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)

CI-921 (NSC 343499; 9-[[2-methoxy-4-[(methylsulphonyl)amino]phenyl]amino] -N,5-dimethyl- 4-acridinecarboxamide) is a topoisomerase II poison with high experimental antitumour activity. It was administered by 15 min infusion to 16 evaluable patients with non-small cell lung cancer (NSCLC) (7 with no prior treatment, 9 patients in relapse following surgery/radiotherapy) at a dose (648 mg/m2 divided over 3 days, repeated every 3 weeks) determined by phase I trial. Patients had a median performance status of 1 (WHO), and median age of 61 years. The histology comprised squamous carcinoma (11), adenocarcinoma (1), mixed histology (2), bronchio-alveolar carcinoma (1) and large cell undifferentiated carcinoma (1). Neutropenia grade greater than or equal to 3 was seen in 15 patients, infections with recovery in 3, and grand mal seizures in 1 patient. Grade less than or equal to 2 nausea and vomiting occurred in 66% courses and phlebitis in the infusion arm in 37%. 1 patient with squamous cell carcinoma achieved a partial response lasting 5 months. Further testing in this and other tumour types using multiple daily schedules is warranted.
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PMID:Phase II study of the amsacrine analogue CI-921 (NSC 343499) in non-small cell lung cancer. 166 18

Fostriecin, a novel anticancer antibiotic produced by Streptomyces pulveraecus, is believed to act via inhibition of topoisomerase II. Single-dose intravenous administration to rats at dose levels of 8.8 to 48 mg/kg resulted in lethality at dose levels of 35 mg/kg and higher. Major toxic effects were observed primarily at 17.5 mg/kg and higher, were reversible, and consisted of bone marrow hypocellularity, leukopenia, neutropenia, thrombocytopenia, and diffuse necrosis of various lymphoid tissues. The kidney was also identified as a target organ. Renal effects were observed primarily at 20 mg/kg, were reversible, and included increases in serum BUN, creatinine, and 24-hr glucose excretion. Twenty-four-hour excretion of Na+, K+ and urine osmolality were decreased postdosing at 10 and 20 mg/kg. Renal lesions, observed primarily at 20 mg/kg, consisted of vacuolization and necrosis of proximal and distal tubular epithelium at the corticomedullary junction extending into the medulla. Repeated daily intravenous administration of fostriecin for 5 days to rats at dose levels of 2.5 to 26.5 mg/kg resulted in death at 10 mg/kg and above and similar hematologic, bone marrow, lymphoid tissue, and renal changes as observed in the single-dose study. Hematological, bone marrow, lymphoid, and renal changes observed in rats were consistent with the cytotoxic mechanism of action of the compound.
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PMID:Preclinical toxicological evaluation of fostriecin, a novel anticancer antibiotic, in rats. 222 54

Vinorelbine is a semi-synthetic vinca alkaloid which was initially developed in France in the 1980's. Due to its unique structure it is considerably less neurotoxic than vincristine. Several phase II studies have shown that vinorelbine is active in metastatic breast cancer therapy with response rates of 20-30% in pretreated and 40-50% in nonpretreated patients respectively. Higher response rates have been noted when vinorelbine is used in combination regimens. The main dose-limiting toxicity seen with this agent has been neutropenia; neurotoxicity manifest as symptomatic paresthesia can be seen in 10% of treated patients. Oral and implantable forms of the drug have also been investigated. The topoisomerase 1 inhibitors topotecan and camptothecin 11 (CPT-11) have been less extensively evaluated in breast cancer therapy. Preclinical studies have indicated that both of these agents are active against breast cancer and some responses have been seen in phase 1 trials of topotecan. An 8% response rate was noted in a phase II trial of CPT-11 in patients with pretreated metastatic breast cancer. Further phase II trials are ongoing at present with both agents.
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PMID:Vinorelbine and the topoisomerase 1 inhibitors: current and potential roles in breast cancer chemotherapy. 774 28

The topoisomerase I inhibitor topotecan is a potent water-soluble camptothecin derivative with activity in a wide variety of preclinical models. Topotecan exhibits schedule dependency in vivo, with the greatest activity being observed on repeated dose schedules. On the basis of the initial clinical studies that showed a short plasma half-life, we attempted to prolong drug exposure by giving topotecan as a 24-h infusion weekly. In a phase I trial, we treated 32 patients at doses ranging from 1.0 to 2.0 mg/m2. The patient population had not been heavily pretreated with chemotherapy and was of good performance status. The incidence of neutropenia, which was dose-limiting, increased sharply with relatively small increments in dose. Doses greater than 1.5 mg/m2 were associated with nadirs that developed after one to three weekly treatments. A patient with metastatic colorectal cancer had a prolonged partial response. The plasma pharmacokinetics of topotecan (lactone and open forms) was characterized in 21 patients. Mean plasma steady-state drug levels were proportional to the dose and were within the range required to exert cytotoxicity in preclinical models. Plasma elimination curves were fit to a one-compartment model, in which the harmonic mean half-life of topotecan was 3.5 h. The ratio of the lactone to the total drug concentrations was constant throughout, which suggests that for this schedule the total drug concentration may be used as a measure of active lactone exposure. This conclusion is supported by the pharmacodynamic analysis, which revealed a positive correlation of both lactone and total drug steady-state concentrations with bone marrow toxicity. The further investigation of this and other infusional schedules in phase II trials will be conducted. The steady-state concentrations of total drug will be measured in several of these trials to establish its potential role in adaptive dosing using this schedule. Such a strategy is justified by the interpatient variability in toxicity and the steep dose-response curve observed in this study. Preliminary evidence of interpatient variability in the mRNA expression of topoisomerase I in the peripheral mononuclear cells and colon mucosa is presented. Trials are under way using biological endpoints for further selection of patients in whom the use of topoisomerase inhibitors may be therapeutically beneficial.
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PMID:Clinical, pharmacokinetic and biological studies of topotecan. 807 27

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

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

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

12 patients: (7 males and 5 females) with recurrent brainstem gliomas were treated with the oral topoisomerase inhibitor VP-16 (Etoposide). Patients ranged in age from 3 to 49 years with a median age of 7 years. All patients had been previously treated with radiation therapy (conventional fractionation: 4; hyperfractionation: 8) and 5 had received prior nitrosourea-based chemotherapy at time of tumor recurrence. Tumor recurrence was documented by radiographic tumor enlargement utilizing brain MRI with gadolinium enhancement (12) and clinical neurologic deterioration (9). Two patients underwent biopsy pathologically documenting tumor recurrence. Each cycle of therapy consisted of 21 days of VP-16 (50 mg/m2/day) followed by a 14 day rest followed by an additional 21 days of VP-16 (50 mg/m2 day). Complete blood counts were followed bi-weekly and a neurologic examination and brain MRI scan with contrast were performed prior to initiation of each cycle of therapy. Treatment related complications included: partial alopecia (5); diarrhea (5); weight loss (4); neutropenia (2); and thrombocytopenia (4). No patient required transfusion or antibiotic treatment of neutropenic fever. There were no treatment related deaths. 12 patients were evaluable of whom 6 demonstrated a radiographic response (1 complete; 3 partial; 2 stable disease) with a median duration of response of 8 months. In summary; oral VP-16 is a well tolerated and relatively non-toxic chemotherapeutic agent with apparent activity in this small cohort of patients with recurrent brainstem gliomas.
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PMID:Recurrent brainstem gliomas treated with oral VP-16. 850 18

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.
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PMID:[Taxotere (docetaxel) and CPT 11 (irinotecan): phase I trials]. 867 54

Amsacrine, a DNA intercalator and topoisomerase II inhibitor, is efficacious as an antileukemogenic agent. This study was conducted to assess the subchronic toxicity of amsacrine in rats following a cyclic clinical dosing regimen and as a range-finding experiment for a subsequent carcinogenicity bioassay. Groups of 30 male Wistar rats were administered drug intravenously at doses of 0, 0.25, 1.0, and 3.0 mg/kg daily for 5 days followed by 23 days without treatment. This cycle of dosing and recovery was repeated six times to simulate human clinical usage of the drug. Assessments of hematology, clinical chemistry, and gross and microscopic pathology were conducted 3 and 21 days following completion of dosing in the first, third, and sixth cycles. There were no deaths during the study. Hair loss, diarrhea, tail injuries, chromodacryorrhea, and rhinorrhea were observed primarily in animals administered 3 mg/kg. Hair loss and diarrhea occurred during periods of dosing and generally resolved during the recovery phase of each cycle. Both of these signs became progressively more severe during the latter half of the study. Body weight loss and reduced food consumption also occurred in the 3 mg/kg group during each week of dosing. At study termination, mean body weight and food consumption of the 3 mg/kg group were significantly less than those of controls by approximately 20 and 50%, respectively. Marked, reversible leukopenia associated with reductions in both neutrophil and lymphocyte counts occurred in cycles one and three in animals administered 1 and 3 mg/kg, respectively. Reversible neutropenia was also observed in the 3 mg/kg group in cycle 6. Similar effects on platelet counts were seen in the 3 mg/kg group in all three cycles analyzed. Absolute and relative testes weights of the 3 mg/kg group were significantly less than the vehicle controls at all time points in the third and sixth cycles. Relative testes weights were also decreased in the 1 mg/kg group in cycle 6. Reversible decreases in absolute relative spleen weights occurred in all drug-treated groups in cycle 1 and for the 3 mg/kg group in cycle 3. Lymphoid depletion (spleen, thymus, lymph node), marked hypocellularity of bone marrow, segmental degeneration of seminiferous tubules, and intestinal epithelial cell degeneration were observed at 3 mg/kg. With the exception of testicular changes which remained evident at the end of cycle 6, pathologic lesions were reversible during the 23-day recovery period of each cycle. The results show that the subchronic toxicity of amsacrine is consistent with a cytotoxic mechanism and that target organs are generally tissues with the highest rates of cell turnover. The doses administered in this study induced a range of effects which were minimal at 0.25 mg/kg and dose-limiting at 3 mg/kg and therefore were considered appropriate for use in the subsequent carcinogenicity bioassay.
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PMID:Subchronic intravenous toxicity of the antineoplastic drug, amsacrine, in male Wistar rats. 881 19


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