2% of patients with recurrent carcinoma and in 7.7% of patients with metastatic ovarian carcinoma. (4) The antitumor effect was evaluated in 12 patients with recurrent carcinoma: CR in 2 patients. PR in 3, NC in 6, and PD in one. The response rate was 41.7%. (5) An antitumor effect was observed in 2 patients with serous carcinoma and in one patient each with mucous carcinoma, clear cell carcinoma and endometrial carcinoma. In conclusion, adverse reactions caused by the combination therapy with CPT-11 and CDDP (CPT-11: 50-60 mg/m2 on days 1, 8 and 15, CDDP: 50-60 mg/m2 on day 1) can be relieved by short term administration of G-CSF and it is suggested that the combination therapy may be effective in treating ovarian carcinoma.
...
PMID:[Combination of irinotecan hydrochloride (CPT-11) and cisplatin as a new regimen for patients with advanced ovarian cancer]. 884 Oct 50

CPT-11 (Campto, irinotecan) is a promising new agent in the treatment of advanced colorectal cancer. Its safety has been assessed in light of the results from recent European phase II studies. In a pivotal French study in which CPT-11 350 mg/m2 was administered once every 3 weeks, neutropenia and delayed diarrhoea were the major adverse events: transient neutropenia occurred in 80% of patients, and severe neutropenia and febrile neutropenia in 47 and 15%, respectively. Delayed diarrhoea occurred in 87% of patients, with 39% having severe (grade 3 or 4) diarrhoea and 16% requiring hospitalisation. None of these adverse events was cumulative. Results of a pilot study to elucidate the mechanism of CPT-11-induced delayed diarrhoea suggest that this toxicity has a secretory mechanism with an exudative component. Early appropriate management of delayed diarrhoea may improve the safety profile of CPT-11. Indeed, the safety profile of CPT-11 was clearly improved in a later (currently ongoing) pan-European study: incidences of severe (grade 3 or 4) delayed diarrhoea and febrile neutropenia (+/-infection) were reduced from 39% to 23% (grade 4: 8% to 2.5%) and from 12% to 6%, respectively. Such an improvement could be attributed to a better understanding of the mechanisms of diarrhoea, improved patient selection criteria, better education of patients and physicians about management of delayed diarrhoea and the use of broad spectrum antibiotics when diarrhoea persisted despite loperamide therapy.
...
PMID:Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: the European perspective. 894 61

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated that CPT-11 is active against a broad spectrum of neoplasms including intractable non-Hodgkin's lymphoma. An early phase II study in lymphoma suggested that a schedule of daily infusions of 40 mg/m2/day for three or five consecutive days is more effective than a single infusion of 200 mg/m2 every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum compounds. To evaluate the maximal tolerated dose (MTD) and the therapeutic efficacy of CPT-11 in combination with carboplatin in relapsed or refractory non-Hodgkin's lymphoma, we conducted a combination phase I/II study. The starting dose of CPT-11 was 20 mg/m2/day (days 1 through 3 and 8 through 10), and dose escalations of 5 mg/m2/day increments were planned, with a fixed dose of carboplatin (300 mg/m2, day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MTDs. The response rate (25%, 2/8) to the combination of the MTDs was not superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.
...
PMID:Combination phase I/II study of irinotecan hydrochloride (CPT-11) and carboplatin in relapsed or refractory non-Hodgkin's lymphoma. CPT-11/Lymphoma Study Group. 900 51

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan [CPT-11 or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptoth eci n]. Irinotecan, and its more potent metabolite SN-38 (7- ethyl-10-hydroxy-camptothecin), interfere with mammalian DNA topoisomerase I and cancer cell death appears to result from DNA strand breaks caused by the formation of cleavable complexes. The main clinical adverse effects of irinotecan therapy are neutropenia and diarrhoea. Irinotecan has shown activity in leukaemia, lymphoma and the following cancer sites: colorectum, lung, ovary, cervix, pancreas, stomach and breast. Following the intravenous administration of irinotecan at 100 to 350 mg/m2, mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using a 2- or 3-compartment model with a mean terminal half-life ranging from 5 to 27 hours. The volume of distribution at steady-state (Vss) ranges from 136 to 255 L/m2, and the total body clearance is 8 to 21 L/h/m2. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and SN-38 increase proportionally to the administered dose, although interpatient variability is important. SN-38 levels achieved in humans are about 100-fold lower than corresponding irinotecan concentrations, but these concentrations are potentially important as SN-38 is 100- to 1000-fold more cytotoxic than the parent compound. SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified metabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents 1 to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. It was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.
...
PMID:Clinical pharmacokinetics of irinotecan. 934 1

Five promising new drugs for gynecological cancer were reviewed. Taxans (Paclitaxel: Taxol and Docetaxel: Taxotere) diterpenoid plant products enhance the polymerization of tublin. Taxol showed significant activity for platinum refractory ovarian cancer in a phase 1 clinical trial in the United States. The combination with cisplatin (CDDP) showed superior results to CDDP plus Cyclophosphamide and has been recognized as a new standard in adjuvant chemotherapy for advanced ovarian cancer. The major toxicities are myelosuppression, alopecia, and hypersensitivity reactions (HSRs). HSRs were overcome by pretreatment with anti-histamines and over 24 hours administration. It was also reported that Taxol was administered safely by over 3 hours infusion with reduced myelotoxicity, but the incidence of HSRs may be increased. Clinical trials of intraperitoneal administration and combination with Carboplatin (CBDCA) are ongoing. Taxotere, an analog of Taxol, is also effective as Taxol with a low incidence of HSRs. Topoisomerase inhibitors (Irinotecan hydrochloride: CPT-11 and Topotecan) have promising antitumor activity for ovarian and cervical cancer. CPT-11 is a semisynthetic camptothesin analog developed in Japan. It was also effective for platinum-resistant ovarian cancer, such as mucinous and clear cell carcinoma. An adverse effect was observed in the combination of CPT-11 and CDDP. The phase 1 clinical trial showed a 40% response rate against recurrent ovarian cancer. CPT-11 50-60 mg/m2 (day 1,8,15) and CDDP 50-60 mg/m2 (day 1) are a recommended schedule. The major toxicities are neutropenia and diarrhea. Thrombocytopenia is not severe and diarrhea is also controllable. Topotecan is also a promising topoisomerase inhibitor and reported superior result to Taxol for platinum refractory ovarian cancer. A phase II trial is ongoing for ovarian and cervical cancer in Japan. Nedaplatin, a new analog of cisplatin, has similar activity especially for cervical cancer with less myelotoxicity and nephrotoxicity.
...
PMID:[Promising new drugs for gynecological cancer]. 935 Feb 38

Preclinical in vitro and in vivo results have demonstrated the conditions required for optimal modulation of 5-FU activity by LV. The ability to increase intracellular concentrations of higher chain length polyglutamates was a function of duration of longer exposure to LV rather than the dose. In rats bearing advanced colorectal tumors, the role of LV dosage was more clearly evident with the weekly 5-FU treatment schedule than with the daily schedule. Phase III clinical trials in patients with advanced colorectal cancer demonstrated that low-dose and high-dose LV (daily x 5) and weekly high-dose LV schedules yielded similar response rates with different toxicity profiles. A phase III trial demonstrated significant therapeutic advantages for a bimonthly schedule of high-dose LV over a monthly schedule of low-dose LV. Taken together, these results provide insight into LV biomodulation, but the optimal conditions for these regimens for individual patients remain undetermined. To date it has not been possible to identify the optimal conditions for modulation of 5-FU by LV in individual patients with advanced colorectal cancer, and response rates are comparable. A regimen that offers the opportunity to manage treatment-induced toxicity is recommended. With diarrhea being the primary dose-limiting toxicity with the weekly 5-FU and high-dose LV (manifested during the 2-3 weeks of treatment), management of toxicity can be achieved by delaying treatment, by dose reduction, and/or by treatment with octreotide47 without compromising efficacy. In contrast, with the daily x 5 schedule, multiple toxicities (mucositis [stomatitis], diarrhea, neutropenia, and hand and foot syndrome) are manifested regardless of the dose of LV administered. An additional advantage to the weekly schedule is that it provides the opportunity to use 5-FU/LV treatment in sequence or combination with other drugs, such as topoisomerase I inhibitors (CPT-11), antifolates (methotrexate, trimetrexate), and platins (oxaliplatin).
...
PMID:Rationale for treatment design: biochemical modulation of 5-fluorouracil by leucovorin. 946 39

We evaluated the mobilization of peripheral blood stem cells (PBSCs) after the administration of chemotherapy including irinotecan (CPT-11) in individuals with advanced thoracic malignancies including lung cancer and mesothelioma. All patients were previously untreated. The numbers of CD34+ cells, CD34+ 38- cells, and colony-forming units granulocyte-macrophage (CFU-GM) in peripheral blood were determined to monitor PBSCs at least twice a week. Granulocyte colony-stimulating factor (G-CSF) (75 micrograms/body per day) was administered at the onset of neutropenia [absolute neutrophil count (ANC) of < 1000/microliter] until the ANC exceeded 5000/microliter. In patients who received G-CSF, sufficient counts of the PBSCs for PBSC transplantation were mobilized at the time when the white blood cell count was > 5000/microliter. CPT-11 with G-CSF is thus a promising induction regimen for PBSC transplantation. Patients who did not develop neutropenia after chemotherapy showed a significantly (p = 0.005) higher number of CD34+ cells in the peripheral blood at steady state (median, 1818; range, 1534 to 4433; n = 8) than those who developed neutropenia (median, 666; range, 608 to 1553; n = 5). This parameter may thus prove a useful marker for predicting neutropenia after the administration of CPT-11.
...
PMID:Mobilization of peripheral blood stem cells in patients with advanced thoracic malignancies after irinotecan (CPT-11) administration. 956 66

Irinotecan hydrochloride (CPT-11) is reportedly effective for the treatment of refractory or recurrent ovarian cancer. We investigated the antitumor efficacy and toxicity of combination therapy with CPT-11 and cisplatin in 25 patients (mean age 55 years, range 35-73 years) with refractory or recurrent ovarian cancer who had previously undergone platinum-based combination chemotherapy. Patients received two or more courses of treatment consisting of 50 or 60 mg/m2 of CPT-11 on days 1, 8 and 15 and 50 or 60 mg/m2 of cisplatin on day 1 administered intravenously. All patients were evaluable for the response and the toxicity profile. Complete responses were obtained in two (8.0%) patients and partial responses were obtained in eight (32.0%) patients, giving an overall response rate of 40% (10 of 25 patients) (95% CI 23.0-59.0%). The median duration of response was 5.5 months (range 2-27 months), the median time to tumor progression was 6 months (range 3-28 months) and the median overall survival was 12 months (range 3-39+ months). Grade 3 or 4 neutropenia, which was the most frequent and severe toxic effect, occurred in 36 (54.5%) of the 66 treatment courses and in 16 (64.0%) of 25 patients. The nadir of the leukocyte count occurred on days 18-19. Neutropenia was reversed by short-term administration of granulocyte colony-stimulating factor for 2-10 days. Less serious hematologic effects and non-hematologic effects, such as diarrhea, were also observed. This preliminary study showed that this regimen of CPT-11 and cisplatin was effective in patients with recurrent ovarian cancer.
...
PMID:Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer. 968 85

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>