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)

Patients with non-small-cell lung cancer (NSCLC) were treated with ICE chemotherapy (ifosfamide 2000 mg/m2, days 1-3; carboplatin 300 mg/m2, day 1; etoposide 75 mg/m2, days 1-3) intravenously (i.v.) during the first 3 d of a maximum of four 28 d treatment cycles. Interleukin-3 (IL-3) was administered in cycles 2 and 4 as a daily subcutaneous (s.c.) injection on days 5-18. Cohorts of three patients were treated at dosage levels of 0.5, 1.25, 2.5, 5.0, 10.0 and 15.0 micrograms/kg/d. At 15.0 micrograms/kg/d a 'flu-like' syndrome of myalgias, arthralgias and fatigue was considered dose-limiting. Other toxicities were headache, fever, urticaria, arrhythmia, chills and flushing. Subsequently, nine patients were added to the group receiving 10 micrograms/kg/d. 27 patients received IL-3 after their second course of ICE. At 10 and 15 micrograms/kg/d, IL-3 in cycle 2 was associated with enhanced haematological recovery. Depth of neutrophil nadir and days of neutropenia (ANC < 0.5 x 10(9)/l) were reduced in 9/13 patients and in 8/11 patients, respectively. No effect was seen on platelet nadir or days of thrombocytopenia. IL-3 was well tolerated up to 10 micrograms/kg/d when given as a daily s.c. injection. Results suggest IL-3 as a potential adjunct to chemotherapy, and further studies to explore administration of IL-3 in combination with other cytokines in this setting are warranted.
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PMID:Effect of recombinant human interleukin-3 on haematological recovery from chemotherapy-induced myelosuppression. 798 6

We have found transient circulating neutropenia and pulmonary sequestration of neutrophils after the intravenous injection of vindesine, a microtubule disruptor. Experiment 1 Ten patients with lung cancer were given a bolus intravenous injection of 3 mg.m-2 vindesine (Fildesine(r)). In all patients, total leukocyte and neutrophil counts in the venous blood fell to 65% and 47% of baseline values respectively within 30 min, and returned to baseline values within 6 h. In contrast, the lymphocyte count was stable. Experiment 2 Male Wistar rats were given saline or 0.08 mg.kg-1 vindesine intravenously and were sacrificed after 30 min. Vindesine produced a 58% reduction in the neutrophil count in the systemic circulation and a threefold increase in the neutrophil/erythrocyte ratio in the pulmonary microvasculature. Experiment 3 We studied the effects of vindesine in vitro on neutrophils and lymphocytes isolated from the venous blood of healthy volunteers. Vindesine (10(-5)-10(-8) mol.l-1) reduced neutrophil deformability (filterability) and induced neutrophil polarization, with reversibility of both effects after washout. These effects of vindesine were completely inhibited by cytochalasin B, an actin filament disrupter. Vindesine did not stimulate the neutrophil functions of adherence to polystyrene tubes, chemotaxis, or superoxide anion generation. The filterability and morphology of lymphocytes were not altered by vindesine. Thus, we conclude that a bolus injection of vindesine produces pulmonary sequestration of neutrophils, which produces circulatory neutropenia, and that it is primarily mediated by a decrease in neutrophil deformability that occurs without activation of the cells.
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PMID:Transient neutropenia after intravenous injection of vindesine in patients with lung cancer. 798 20

Etoposide has been used in the treatment of a wide variety of neoplasms, including small-cell lung cancer, Kaposi's sarcoma, testicular cancer, acute leukemia, and lymphoma. Its current therapeutic use is limited by myelosuppression, particularly neutropenia. Pharmacodynamic studies of etoposide show that this toxicity can be modeled using a modified Hill equation and that the dose intensity of etoposide can be successfully increased by adaptive control using this model. Significant influences on the degree of myelosuppression include the pretreatment leukocyte count, the performance status, the extent of prior erythrocyte transfusions, and the serum albumin level. In the past 7 years, interest has developed in a distinct subset of acute nonlymphocytic leukemia that is associated with prior exposure to etoposide. This syndrome has been described in several studies and is characterized by the lack of a preleukemic phase, M4 or M5 morphology, and distinct translocations involving the chromosome 11q23 region. In addition, secondary acute lymphocytic leukemias (involving 11q23) have also been associated with prior epipodophyllotoxin exposure.
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PMID:Pharmacodynamics and long-term toxicity of etoposide. 807 30

Etoposide is a schedule-dependent cytotoxic drug with high single agent activity in small-cell lung cancer and lymphoma. Despite its clear dose-dependent myelosuppressive activity, dose-dependent evidence of its anti-tumour activity is harder to demonstrate. A number of reports have correlated haematological toxicity with pharmacokinetic and physiological parameters, which explains some of the variability in dynamic effects that exists between patients. Recent reports have also suggested that anti-tumour response may be related to plasma etoposide concentration. In our own studies we have investigated factors that influence the pharmacodynamic effects of etoposide, principally with regard to haematological toxicity, and these studies have highlighted a number of patient groups who are at risk. Impaired renal function causes a reduction in clearance of etoposide, resulting in increased systemic exposure and more profound myelotoxicity. A 30% dose reduction in this group is recommended to normalise the area under the plasma concentration-time curve (AUC). Patients with low serum albumin concentrations (< 35 g/l) also showed significantly worse haematological toxicity, but with no apparent change in total drug pharmacokinetics. There was, however, an increase in the free drug fraction in this group due to decreased protein binding, such that the free drug AUC was similar to that found in patients with renal dysfunction. This would also indicate that a dose reduction of around 30%-40% is required in this patient group. Patients with normal albumin levels but liver enzyme values (aspartate transaminase or gamma-glutamyl transpeptidase) more than 3 times the upper limit of normal also had a less marked but significant increase in neutropenia. In patients with normal organ function, age was the only significant factor in predicting the degree of leukopenia/neutropenia, and increasing age was also associated with decreasing drug clearance and an increase in drug AUC. A small dose reduction and/or careful monitoring is required in this patient group. Further studies are required to elucidate further the relationship between the pharmacokinetics of etoposide and its pharmacodynamics, particularly with regard to anti-tumor activity, and to determine the role of individualised therapy, based on a pharmacokinetic parameter, in reducing the dynamic variability and optimising the use of this drug.
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PMID:Etoposide dosage and pharmacodynamics. 807 31

A number of topoisomerase II-acting drugs have been described, but few demonstrate schedule-dependent anti-tumour activity. The activity of the epipodophyllotoxins etoposide and teniposide and the acridine dye derivative amsacrine is clearly schedule-dependent, and this related not only to the observation that the activity of topoisomerase II varies throughout the cell cycle but also to the finding that these drugs are rapidly cleared from the cell following exposure, permitting DNA repair. Etoposide has been most clearly shown to be schedule dependent in clinical studies. The response rates of patients with small-cell lung cancer receiving a 24-h infusion was only 10% as compared with 89% when the same dose was given over 5 days. Pharmacokinetic studies performed in these patients demonstrated that although the total systemic exposure (area under the plasma concentration-time curve, AUC) was the same in both arms of the study, the duration of exposure to low levels of drug (> 1 microgram/ml) was doubled in the 5-day arm. Haematological toxicity was the same in both arms of the study, as was the duration of exposure to higher plasma levels (> 5 micrograms/ml), suggesting that this toxicity may be associated with higher plasma concentrations, whereas anti-tumour activity is related to prolonged exposure to low levels of drug. This was confirmed in a subsequent study, where prolongation of treatment to 8 days compared to 5 days resulted in a similar exposure to low plasma concentrations and no difference in response rates or survival. Haematological toxicity in this study was worse in the 5-day arm, which also had an increase exposure to high levels of drug (> 5 micrograms/ml). More recently, interest has focused on even more prolonged etoposide administration, typically involving small daily doses repeated for 14-21 days. Although this schedule shows high activity in relapsed small-cell lung cancer and lymphoma, it is associated with significant toxicity (around one-third of patients experience grade III/IV leukopenia or neutropenia), which may be related to the observation that the etoposide dose delivered per course in these studies is higher than that obtained with standard dosing over 3-5 days. Further randomised studies are required to determine the optimal dose and schedule of etoposide.
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PMID:Schedule-dependent topoisomerase II-inhibiting drugs. 807 33

A 53-year-old man underwent chemotherapy (CDDP, VDS, MMC) for treatment of lung cancer. He was given 125 micrograms/m2 of GM-CSF subcutaneously every day for 8 consecutive days, in order to prevent neutropenia. Three days after starting GM-CSF therapy, marked eosinophilia in peripheral blood was observed. The maximum eosinophil count was 89% of leukocytes. Nine days after stopping the treatment with GM-CSF, the number of eosinophils had normalized spontaneously. There were no clinical symptoms except for slight fever, up to 37.5 degrees C. Moreover, there was no relationship between the number of eosinophils and the serum levels of cytokines (IL-3, IL-5, GM-CSF), although we observed minimal but significant elevation of serum ECP level. This case indicates that GM-CSF may induce marked eosinophilia rather than widely stimulating granulocytes and monocytes.
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PMID:[A case of marked eosinophilia in peripheral blood induced by rhGM-CSF]. 812 Oct 93

Intravenous-bolus etoposide has modest activity in sarcomas when given daily for 3-5 days. Low frequent doses theoretically inhibit topoisomerase II activity over a longer duration and have been reported to have increased activity in small-cell lung cancer. A phase I trial of oral etoposide resulted in partial responses in two patients with soft-tissue sarcomas. To estimate more accurately the response rate for daily oral etoposide in sarcomas, we treated 25 patients with 50 mg/m2 per day by mouth for 21 days every 4 weeks. Treatment-related toxicity included > or = grade 2 neutropenia in 6 of the 25 patients and thrombocytopenia in 3. One brief partial response was observed (4%; 95% confidence interval for true response rate, 0-11%). Disease stabilized in five patients for periods ranging from 3 to 18 months. At this dose and on this schedule, daily oral etoposide appears to have little activity against soft-tissue sarcomas.
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PMID:Phase IV trial of daily oral etoposide in the treatment of advanced soft-tissue sarcoma. 817 7

A multicenter early Phase II clinical study of KW-2307, a new vinca alkaloid derivative, in patients (pts) with lung cancer was conducted in 15 hospitals. Ninety-seven pts were enrolled, among whom 95 were eligible. Seventy of the eligible pts had non-small cell cancer (NSCLC) and 25 had small cell cancer (SCLC). PR was obtained in 13 (18.6%) of NSCLC pts and 3 (12%) of SCLC pts. Only those who had no previous chemotherapy showed PR in NSCLC pts, and the response rate in these pts was 29.5% (13/44). As to the correlation between dosage and tumor effect, a better effect was exhibited at higher doses, with response rates of 21.7% (5/23) and 38.1% (8/21) at 20 mg/m2 and 25 mg/m2, respectively. The major adverse effect of this drug was leukopenia (neutropenia), which was Grade 3 or 4 in many cases. Recovery from this complication, however, was rapid. Other adverse effects included mild hepatic dysfunction, anorexia, nausea/vomiting, fever, general fatigue, phlebitis and constipation. The incidence of peripheral nervous disorder such as the paresthesia commonly observed with vinca alkaloids, was as low as 10%, and the symptoms, if any, were mild.
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PMID:[Early phase II clinical study of KW-2307 in patients with lung cancer. Lung Cancer Section in KW-2307 Study Group]. 818 36

A phase II study was designed to evaluate objective response rate and toxicity of fotemustine as single-drug chemotherapy in non-small-cell lung cancer. Eighty-seven patients with unresectable non-small-cell lung cancer took part in the study. Seventy-seven were evaluable for response. Of these, 60% had received prior chemotherapy and 74% had metastatic disease. Moreover, 22 patients had central nervous system metastases (of whom 12 were evaluable for this site). Treatment consisted of fotemustine 100 mg m-2 administered on days 1 and 8 followed by a 5 week rest period. Afterwards, responding or stabilised patients received fotemustine 100 mg m-2 every 3 weeks as a maintenance therapy. Toxicity and quality of life were recorded during therapy. Thirteen patients (17%; 95% CI 9-25%) had an objective response (11% for pretreated, 26% for non-pretreated) with a median duration of 22 weeks (range 7-41 weeks). Two objective responses were observed among the 12 patients with evaluable brain metastases. No response was observed among the 14 patients with adenocarcinoma. Haematological, gastrointestinal, hepatic and renal toxicities were mild to moderate and manageable. The most frequent biological adverse reactions were delayed thrombocytopenia and neutropenia. Quality of life did not significantly decrease during the first 6 treatment weeks. Moreover, it remained stable during the study period in patients with response or stabilisation, whereas it significantly decreased in patients who experienced progression of the disease. Fotemustine is feasible for single-drug chemotherapy in non-small-cell lung cancer even though poor prognostic variables such as brain metastases are present. It can be administered on an outpatient basis and toxicity is moderate and manageable. Thus, fotemustine can be considered as a putative drug in further combinations.
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PMID:Phase II study of nitrosourea fotemustine as single-drug chemotherapy in poor-prognosis non-small-cell lung cancer. 819 82

Irinotecan hydrochloride (CPT-11), topotecan, sobuzoxane, NC-190, and IST-622 are unique topoisomerase inhibitors and are investigational in Japan. CPT-11 is a water-soluble, semisynthetic derivative of camtothecin. CPT-11 shows its anticancer activity by inhibiting topoisomerase I activity, now a target of anticancer agents with major interest. Recent clinical trials reveal that CPT-11 is very effective in the treatment of cancer including lung cancer, cervical cancer, ovary cancer, stomach cancer, colon cancer, and non-Hodgkin's lymphoma. Major dose limiting toxicities are leukopenia and diarrhea, and are dose related. Topotecan is an another semisynthetic derivative of camtothecin and is also topoisomerase I inhibitor. Topotecan has undergone phase I clinical evaluations in USA, europe, and recently in Japan. DLF are leukopenia and neutropenia. Topotecan is more hydrophilic than its parent compound and shows lesser protein binding. Renal excretion appears to be the major route of elimination. Sobuzoxane (MST-16) is a unique derivative of dioxopiperazine, an inhibitor of topoisomerase II. In phase II studies, definite anticancer effects are observed in patients with non-Hodgkin's lymphoma and adult T-cell leukemia/lymphoma. Responses are seen even in pretreated cases. Leukopenia is also dose-limiting. Non-hematologic toxicities are mild and include alopecia and G.I. toxicities. NC-190 is a novel benzophenazine derivative with excellent antitumor activities against murine tumors. NC-190 also inhibits topoisomerase II. Now the drug is an early clinical phase II studies in Japan. Toxicities include bone marrow suppression, transient mild to moderate liver enzyme elevation, alopecia and mild G.I. toxicities. Tumor responses are occasionally encountered. IST-622 is a semisynthetic derivative of chartreusin. The drug is an inhibitor of topoisomerase II (and I in high concentration). IST-622 shows excellent, broad anticancer activity against murine tumors. The drug is well absorbed from small intestine. IST-622 is now in phase I clinical trial in Japan.
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PMID:[Topoisomerase inhibitors developing in Japan]. 842 86


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