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)

Myelosuppression following intensive chemotherapy in cancer patients is associated with increased morbidity and mortality. Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone or in combination with interleukin-1 (IL-1), have been shown to counteract myelosuppression resulting from some, but not all, chemotherapeutic regimens. In an attempt to apply these findings to intensive therapy with proliferation-dependent chemotherapeutic drugs such as fluorouracil (5-FU), we investigated combination biochemotherapy in a murine model. Female CD8F1 [(BALB/c X DBA/8)F1] mice bearing first-passage transplants of spontaneous CD8F1 breast tumors were treated intraperitoneally once a week for 3 successive weeks with a course of 5-FU alone or with a course of 5-FU in combination with recombinant human interleukin-1 beta (rHuIL-1 beta) alone or in combination with CSFs. rHuIL-1 beta alone or in combination with rHuG-CSF or recombinant murine GM-CSF significantly improved tumor growth inhibition (60% vs. 90%) and survival (20% vs. 90%-100%), increased the maximally tolerated dose of 5-FU, accelerated recovery of neutrophil counts in peripheral blood, and reduced duration of significant neutropenia and loss of body weight (29% vs. 10% loss). Clinical trials of IL-1 have been initiated in patients with advanced cancer receiving multiple courses of high-dose 5-FU.
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PMID:Hematologic effects of interleukin-1 beta, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil. 169 5

The effect of rhIL-3 was investigated in 32 patients with newly diagnosed non-Hodgkin lymphoma in a phase I/II trial. All patients received 6 cycles of standard CHOP chemotherapy, and each patient was his own control where rhIL-3 was given as a daily s.c. injection for 14 days (day 2-15) in cycle 2 and 4, while cycle 1 and 3 were control cycles. Five dose levels were examined (0.5 - 1 - 5 - 7.5 - 10 micrograms/kg). Compared to the other more lineage-specific hemopoietic growth factors G- and GM-CSF, the effect of rhIL-3 on the hemopoiesis was less dramatic and more delayed, i.e. the most apparent effect was observed in the 2 weeks of treatment. Thus, the neutrophil counts from days 15 to 22 following CHOP were significantly raised and the duration of neutropenia was shorter (significantly only at 10 micrograms/kg), while the nadir values were unaffected. Platelet recovery from days 12-22 was significantly increased and nadir values occurred earlier compared to control cycles, but were only increased in some subsets. Other cell populations affected moderately in the recovery period were eosinophils and monocytes. Reticulocytes increased, but no effect on hemoglobin or RBC transfusion requirement was noted. Only moderate adverse reactions occurred such as fever, chills, flushing of the face and flu-like symptoms. There was no evidence of stimulation of tumor growth. Most significant, the rhIL-3 treatment at all but the lowest dose levels led to an improved tolerance to chemotherapy, as indicated by a decline in number of delayed cycles. A conclusion concerning the role of rhIL-3 as post-chemotherapy adjuvant should await studies using rhIL-3 in combination with more lineage-restricted hemopoietic growth factors.
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PMID:Effects of interleukin-3 following chemotherapy of non-Hodgkin's lymphoma. A prospective, controlled phase I/II study. 769

Local hyperthermia and the hypoxic cytotoxin SR 4233 were administered to nude mice with 693 +/- 47 mm3 (mean +/- SE) s.c. HCT-8 human colonic adenocarcinoma xenografts in an attempt to enhance the antitumor effects of radioimmunotherapy. Biodistribution studies revealed preferential binding of NR-Lu-10, a murine monoclonal antibody, to the tumors compared with an isotype-matched control antibody, CCOO16-3.A single injection of 25 microCi 90Y-NR-Lu-10 significantly inhibited tumor growth (control versus 90Y-NR-Lu-10: P = 0.048). The administration of hyperthermia at 41.5 degrees C for 1 h immediately following the injection of 111In-labeled NR-Lu-10 up-regulated tumor-associated antigen expression and increased antibody uptake in the tumors by 73% (P = 0.001) without significantly affecting antibody uptake in normal tissues. However, the heat treatment did not produce a more homogeneous distribution of the antibodies in the tumors and did not significantly enhance the tumor growth delay produced by 90Y-NR-Lu-10 (P = 0.07). The administration of local hyperthermia at 43.0 degrees C for 1 h, on the other hand, had direct cytotoxic effects (P = 0.03) and enhanced the tumor growth delay produced by 90Y-NR-Lu-10 (P = 0.01). SR 4233 also enhanced the tumor growth delay produced by 90Y-NR-Lu-10 (P = 0.03). The greatest antitumor effects were observed when both hyperthermia at 43.0 degrees C and SR 4233 were administered in combination with 90Y-NR-Lu-10 (P = 0.002). No toxicity was produced by the local hyperthermia, and the only toxicities produced by 90Y-NR-Lu-10 and SR 4233 were neutropenia and weight loss.
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PMID:Local hyperthermia and SR 4233 enhance the antitumor effects of radioimmunotherapy in nude mice with human colonic adenocarcinoma xenografts. 831 9

Experiments were performed to determine whether treatment with recombinant human IL-1 alpha (rhuIL-1 alpha) would protect C3H mice from the toxic effects of the widely used chemotherapeutic agent, doxorubicin (DXR). Pretreatment of mice with rhuIL-1 alpha was found to protect 85-90% of mice tested from the acute toxic effects of a lethal dose of doxorubicin (25 mg/kg). Late deaths (> 20 days post-DXR) were observed in a substantial proportion (40-45%) of rhuIL-1 alpha-pretreated mice. However, the data clearly demonstrate a beneficial effect of rhuIL-1 alpha pretreatment on the overall survival of mice challenged with DXR, since both the median survival (32 days) and proportion (53%) of surviving mice were significantly increased (P < 0.0001) compared to the control group (8 days and 14%, respectively). The beneficial effects mediated by rhuIL-1 alpha treatment were both dose- and schedule-dependent and were associated with decreases in the level and duration of DXR-induced neutropenia, and amelioration of the suppressive effects of DXR on myeloid progenitor cells (granulocyte/monocyte colony forming units) as evidenced by milder depressions in marrow cellularity and enhanced recovery of granulocyte/monocyte colony forming unit activity. Finally, pretreatment of mice bearing a solid tumor with rhuIL-1 alpha permitted effective dose escalation with DXR that resulted in decreased tumor growth rates and increased survival (90%) as compared to non-rhuIL-1 alpha-treated groups (20% survival). Thus, effective chemotherapeutic dose escalation is made feasible by rhuIL-1 alpha pretreatment of mice, but may ultimately be limited by nonhematological toxicities associated with DXR.
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PMID:Protective effects of recombinant human interleukin-1 alpha in doxorubicin-treated normal and tumor-bearing mice. 845 24

Hematopoiesis occurs in a microenvironment containing a variety of growth factors. Normal hematopoietic cells require these growth factors for viability, proliferation, and differentiation. The purification and molecular cloning of human growth factors has permitted a detailed analysis of hematopoiesis. Furthermore, the commercial production of growth factors resulted in their widespread introduction into clinical practice to limit chemotherapy-induced neutropenia. Recently, clinical trials of growth factors have expanded to test their direct anticancer effects, to improve the efficacy of chemotherapy by stimulating cell division, and to use them as biological modulators to inhibit tumor growth. This review focuses on a few clinical uses of recombinant growth factors.
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PMID:Clinical applications of the hematopoietic growth factors. 937 Dec 97

The data on the treatment of 82 patients with advanced colorektal carcinoma are presented. Tomudex was given as first-line treatment to 18 cases. Apparent response was reported in 31% including complete (6%) and partial (25%) regression. Tumor growth control (apparent response + stabilization) was registered in 62%. Median survival rate was 38.4 weeks. Neutropenia, diarrhea and hepatotoxicity formation limited the modality. The treatment can be recommended for out-patients thanks to good tolerability and practical convenience. The following regimens of irinotecan were employed as first- and second-line chemotherapy (64): 250-350 mg/sq.m, every three weeks (44) and 100-125 mg/sq.m/week, x 4 every 6 weeks (20). Response was 15 and 16%, tumor growth control--60 and 63%, median survival--41.6 and 51.6% weeks, respectively. Leuko- and neutropenia and diarrhea development limited both regimens. Weekly infusions seemed to offer more advantage for out-patient treatment, particularly, in feeble patients and those who are a high risk for grave side-effects. Tomudex and irinotecan toxicity was predictable, moderate, reversible and non-cumulative.
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PMID:[Irinotecan and tomudex in the treatment of patients with advanced cancer of the large intestine]. 1182 99

Phase I/II studies suggest that the combination of irinotecan with capecitabine is feasible and has promising activity. Diarrhea and neutropenia are dose limiting. Overall response rates (RRs) in the 40% to 60% range are seen from preliminary data. Work in progress is assessing the combination of irinotecan with UFT/leucovorin (LV). The use of irinotecan together with raltitrexed is also being investigated, as is its combination with oxaliplatin. Two phase II studies of irinotecan plus oxaliplatin in second-line patients report median survivals of 11-12 months. It seems possible to safely escalate the dose of single-agent irinotecan to 500 mg/m(2) in patients showing good tolerance of the drug. Irinotecan can be used in combination with LV5FU2 at doses up to 260 mg/m(2), especially if only one bolus of 5-fluorouracil (5-FU) is given. Control of tumor growth is achieved in 90% of patients. Preliminary data suggest that regimens based on 5-FU/LV and irinotecan can safely be combined with the anti-epidermal growth factor receptor (EGFR) antibody cetuximab. In patients with EGFR-positive tumors, this may prove an effective means of increasing response rate or combating treatment resistance. Following evidence that COX-2 inhibition can slow progression in familial adenomatous polyposis, celecoxib is to be studied in metastatic colorectal cancer (CRC). In vitro, the cyclin-dependent kinase inhibitor flavopiridol enhances the induction of apoptosis by chemotherapy. Clinically, it can safely be administered with irinotecan, and studies in CRC are planned.
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PMID:Irinotecan in metastatic colorectal cancer: dose intensification and combination with new agents, including biological response modifiers. 1281 Apr 53

The aim of this phase II study was to investigate the tolerance and efficacy of a second-line irinotecan/mitomycin C combination in patients with advanced gastric or colorectal cancer, pretreated with 5-fluorouracil. Forty patients who had received 5-fluorouracil-based chemotherapy for advanced disease or adjuvant 5-fluorouracil treatment were enrolled. Chemotherapy consisted of irinotecan 125 mg/m2 and mitomycin C 5 mg/m2, given every 2 weeks. Treatment was continued until progression or limiting toxicity occurred. Five partial responses (12.5%), 22 cases of stable disease (55%) and 13 of progression (32.5%) were registered, giving an overall response rate of 12.5% [95% confidence interval (CI), 4.2-26.8%] and an overall control of tumor growth in 67.5% (95% CI, 50.8-81.4%) of patients. Median progression-free survival was 5 months, median survival time 8 months, and 1-year probability of survival was 21.6%. Diarrhea and neutropenia affected 25% and 12.5% of patients respectively, with only 7.5% experiencing grade 3-4 toxicity. There were no chemotherapy-related deaths or hospitalizations. This combination regimen was shown to be moderately effective with substantially lower toxicity than irinotecan monotherapy in 5-fluorouracil-pretreated patients with advanced gastric or colorectal cancer. It may represent an attractive option in patients at high risk for developing specific irinotecan toxicity.
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PMID:Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. 1286 55

We carried out a single-center series with the combination of irinotecan (CPT-11) plus protracted 5-fluorouracil (5-FU) infusion as second-line chemotherapy for patients previously treated with a single-agent fluoropyrimidine as monotherapy or in combination with oxaliplatin. Twenty-five patients diagnosed with advanced colorectal cancer (CRC) received CPT-11 300 mg/m2 every 3 weeks plus 5-FU 250 mg/m2/day as a protracted infusion. Results were as follows. Twenty-four of 25 patients were evaluable for response. Two patients achieved a complete response and five a partial response, resulting in an overall response rate of 28%. Disease stabilization was obtained in 10 patients (40%), resulting in a tumor growth control rate of 68% (17 patients) and disease progression in seven (28%). Median progression-free interval was 6 months and median overall survival was 12 months. Neutropenia and diarrhea appeared as the most frequent adverse events, being grade 3/4 in 12 and 16% of patients, respectively. Mucositis, emesis, and hand and foot syndrome were mild. We conclude that protracted 5-FU infusion plus CPT-11 is an active and safe regimen for patients with advanced CRC. A phase III trial comparing this schedule with conventional CPT-11 monotherapy is warranted.
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PMID:5-fluorouracil as a protracted continuous infusion plus irinotecan (CPT-11) in patients with advanced colorectal cancer treated with fluoropyrimidine-based regimens as first line. 1296 Jul 38

The hematopoietic growth factors granulocyte- and granulocyte-macrophage colony stimulating factor (G-CSF and GM-CSF) are nowadays widely used in routine cancer therapies as potent factors to control radiation and chemotherapy induced neutropenia, a side effect that frequently endangers the success of tumor therapies. However, there is little information about the role of G-CSF and GM-CSF for tumor growth or progression. We were interested in the expression and potential role of both factors in human meningiomas, tumors of arachnoidal origin that account for about 20% of all primary intracranial tumors. Therefore, we analyzed immunohistochemically the protein expression of G-CSF, GM-CSF and their respective receptors in 30 meningioma tissues of different malignancy and histopathological type. Both factors and receptors were not expressed in the corresponding normal tissue. In contrast, G-CSF, GM-CSF and their receptors were expressed to a varying degree in human meningiomas. Increasing expression of both factors and receptors correlated significantly with enhanced proliferation in the tumor and thus with higher malignancy. In addition, a strong perivascular expression of G-CSF was associated with a highly vascularized tumor type. Thus, expression of both G-CSF and GM-CSF is associated with the expression of proliferation vascularization, two markers of an increasingly malignant tumor phenotype, suggesting a contribution of both factors to tumor progression.
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PMID:Expression of G-CSF and GM-CSF in human meningiomas correlates with increased tumor proliferation and vascularization. 1521 49


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